Xanuunka Neuroinflammation iyo Xanuunka Dhimirka

Xanuunka dareemayaasha:

aan la taaban karin

Khadadka badan ee caddayntu waxay taageerayaan doorka cudur-sidaha ee neuroinflammation ee jirrooyinka dhimirka. Iyadoo cudurada nidaamka difaaca jirka ay si fiican u qoran yihiin sababaha xanuunka dhimirka ee neuropsychiatric, synaptic autoimmune encephalitides oo leh calaamado nafsi ah ayaa inta badan la aqoonsan yahay. Marka la barbar dhigo xiriirka ka dhexeeya calaamadaha dhimirka iyo difaaca jirka ee cudurrada difaaca jirka, cilladaha neuroimmunological waxay ku dhacaan xanuunnada dhimirka ee qadiimiga ah (tusaale, niyad-jabka weyn, laba-cirifoodka, schizophrenia, iyo cudurrada waswaaska ah). Baadhitaannada cilmi-nafsiga ee xaaladahan ayaa dhaqan ahaan culays saaray hab-dhiska hab-dhiska glutamatergic iyo monoaminergic, laakiin hababka keenaya cilladaha neurotransmitter-ka ayaa weli ah kuwo la fahmi karo. Waxaan dib u eegis ku sameyneynaa xiriirka ka dhexeeya difaaca jirka iyo cudurrada neerfaha, iyo caddaynta bini'aadamka iyo tijaabada ah ee taageeraya doorka xanuunka neuroinflammation ee xanuunada dhimirka ee qadiimiga ah ee la doortay. Fahamka sida ay u falgalaan cilmi-nafsi-bulsho, hidde-side, is-difaac iyo hab-dhiska neerfaha waxay muujin karaan tilmaamo cudur-sidaha ah waxayna gacan ka geysan karaan beegsiga daawaynta cusub ee ka-hortagga iyo astaamaha.

Keywords:

• Xanuunka neerfaha,
• Cilmi-nafsiga Cilmi-nafsiga,
• Astrocyte,
• Microglia,
• Cytokines,
• Cadaadiska Oxidative,
• Niyad-jabka,
• Disorder Waswaaska khasban,
• Laba-cirifoodka, Schizophrenia

Hordhac

Maadaama cilladaha bayoolojiga ay si sii kordheysa loogu aqoonsaday bukaannada qaba cudurrada dhimirka, farqiga u dhexeeya cudurrada neerfaha iyo dhimirka ayaa sii yaraanaya. Marka lagu daro cudurrada nidaamka difaaca jirka ee la xidhiidha muujinta dhimirka (tusaale, lupus) [1], dhawaanahan, bukaannada qaba cudurka nafsiga ee go'doonsan ayaa lagu aqoonsaday encephalitides-ka 'synaptic autoimmune encephalitides' (Shaxda 1) [2-6]. Bukaan-socodkan ayaa inta badan si khalad ah loogu ogaadaa cilladaha dhimirka ee aasaasiga ah, dib u dhigista bilaabista daaweynta difaaca ee waxtarka leh (Shaxda 1). Intaa waxaa dheer, caddaynta sii kordheysa waxay taageertaa doorka pathogenic ee unugyada ka-hortagga neerfaha ee xanuunka dhimirka [7].

Kala soocidda xanuunada neerfaha iyo maskaxda, oo ay taageerto fikradda Descartes ee maskaxda sida wax ontological ahaan u gooni ah iyo soo saarista cilladaha neerfaha, daawooyinka ugu badanqarniyadii 19aad iyo horraantii 20aad [8]. Tan iyo markaas, ururinta sii kordhaysa ee sababaha bayooloji ee dib loo soo saari karo, laga bilaabo neurosyphilis, dhaawac madaxa, istaroogga, buro, demyelination iyo qaar kale oo badan ayaa sababay calaamado isku dhafan kuwaas oo ku soo kordhay xanuunnada dhimirka ee caadiga ah [9-11]. Dhawaanahan, cilladaha neerfaha iyo is-difaaca jirka ayaa lagu diiwaangeliyay bukaannada qaba cudurrada dhimirka ee caadiga ah.

Hababka difaaca ee durugsan waxay keeni karaan calaamadaha cudurka dhimirka ee moodooyinka xayawaanka iyo aadanaha [12-19]. Xayawaanada caafimaadka qaba lagu muday pro-inflammatory IL-1? iyo cytokines factor necrosis alpha (TNF-?) cytokines waxay muujinayaan dabeecadda jirrada ee la xiriirta ka-noqoshada bulshada [12]. Bini'aadamka, cirbadaha endotoxin-yar ee qiyaasta hooseeya waxay demisaa marinka ventral striatum, oo ah gobol muhiim u ah ka-hortagga abaal-marinta, soo saarista anhedonia calaamad niyad-jab ah oo daciif ah [14]. Ku dhawaad ​​45% cagaarshowga C ee aan niyad-jabka qabin iyo bukaanka kansarka lagu daweeyey IFN-? yeeshaan calaamadaha niyad-jabka ah ee la xidhiidha korodhka serum IL-6 heerarka [12,15,17,18].

Xaaladaha caafimaad ee la xidhiidha bararka dabadheeraad ah iyo cilladaha difaaca jirka, oo ay ku jiraan cayilka, sonkorowga, malignancies, rheumatoid arthritis-ka, iyo sclerosis badan, ayaa ah arrimo halis u ah niyad-jabka iyo xanuunka laba-cirifoodka [10,12,13,15,17,18]. Midda toganxidhiidhka ka dhexeeya xaaladahan caafimaad iyo jirrooyinka dhimirka ayaa soo jeedinaya jiritaanka habka bararka hoose ee baahsan ee saameeya maskaxda xubnaha kale [10,19,20]. Daraasad la sameeyay 30 sano oo dad-ku-salaysan ayaa muujisay in lahaanshaha Cudurka autoimmune ama isbitaal dhigista hore ee caabuqa halista ah waxay kordhisay khatarta ah inuu ku dhaco schizophrenia 29% iyo 60%, siday u kala horreeyaan [16]. Dheeraad ah, fayraska herpes simplex, Toxoplasma gondii, cytomegalovirus, iyo hargabka inta lagu jiro uurka waxay kordhiyaan khatarta ah inuu ku dhaco schizophrenia [16].

Unugyada gacanta [21,22] (Shaxda 2), iyo cilladaha difaaca jirka ee humoral [13,21-23] ayaa aad ugu badan bukaannada dhimirka marka loo eego kontaroolada caafimaadka qaba. Labada duuliye (n = 34 bukaan oo qaba xanuunka weyn ee niyad-jabka (MDD), n = 43 kontaroolo caafimaad leh) iyo daraasado dib-u-celin (n = 36 MDD, n = 43 kontaroolo caafimaad leh), baaritaanka serum oo ka kooban sagaal biomarkers serum ayaa ka soocay maaddooyinka MDD ee caafimaadka qaba. kontaroolada leh 91.7% dareenka iyo 81.3% gaar ahaaneed; biomarkers aad u sarreeya ee calaamadaha neerfaha maskaxda waxay ahaayeen unugyada difaaca jirka alfa 1 antitrypsin, myeoperoxidase, iyo TNF- milmay? receptor II [23].

Waxaan marka hore dib u eegis ku samaynaa xidhiidhka ka dhexeeya difaaca jidhka iyo xanuunada maskaxda, oo ay ku jiraan: 1) systemic lupus erythematosus (SLE) oo ah prototype of systemic auto-immune disease; 2) autoimmune encephalitides oo la xidhiidha serum anti-synaptic iyo glutamic acid decarboxylase (GAD) autoantibodies; iyo 3) xanuunada isdifaaca jirka ee neuropsychiatric ee carruurta ee la xidhiidha caabuqyada streptococcal (PANDAS) iyo xanuunka waswaaska saafiga ah (OCD) ee la xidhiidha anti-basal ganglia/thalamic autoantibodies. Waxaan markaa ka wada hadalnaa doorka caabuqa / is-difaaca jirka ee jirrooyinka dhimirka ee caadiga ah, oo ay ku jiraan MDD, laba-cirifoodka (BPD), schizophrenia, iyo OCD.

Xanuunada Maskaxda ee Neuropsychiatric ee La Xiriira Is-difaacidnimada

Nidaamsani lupus erythematosus

Inta u dhaxaysa 25% ilaa 75% ee bukaanada SLE waxay leeyihiin habka dhexe ee neerfayaasha (CNS), oo leh calaamadaha dhimirku sida caadiga ah waxay dhacaan labada sano ee ugu horeeya ee cudurka. Calaamadaha dhimirka waxaa ka mid noqon kara walaac, niyadda iyo khalkhal maskaxeed [97]. Maskaxda falcelinta resonance imaging (MRI) waa caadi ku dhawaad ​​42% kiisaska SLE neuropsychiatric [97]. Microangiopathy iyo Dhiigga xannibaadda maskaxda (BBB) ​​waxay u oggolaan kartaa gelitaanka unugyada difaaca jirka ee maskaxda [97]. Unugyadaan waxaa ka mid ah anti-ribosomal P (oo ku wanaagsan 90% bukaannada SLE nafsiga ah) [1], unugyada anti-endothelial, anti-ganglioside, anti-dsDNA, anti-2A/2B qaybahooda N-methyl-D-aspartate reseptors ( NMDAR) iyo unugyada difaaca-ka-hortagga fosfolipid [97]. Cytokines pro-bararka gaar ahaan IL-6 [97], S100B�[97], molecule adhesion intra-cellular 1 [97] iyo matrix-metalloproteinase-9 [98] ayaa sidoo kale kor loogu qaaday SLE. Calaamadaha dhimirka ee SLE, Sjo?grens disease, Susac's syndrome, CNS vasculitis, CNS Whipples disease, iyo Behc?et's cudurka ayaa dhawaan dib loo eegay [1].

Neuropsychiatric Autoimmune Encephalitides oo ku xidhan Serum Anti-Synaptic & Glutamic Acid Decarboxylase

Abaabulidda

Autoimmune encephalitides waxaa lagu gartaa bilawga degdega ah ee suuxdin ku meel gaar ah, astaamaha maskaxda, iyo cilladaha garashada [2,3,99-108]. Cilmi-nafsiyeedka waxaa caadi ahaan dhexdhexaadiya autoantibodies bartilmaameedka synaptic ama intracellular autoantigens iyada oo lala kaashanayo balaastig paraneo ama asal aan paraneoplastic [3]. Anti-synaptic autoantibodies bartilmaameedka NR1 qaybihiisa NMDAR [100,108,109], korantada-gated kanaalka potassium (VGKC) dhismooyin (Kv1 subunit, leucine-rich glioma inactivated (LGI1) iyo contactin la xidhiidha borotiinka 2 (CASPR2)) [101,102,106,G1,GL,2,G,3. Qaybaha GluR5 ee amino-4-hydroxy-6,110,111-methyl-l-1-isoxazolepropionic acid reseptor (AMPAR) [3,99,103] iyo qaybaha B65 ee ?-aminobu-tyric acid B receptors (GABABR) [2,3]. Anti-intracellular autoantibodies bartilmaameedka onconeuronal iyo GAD-XNUMX autoantigens [XNUMX].

Caabuqa la xidhiidha autoantibodies anti-synaptic, gaar ahaan NMDAR-autoantibodies, ayaa caadi ahaan aad uga fudud kan la xidhiidha GAD-autoantibodies ama anti-neuronal autoantibodies ee la xidhiidha cilladaha difaaca jirka ee nidaamka ama cilladaha paraneoplastic [2,107].

Inkasta oo calaamadaha neerfaha ay ugu dambeyntii soo baxaan, calaamadaha dhimirka, oo u dhexeeya walaaca [2,3] ilaa maskaxiyan isku dayaya schizophrenia [2-6], waxay marka hore xukumi karaan ama ka hor marin karaan sifooyinka neerfaha. Ilaa saddex-meelood laba meel bukaannada qaba anti-NMDAR autoimmune encephalitis, oo marka hore u soo baxa adeegyada dhimirka [5]. Anti-synaptic-ka difaaca jirka-dhexdhexaadinta autoimmune encephalitides waa in lagu tixgeliyo kala duwanaanshaha nafsiyeedka degdega ah [2-6]. Bandhigyada dhimirka waxaa ka mid noqon kara maskaxda caadiga ah ee MRI iyo falanqaynta dareeraha maskaxda (CSF), iyada oo aan lahayn encephalopathy ama suuxdin [2,3,5,6,107]. Waxaan soo sheegnay kiis ka mid ah unugyada difaaca jirka ee 'GAD autoantibodies' ee la xidhiidha biopsy-la xaqiijiyay neuroinflammation, in kasta oo maskaxda caadiga ah ee MRI iyo falanqaynta CSF, halkaas oo bukaanku uu ku soo bandhigay cilmi nafsi gooni ah oo lagu ogaaday sida schizophrenia by Diagnostic and Statistical Buugga Cudurrada Maskaxda, 4th Edition (DSM-IV) shuruudaha [2]. Dheeraad ah, seronegative autoimmune encephalitides ayaa sidoo kale soo bandhigi kara khalkhalgelinta neuropsychiatric caan ah, samaynta ogaanshaha mid aad u adag [107,112,113]. Astaamaha maskaxda iyo neerfaha ee la xidhiidha anti-synaptic iyo GAD autoantibodies ayaa lagu soo koobay Shaxda 1 [1-6,99-108,114].

Serum anti-synaptic iyo GAD autoantibodies ayaa laga yaabaa inay ku dhacaan bukaanada qaba xanuunada maskaxda saafiga ah [2,4,5,112,115-121]. Kooxda mustaqbalka ee maadooyinka 29 kuwaas oo la kulmay shuruudaha DSM-IV ee shisoofrani, serum anti-NMDAR autoantibodies ayaa laga helay saddex maaddo, iyo anti-VGKC-isku-dhafka autoantibodies ayaa laga helay hal maado [5]. Isticmaalka farsamooyin xasaasi ah oo dheeraad ah si loo ogaado immunoglobulin G (IgG) NR1 auto-antibodies ee bukaannada 100 ee qaba shisoofrani qeexan, ma jiro autoantibodies la aqoonsaday [122]. Si kastaba ha ahaatee, daraasaddan ma aysan qiimeynin unugyada difaaca jirka ee lagu beegsanayo qeybta NR2 ee NMDAR. Daraasado kale ayaa sheegay in ay si weyn u korodhay jaanisyada sare u kaca (?90th boqolkiiba heerarka kantaroolka aan maskaxda ahayn) NR2 heerarka antibody (qiyaasta isdhaafsiga (OR) 2.78, 95% u dhexeeya kalsoonida (CI) 1.26 ilaa 6.14, P = 0.012) oo ka mid ah shakhsiyaadka qaba waalli ba'an ( n = 43), laakiin aan ku jirin waallida joogtada ah ama schizophrenia [116].

PANDAS & Xanuunka Wasaska saafiga ah ee Wassalka ah oo La Xiriira Anti-Basal Ganglia/Thalamic Autoantibodies

OCD waxay inta badan adkeyneysaa xanuunada neerfaha ee ku lug leh ganglia basal ganglia oo ay ku jiraan Sydenham chorea, cudurka Huntington iyo cudurka Parkinson. Ka-hortagga ganglia-ga lidka-basal ganglia waxay ku lug leeyihiin Sydenham chorea [123]. PANDAS waxaa lagu gartaa ka sii daridda ba'an ee calaamadaha OCD iyo/ama mootada/maqaarka dhawaaqa ka dib kooxda prodromal A ?-hemolytic streptococcal infection. Cilmi-nafsiga cilmi-nafsiga waxaa loo maleynayaa inuu ku lug leeyahay fal-celinta fal-celinta ka-hortagga difaaca-ka-hortagga-streptococcal-ka iyo borotiinnada ganglia basal [124]. Isku dhafka bukaan-socodka ee u dhexeeya PANDAS iyo OCD saafi ah ayaa soo jeedinaya habka etiological caadiga ah [125].

Waxaa ka mid ah koox aan kala sooc lahayn oo ah 21 bukaanno OCD oo saafi ah, 91.3% waxay lahaayeen CSF anti-basal ganglia (P <0.05) iyo anti-thalamic autoantibodies (P <0.005) ee 43 kDa [88], cillado isbarbar socda oo ku jira cortico-striatal-thalamo - wareegga cortico ee maadooyinka OCD [84]. Daraasad kale ayaa diiwaangelisay in 42% (n = 21) ee maadooyinka OCD ee carruurta iyo dhalinyarada ay leeyihiin serum anti-basal ganglia autoantibodies at 40, 45, iyo 60 kDa marka la barbardhigo 2% ilaa 10% kontaroolada (P = 0.001) [7]. Antibasal ganglia autoantibodies ayaa lagu ogaadey 64% maadooyinka PANDAS (n = 14), marka la barbar dhigo kaliya 9% (n = 2) ee kontaroolada streptococcal-positive / OCD-negative (P <0.001) [126]. Mid ka mid ah daraasadda ma helin wax farqi ah oo u dhexeeya baahsanaanta basal ganglia autoantibodies ee OCD (5.4%, n = 4) oo ka soo horjeeda kontaroolada MDD (0%) [127]; si kastaba ha ahaatee, xaddidaaddu waxay ahayd isticmaalka random ee kiliyaha jiirka iyo ganglia basal bovine iyo kortex laga yaabo inay xaddiddo aqoonsiga kiisaska seropositive.

Ganglia autoantigens basal waa aldolase C (40 kDa), neuronal-specific / non-neuronal enolase (45 kDa doublet) iyo pyruvate kinase M1 (60 kDa)

Bogga 3 ee 24 iyo calaamadaynta unugga [128]. Enzymes-yadani waxay muujinayaan qaab-dhismeed la taaban karo oo ku saabsan borotiinnada streptococcal [129]. Daraasadii ugu dambeysay (96 OCD, 33 MDD, 17 maaddooyinka schizophrenia) waxay tijaabiyeen serum bukaan oo ka soo horjeeda pyruvate kinase, aldolase C iyo enolase, gaar ahaan; Qayb weyn oo ka mid ah maaddooyinka OCD waxay ahaayeen sero-positive marka loo eego kontaroolada (19.8% (n = 19) marka loo eego 4% [n = 2], P = 0.012) [130].

Hase yeeshee, isla daraasaddan oo keliya mid ka mid ah 19-kii maaddooyinka sero-positive OCD ayaa sidoo kale lahaa anti-streptolysin O antibody titers, taasoo soo jeedinaysa in OCD saafi ah anti-streptolysin O antibody seronegativity kama saarayso joogitaanka anti-basal ganglia autoantibodies. .

OCD saafi ah, sero-positivity for anti-basal ganglia / thalamic antibodies waxay la xiriirtaa heerarka kordhay ee CSF glycine (P = 0.03) [88], taasoo soo jeedinaysa in kuwan ka hortagga ah ay gacan ka geystaan ​​​​hyperglutamatergia ee lagu arkay OCD [84,88,131]. Hagaajinta caabuqa-kicinta OCD ee leh daawaynta difaaca jirka waxay taageertaa cudur-sidaha autoantibodies-kan [132]. Tijaabo weyn oo NIH ah oo lagu qiimaynayo waxtarka tallaalka xididka immunoglobulin (IVIG) ee carruurta leh bilawga degdega ah ee OCD iyo ka hortagga-streptococcal ayaa socota (ClinicalTrials.gov: NCT01281969). Si kastaba ha noqotee, helitaanka wax yar oo ka sarreeya heerarka CSF glutamate ee bukaannada OCD ee qaba CSF anti-basal ganglia / thalamic anti-body marka la barbardhigo kuwa leh unugyada difaaca jirka ee CSF waxay soo jeedinayaan in hababka aan difaaca jirka ahayn ay door ka ciyaari karaan OCD [84]. Hababka kale, oo ay ku jiraan caabuqa dhexdhexaadinta cytokine (Shaxda 2), ayaa sidoo kale la qiyaasaa.

Xanuunada Dhimirka Ee La Xidhiidha Caabuqa Innate

Xanuunada caabuqa/is-difaaca jidhka ku dhasha ayaa ku dhaca bukaanada qaar ee qaba xanuunada dhimirka ee caadiga ah. Waxaan ka wada hadalnaa cilladaha CNS-ku-xiran ee caabuqa ee gudaha ku jira oo ay ku jiraan glial pathology, heerarka cytokines oo sarreeya, firfircoonida cyclo-oxygenase, dysregulation glutamate, korodhka heerarka S100B, cadaadiska oksaydhka oo kordhay, iyo BBB cillad la'aan - MDD, BPD, schizophrenia, iyo OCD. Waxaan sidoo kale sharaxnay sida caabuqa gudaha uu si farsamaysan ugu xiriirin karo monoaminergic-ka caadiga ah iyo cilladaha glutamatergic ee laga soo sheegay xanuunnadan (Jaantusyada 1 iyo 2). Doorka daawaynta ee wakiilada caabuqa ka hortaga ee xanuunada dhimirka ayaa sidoo kale dib loo eegay.

Astroglial & Oligodendroglial Histopathology

Astroglia iyo oligodendroglia ayaa lagama maarmaan u ah neerfaha dheefshiidka homeostasis, habdhaqanka iyo hawlaha garashada sare [54-56,133-136]. Astroglia quiescent caadiga ah waxay siisaa tamar iyo taageero trophic neurons, nidaamisa neurotransmission synaptic (Jaantuska 2), synaptogenesis, socodka dhiigga maskaxda, iyo ilaalinta daacadnimada BBB [134,136,137]. Oligodendroglia qaan-gaarka ah waxay siisaa tamar iyo taageero trophic neurons waxayna ilaalisaa daacadnimada BBB, waxayna nidaamisaa dayactirka axonaliyo myelination ee marinnada walxaha cad ee bixiya isku xirka inter-iyo intra-hemispheric [54-56]. Astroglia iyo oligodendroglia labaduba waxay soo saaraan cytokines anti-bararka kuwaas oo hoos u dhigi kara bararka waxyeelada leh [52,55].

MDD gudaheeda, luminta astroglial waa helitaan joogto ah oo dhimashada ka dib meelaha laxiriirta, oo ay ku jiraan kiliyaha hore ee cingulate, kiliyaha prefrontal, amygdala, iyo walxaha cad [35-38,42-46,55,138-147], iyada oo wax yar laga reebo [42,43] ,37,38]. Daraasadaha dhimashada ka dib ayaa shaaca ka qaaday hoos u dhaca borotiinka glial fibrillary acidic (GFAP) - cufnaanta astroglial togan ugu horreyntii kiliyaha hore [36] iyo amygdala [39]. Falanqaynta borotiinka weyn ee kiliyeyaasha hore ee bukaannada niyad-jabka ah waxay muujisay hoos u dhac weyn oo ku yimid saddex qaybood oo GFAP ah [75]. In kasta oo hal daraasad oo aan soo sheegin khasaare weyn oo glial ah, falanqaynta koox-hoosaadka ayaa muujisay hoos u dhac weyn (45%) cufnaanta astroglial GFAP-positive ee maadooyinka daraasadda ka yar 35 sano [148]. Daraasad morphometric ah ayaa si la mid ah u muujisay wax isbeddel ah oo ku yimid cufnaanta glial ee maskaxda MDD ee nolosha dambe [35]. Waxaan qiyaasaynaa in maqnaanshaha muuqda ee luminta astroglial ee bukaannada MDD ee da'da weyn ay ka tarjumayso astrogliosis labaad [42,50] oo la xidhiidha da'da weyn [XNUMX] halkii ay ka ahaan lahayd mid xun oo run ah.

Daraasadaha xayawaanku waxay la socdaan daraasadaha bini'aadamka ee muujinaya luminta astroglial ee MDD. Jiirka Wistar-Kyoto� loo yaqaan inay muujiyaan dabeecado niyad-jabka oo kale ah ayaa daaha ka qaaday cufnaanta astroglial-ka oo yaraatay isla aagagga sida lagu arkay aadanaha [40]. Maamulka wakiilka sunta astroglial, L-alpha-aminoadipic acid, waxay keentaa calaamadaha niyad-jabka ah ee jiirka, taas oo soo jeedinaysa in luminta astroglial ay tahay cudur ku dhaca MDD [41].

Daraasadaha dhimashada ka dib ee maadooyinka MDD waxay diiwaangeliyeen cufnaanta oligodendroglial ee kortex hore iyo amygdala [54-57,66], taas oo laga yaabo inay la xiriirto maskaxda MRI isbeddelka arrimaha cad ee mararka qaarkood lagu xusay bukaannada MDD qaarkood [57]. Si kastaba ha ahaatee, cilladaha microvascular ayaa sidoo kale laga yaabaa inay gacan ka geystaan ​​isbeddeladan [57].

Gudaha BPD, daraasadaha qaarkood waxay muujinayaan khasaare weyn [138,143,149,150], halka kuwa kalena aysan [37,44-46] samayn. Natiijooyinkan aan joogtada ahayn waxay ka dhalan karaan xakameyn la'aanta: 1) daaweynta niyadda xasiliyayaal, sababtoo ah falanqaynta post-hoc ayaa lagu soo warramey cilmi-baarisyada qaarkood waxay muujiyeen hoos u dhac weyn oo ku yimaada glial khasaaro kaliya ka dib markii la xakameeyey daaweynta lithium iyo valproic acid [46]; 2) Noocyada qoyska ee BPD, sida luminta glial ayaa si gaar ah uga dhex muuqda bukaannada BPD ee leh taariikh qoys oo xooggan [143]; iyo/ama, 3) xaaladda ugu badan ee niyad-jabka iyo waallida, maadaama luminta glial ay ku badan tahay MDD [35-38,42-46,55,138-147]. Haddii astroglia ama oligodendroglia ay ku xisaabtamaan inta badan khasaaraha glial ma cadda; halka falanqaynta proteomic ay muujisay hoos u dhac weyn oo ku yimid hal astroglial GFAP isoform [39], dhowr daraasadood oo kale oo dhimashada ka dib ayaa lagu helay mid aan isbeddelin [36,37] ama hoos u dhigista GFAP-positive astroglial cortex ee kortex orbitrofrontal [47], ama hoos u dhaca cufnaanta oligodendroglial. 54-56,58,59].

schizophrenia, luminta astroglial waa helitaan aan iswaafaqayn [48,150]. Inkastoo cilmi-baarisyada qaarkood aysan muujin wax khasaare ah oo astroglial ah [42,50,51], dhowr qof oo kale ayaa laga helay cufnaanta astroglial oo yaraaday [37,38,43,44,48,49,151] iyo hoos u dhac weyn oo ku yimid laba qaybood oo GFAP ah [39]. Natiijooyinka aan iswaafaqsanayn ayaa laga yaabaa inay ka dhashaan: 1) Cudurka MDD, kaas oo inta badan la xidhiidha luminta glial; 2) kala duwanaanta da'da, maadaama bukaannada da'da ah ay kordhiyeen GFAP-positive astroglia [35,42,50]; 3) gobolka [150] iyo isbeddelka lakabka kortikal [48]; 4) daaweynta daawooyinka dhimirka, sida daraasadaha tijaabada ah ayaa muujinaya labadaba la dhimay [152] oo kordhay [153] cufnaanta astroglial-cufnaanta ee la xiriirta daaweynta xanuunka dhimirka ee joogtada ah [70]; iyo 5) xaalad cudur (tusaale ahaan, isdil iyo dabeecad aan is-dilid) [154]. Daraasadaha dhimashada ka dib ayaa diiwaangeliyay luminta oligodendroglial [54,56,60-65,148,155,156], gaar ahaan kiliyaha hore, kortex cingulate hore, iyo hippocampus [148]. Baaritaanka ultrastructural ee gobolka prefrontal ayaa muujiyay fiilooyinka aan caadiga ahayn ee myelinated ee labadaba cawl iyo caddaan; da'da iyo muddada jirrada labadaba waxay si togan ula xiriireen cilladaha aan caadiga ahayn ee cadaanka [157].

Si ka duwan xanuunka neurodegenerative ee sida caadiga ah lala xiriiriyo kororka astroglial [136], xanuunada dhimirka ayaa bedelkeeda lala xiriiriyaa cufnaanta astroglial-ka oo la dhimay ama aan isbeddelin [138]. Maqnaanshaha korodhka cufnaanta glial ee xanuunka dhimirka ee bilawga hore [44,138] ayaa laga yaabaa inay ka tarjumayso heerka gaabis ee horumarka xumaanshaha cudurada dhimirka [138].

Waxaan soo bandhigeynaa in isbeddelada xumaanta ee la xidhiidha xanuunka dhimirku ay yihiin kuwo khafiif ah oo aan aad u daran ahayn si ay u kiciyaan astroglial intracellular transcription astrogliosis kuwaas oo si sax ah u maamula astrogliosis, oo ay ku jiraan qalabeeyaha signalka ee qoraalka 3 iyo nukliyeerka kappa B (NF-?B) [136].

In kasta oo inta badan daraasadaha dhimashada ka dib ay diiradda saareen isbeddelka cufnaanta glial ee MDD, BPD, iyo schizophrenia, kuwa kale waxay ku tilmaameen isbeddelka unugyada glial morphology, oo leh natiijooyin isku dhafan. MDD iyo BPD, cabbirka glial-ka ayaa la kordhiyey ama isbeddelin [55]. Hal daraasad ayaa lagu ogaaday in cabbirka glial uu hoos u dhacay BPD iyo schizophrenia laakiin aan ku jirin MDD [43]. Daraasad dhimashada ka dib ee bukaannada niyad-jabsan ee is-dilay waxay heleen cabbirka astroglial-ka ee kor u kaca ee xuubka hore ee cad-cad laakiin aan ku jirin kiliyaha [158]. Mid ka mid ah daraasadda maaddooyinka schizophrenic ayaa lagu helay hoos u dhac weyn oo cabbirka astroglial ee lakabka V ee kiliyaha hore ee dorsolateral, in kasta oo cufnaanta astroglial ay labanlaab ka tahay kontaroolada isla lakabka [48]. Natiijooyinka isku dhafan ayaa laga yaabaa inay qayb ahaan ka tarjumaan daraasadihii hore ee isbeddellada glial ee cudurrada dhimirka ee aan caddayn astroglia iyo oligodendroglia [148].

Luminta glial ee cudurrada dhimirka ayaa laga yaabaa inay gacan ka geysato neuroinflammation iyada oo loo marayo habab dhowr ah, oo ay ku jiraan heerarka cytokine aan caadi ahayn (eeg qaybta Cytokine), dheef-shiid kiimikaad glutamate ah oo aan hagaagsaneyn (eeg qaybta Glutamate), borotiinka S100B oo sarreeya (fiiri qaybta S100B), �oo beddelay shaqada BBB (eeg qaybta xannibaadda maskaxda ee dhiigga), taasoo keentay garaadka iyo dhaqanka daciifka ah [44,45,54,133,159].

Microglial Histopathology

Microglia waa unugyada difaaca jirka ee CNS. Waxay bixiyaan ilaalin difaac joogto ah waxayna nidaamiyaan manjooyin synaptik korriin [160,161]. Dhaawaca CNS waxa uu u beddelaa microglia nasasho oo nasasho leh oo firfircoon oo firfircoon oo usha qaabaysan iyo unugyo macrophage-u eg oo fagocytic amoeboid ah kuwaas oo sii kordhaya oo u guuraya goobta dhaawaca iyada oo la raacayo jaangooyooyinka kiimikaad (taas oo ah, firfircoonida micro-glial and proliferation (MAP)) [161]. Unugyada microglial-ka bini'aadamka waxay muujinayaan NMDARs kuwaas oo dhexdhexaadin kara MAP taasoo u horseedaysa dhaawaca neuronal [162].

MDD, BPD iyo schizophrenia, natiijooyinka daraasadaha dhimashada ka dib ee lagu baadho joogitaanka MAP waa isku dhafan yihiin. Daraasadaha dhimashada ka dib ayaa muujiyay MAP oo sarreeya mid ka mid ah shantii maaddo ee MDD [67]. Qaar ka mid ah bukaannada BPD-da, korodhka leukocyte antigen-DR-positive microglia oo muujinaya hababka dhumucsan ayaa lagu diiwaangeliyay kiliyaha hore [69]. Shisoofrani, halka cilmi-baadhisyada qaarkood ay sheegeen in MAP ay sare u kacday marka loo eego kantaroolka, kuwa kalena ma muujin wax farqi ah oo u dhexeeya kooxaha [22,67,70]. Daraasad dhimasho ka dib oo lagu qiimeeyay MAP gudaha MDD iyo BPD; Cufnaanta unugyada microglial ee quinolinic acid-positive ayaa lagu kordhiyey kiliyaha hore ee cingulate cortex iyo kiliyaha dhexe ee dhexe ee MDD iyo bukaannada BPD kuwaas oo isdilay marka loo eego kantaroolka [53]. Falanqaynta hoc ka dib ayaa shaaca ka qaaday MAP-gan korodhay inuu yahay mid loo aanayn karo MDD oo aan ahayn BPD, tan iyo markii la helay difaaca jirka ee microglial ee maadooyinka MDD aad ayuu uga weyn yahay kan ku jira koox-hoosaadka BPD ee labada qaybood ee hore ee hore iyo midcingulate, iyo tan iyo markaas. cufnaanta microglia waxay la mid tahay labada BPD iyo kooxaha kantaroolka [53]. Daraasad la barbardhigay dhammaan saddexda cilladood (sagaal MDD, shan BPD, afar iyo toban schizophrenia, toban kontaroolo caafimaad leh) ma muujin farqi weyn oo u dhexeeya cufnaanta microglial ee afarta kooxood [68].

Natiijooyinkan isku dhafan ayaa laga yaabaa in loo aaneeyo calaamadaha is-difaaca jirka ee isbeddelka microglial ee loo isticmaalo daraasado kala duwan [70] iyo / ama ku guuldareysiga in la xakameeyo darnaanta cudurka [22,53,68]. Waxaa xusid mudan, seddexda daraasadood ee dhimashada ka dib ee MDD iyo maaddooyinka schizophrenic waxay diiwaangeliyeen xiriir wanaagsan oo u dhexeeya MAP iyo isdilka ee kortex cingulate hore iyo mediodorsal thalamus, oo ku tiirsan ogaanshaha cudurka dhimirka [22,53,68]. Markaa, MAP waxay noqon kartaa dawlad halkii ay ka ahaan lahayd calaamad muujinaysa MDD iyo schizophrenia.

Gudaha OCD, moodooyinka xayawaanku waxay soo jeedinayaan in cillad la'aanta iyo dhimista qaar ka mid ah phenotypes microglial, sida kuwa muujinaya hidda-wadaha Hoxb8, kaas oo qeexaya qodobka qoraalka homeobox, wuxuu sababi karaa dabeecad u eg OCD [71,72].

Jiirarka garaaca ee Hoxb8 waxay muujinayaan habdhaqan qurux badan iyo walaac iyada oo lala kaashanayo cufnaanta microglial oo hoos u dhacday [71,72]. Dabeecaddan xad-dhaafka ah ee is-qurxintu waxay u egtahay dabeecadaha dabeecadda OCD ee bini'aadamka. Duritaanka Hoxb8 ee qaangaarka Hoxb8 jiirarka garaaca ayaa ka noqda luminta microglial waxayna soo celisaa dabeecadda caadiga ah [71,72]. Doorka kuwan gaarka ah ee phenotypes microglial ee OCD aadanaha ma cadda.

Xogta tijaabadu waxay soo jeedinaysaa in MAP ay ka kooban tahay phenotypes waxyeello leh iyo kuwa ilaalinta neerfaha (Jaantuska 2). Microglia waxyeellada leh ma muujiso kakan II (MHC-II) iyo, sidaa darteed, uma dhaqmi karto sidii unug soo bandhiga antigen (APC) [163,164]; waxay kor u qaadaan saamaynta tirtirka ah [17,69,165] iyada oo loo marayo soosaarka cytokine proinflammatory, nitric oxide synthase signaling [17,166], kor u qaadida glial iyo BBB-pericyte / endothelial cyclooxygenase-2 (COX-2) muujinta [167], soo jiidashada astroglial S100 S100 sirta qaybta), iyo siidaynta microglial glutamate [17,136,168,169]. Microglia waxyeellada leh ayaa sidoo kale qarsoodi ah prostaglandin E-2 (PGE-2) kaas oo kor u qaada wax soo saarka cytokines proinflammatory, taas oo kor u qaadeysa heerarka PGE-2 ee wareegga quudinta [29]. Dheeraad ah, PGE-2 waxay kicisaa COX-2 muujinta, taas oo dhexdhexaadinaysa beddelka aashitada arachidonic ee PGE-2, dejinta wareeg kale oo quudin ah [29].

Microglia neuroprotective marka la barbardhigo waxay awood u leedahay: 1) MHC-II in vivo iyo in vitro [163,166] oo u dhaqmaan sida APC cognate (Jaantus 2) [163,164,166]; 2) fududaynta bogsashada iyo xaddididda dhaawaca neerfaha iyada oo kor u qaadeysa dheecaanka cytokines antiinflammatory [17], maskaxda ka soo jeeda neurotrophic factor [17], iyo factor koritaanka insulin-sida-1 [166]; iyo 3) waxay muujinayaan xamaasadda amino acid transporter-2 (EAAT2) taas oo meesha ka saaraysa glutamate-ka ka baxsan unugyada [163,166], oo kor u qaada neuroprotective T lymphocytic autoimmunity (Jaantus 2) [163,164]. Si kastaba ha ahaatee, daraasado badan ayaa loo baahan yahay si loo xaqiijiyo doorka waxtarka leh ee microglia neuroprotective ee xanuunada maskaxda ee bini'aadamka.

 

In vitro Daraasadaha xayawaanku waxay soo jeedinayaan in saamiga waxyeellada leh ee ka soo horjeeda microglia neuroprotective ay saameyn ku yeelan karto saameynta saafiga ah ee hababka xakamaynta bararka [15,74,164,166]. Hababkaan waxaa ka mid ah tirada unugyada neuroprotective CD4 + CD25 + FOXP3 + T unugyada nidaaminta ((T regs) Jaantuska 1) [15,74,164,166] iyo heerarka cytokine maskaxda; hooseeyo IFN-? Heerarka ayaa laga yaabaa inay kor u qaadaan microglia neuroprotective (Jaantus 2) [166], halka heerarka sare ay kor u qaadi karaan phenotype waxyeelada leh [166].

Doorka Cytokines

Cytokines proinflammatory waxaa ka mid ah IL-1?, IL-2, IL-6, TNF-? iyo IFN-?. Waxa ugu horrayn sir ah micro-glia, Th1 lymphocytes iyo M1 phenotype monocytes/macrophages (Jaantus 1) [15,170]. Waxay kor u qaadaan bararka waxyeellada leh. Cytokines ka-hortagga caabuqa waxaa ka mid ah IL-4, IL-5 iyo IL-10. Waxay ugu horrayn qarsoodi u yihiin astroglia,�Th2 lymphocytes, T regs iyo M2 phenotype monocytes/macrophages [15,52,74]. Waxay xaddidi karaan caabuqa waxyeelada leh [15,74] iyaga oo u beddelaya nooca proinflammatory M1-phenotype ee faa'iido u leh antiinflammatory M2-phenotype [15], iyo suurtogalnimada iyaga oo kor u qaadaya phenotype microglial neuroprotective [15,17,74,163,166]. Doorka cytokines proinflammatory / anti-bararka cytokines ee xanuunka dhimirka waxaa taageera dhowr xariiq oo caddayn ah (Jaantus 1, Shaxda 2) [15,17,29,52,74].

MDD, falanqaynta ugu dambeysay ee falanqaynta (29 daraasaadka, 822 MDD, 726 kontaroolada caafimaadka leh) ee cytokines serum proinflammatory cytokines ayaa xaqiijiyay in soo dhaweynta IL-2 ee milmay, IL-6 iyo TNF-? Heerarka waxaa lagu kordhiyey MDD (calaamadaha astaamaha) [91], halka, IL-1?, IL-2, IL-4, IL-8 iyo IL-10, aan xisaab ahaan ka duwanayn kantaroolka [91]. Daraasada aasaasiga ah ee cytokine ee isbarbardhigga kooxo-hoosaadyada MDD (47 isdil- MDD, 17 aan is-dilin MDD, 16 kontaroolada caafimaadka), labadaba sera IL-6 iyo TNF-? aad bay u sarreeyaan, halka heerarka IL-2 ay aad uga hooseeyaan maadooyinka MDD kuwaas oo isdilay marka loo eego labada kooxood ee kale [96]. Natiijooyinkani waxay soo jeedinayaan in IL-6 iyo TNF-? sidoo kale waa calaamadaha gobolka ee MDD [96]. Hoos u dhaca heerarka serum IL-2 ee la xidhiidha hab-dhaqanka is-dilka ee degdega ah waxa laga yaabaa inay ka tarjumaan ku xidhnaanta kordheysa ee soo-dhoweynta maskaxda ee maskaxda; oo la mid ah falanqaynta-meta-falanqaynta ee aan soo sheegnay oo muujinaysa kororka soo-dhoweynta IL-2 ee MDD [91]. Daraasadaha lagu baarayo muhiimada kiliinikada ee cytokines ee MDD waxay muujisay in heerarka serum cytokine ay sare u kaceen inta lagu jiro marxaladaha niyadjabka ba'an [171,172] iyo caadi ahaan ka dib markii lagu guuleysto, laakiin aan ku guuldareysan, daaweynta antidepressants [17] iyo daawaynta korantada [29]; Natiijooyinkani waxay soo jeedinayaan doorka cudur-sidaha ee suurtogalka ah ee cytokines.

Gudaha BPD, isbeddellada serum cytokine ayaa lagu soo koobay dib u eegis dhowaan; TNF-?, IL-6 iyo IL-8 ayaa sare loo qaaday inta lagu jiro wajiyada maskaxda iyo niyad-jabka, halka IL-2, IL-4 iyo IL-6 ay sare u kaceen inta lagu jiro waallida [92]. Daraasado kale ayaa muujiyay in sera IL-1? iyo IL-1 heerarka reseptor ma aha kuwo tirokoob ahaan ka duwan kantaroolka caafimaadka qaba [92], in kasta oo daraasaadka unugyada ay diiwaangeliyeen heerarka korodhay ee IL-1? iyo IL-1 reseptor ee kiliyaha hore ee BPD [69].

schizophrenia, natiijooyinka ka soo baxa daraasadaha lagu baarayo cilladaha cytokine waa iska hor imaanayaan (Shaxda 2). Iyadoo cilmi-baarisyada qaarkood ay heleen labadaba hoos u dhaca serum proinflammatory (IL-2, IFN-?) iyo korodhka serum iyo CSF ​​antiinflammatory cytokines (IL-10) [52], kuwa kale waxay heleen serum pro- iyo cytokines anti-bararka, oo leh nooca proinflammatory nooca [22,173,174]. ]. Mid ka mid ah falanqaynta cytokine meta-falanqaynta (62 daraasado, 2,298 schizophrenia, 858 kontaroolada caafimaadka leh) ayaa muujiyay heerarka korodhay ee IL-1R antagonist, sIL-2R iyo IL-6 [174]. Si kastaba ha ahaatee, daraasaddan laguma xisaabin isticmaalka antipsychotics, taas oo loo maleynayo inay kor u qaadayso wax soo saarka cytokine proinflammatory [52]. Falanqaynta maadada cytokine ee dhowaantan (40 daraasadood, 2,572 schizophrenics,�4,401 kontaroolada) kuwaas oo ku xisaabtamay antipsychotics, waxay ogaadeen in TNF-?, IFN-?, IL-12 iyo sIL-2R ay si joogto ah kor ugu qaadaan shisoofrani dabadheeraad ah oo ka madax banaan dhaqdhaqaaqa cudurka (calaamadaha calaamadaha), halka IL-1?, IL-6 iyo Beddelida qodobka koritaanka beta ayaa si togan ula xidhiidha dhaqdhaqaaqa cudurka (calaamadaha gobolka)[173]. Dhaqamada unugyada unugyada unugyada mononuclear-ka ee dhiigga (PBMC) ee laga helay bukaannada schizophrenic waxay soo saareen heerar sare oo IL-8 iyo IL-1? si kedis ah iyo sidoo kale ka dib kicinta LPS, oo soo jeedinaysa doorka firfircoonida monocytes / macrophages ee pathology schizophrenia [175].

Gudaha OCD, natiijooyinka ka soo baxa sahan random ee sera iyo CSF ​​cytokines, iyo LPS-kicinta daraasadaha PBMC, waa kuwo iswaafaqaya [93-95,176-179]. Waxaa jira xiriir ka dhexeeya OCD iyo polymorphism shaqeyneysa ee gobolka dhiirrigeliyaha ee TNF-? hidda-wadaha [34], in kasta oo daraasadaha awoodda yar aysan xaqiijin ururkan [180]. Sidaa darteed, natiijooyinka isku dhafan ee ka soo baxa daraasado muujinaya mid kordhay ama hoos u dhacay TNF-? Heerarka cytokine [93,176-178] ayaa laga yaabaa inay ka turjumaan ku daritaankooda doorsooma ee maadooyinka OCD oo wata polymorphism-ka gaarka ah ee kooxahooda.

Jawaabta Cytokine Polarization ee Niyad-jabka Weyn & Shisoofrani

Noocyada jawaab-celinta cytokine waxaa loo kala saaraa mid ka mid ah Th1 (IL-2, IFN-?) ama Th2 (IL-4, IL-5, IL-10) iyadoo loo eegayo hawlaha difaaca ee ay nidaamiyaan. Iyadoo cytokines Th1 ay nidaamiyaan difaaca dhexdhexaadka ah ee unuggu si toos ah uga hortagayo antigens-ka-unugyada, Th2 cytokines waxay nidaamisaa difaaca jilicsan ee loogu talagalay antigens-ka ka baxsan unugyada [29,52]. Th1 cytokines waxaa soo saaray Th1 lymphocytes iyo M1 monocytes halka Th2 cytokines ay soo saaraan Th2 lymphocytes iyo M2 monocytes [29,52]. Maskaxda dhexdeeda, microglia ayaa inta badan sirta Th1 cytokines, halka astroglia ay si weyn u qariso Th2 cytokines [29,52]. Saamiga is-dhaafsiga ee Th1: Th2 cytokines, hadda ka dib - Th1-Th2 seesaw,� waxaa saameeya saamiga microglia firfircoon (dhaaf Th1) ilaa astroglia (th2 xad dhaaf ah) iyo isdhexgalka u dhexeeya unugyada T firfircoon ee firfircoonida iyo heerarka glutamate ee CNS ee xad-dhaafka ah ee aan qiyaasnay. in loo xagliyo jawaabta Th1 (Jaantuska 2) [29,163,166].

Isku dheelitir la'aanta th1-Th2 seesaw waxay saameyn kartaa dheef-shiid kiimikaadka tryptophan iyadoo bedelaysa enzymes-keeda [21,52] taas oo u beddesha tryptophan catabolism dhanka kynurenine (KYN) iyo KYN catabolism dhinaca mid ka mid ah labadiisa dheef-shiid kiimikaad hoose; microglia quinolinic acid kaas oo ah jawaab-celinta Th1 ama astroglial kynurenic acid (KYNA) (Jaantuska 1) kaas oo ah jawaab-celinta Th2 [21,29,170].

Enzymes dheef-shiid kiimikaad ee tryptophan uu saameeyay Th1-Th2 seesaw waxaa ka mid ah (Jaantuska 1): indoleamine 2,3-dioxygenase (IDO) oo ay muujiyeen microglia iyo astroglia, enzymes-ka xaddidan ee dhexdhexaadiya beddelka tryptophan ilaa KYN iyo serotonin ilaa 5- Hydroxyndoleacetic acid[21,29]. Kynurenine 3-monooxygenase (KMO), oo kaliya lagu muujiyay microglia, waa qiyaasta xaddidaadda enzyme ee u beddelaya KYN ilaa 3-hydroxykynurenine (3-OH-KYN), kaas oo lagu sii daayo quinolinic acid [21,29]. Tryptophan-2,3-dioxygenase (TDO), oo ay muujisay kaliya astroglia, waa enzyme xad-dhaaf ah oo beddelatryptophan ilaa KYN [21,29]. Kynurenine aminotransferase (KAT), oo lagu muujiyay ugu horreyn hababka astroglial, waa enzyme xad-dhaaf ah oo dhexdhexaadiya beddelka KYN ee KYNA [21,29].

Cytokines Th1 waxay kicisaa microglial IDO iyo KMO, waxayna u beddeshaa catabolism microglial KYN dhanka quinolinic�Acid (NMDAR agonist) isku-darka, halka Th2 cytokines-ka-dhaqdhaqaaqa microglial IDO iyo KMO, u beddelaya astroglial KYN catabolism xagga TDO-iyo KAT-dhexdhexaadinta KYNA (NMDAR antagonist) isku-dhafka (Jaantus 1) [21,29].

Th1 iyo Th2 immunophenotypes ugu sarreeya ayaa loo soo jeediyay MDD iyo schizophrenia, siday u kala horreeyaan, oo ku salaysan durugsan, halkii ay ka ahaan lahaayeen CNS, qaababka cytokines [52,173]. Waxaan aaminsanahay in qaababka cytokines-ka durugsan ay yihiin calaamado aan la isku halleyn karin ee kuwa ku jira CNS. Runtii, heerarka cytokine-ka durugsan waxaa saamayn kara doorsoomayaal badan oo CNS-ka-dheeraad ah, kuwaas oo aan si joogto ah loo koontaroolin dhowr ka mid ah daraasadaha cytokines-ka durugsan, oo ay ku jiraan: 1) da'da, index mass index, daawooyinka nafsaaniga ah, sigaar-cabista, walbahaarka iyo isbeddellada wareegga; 2) saamaynta �dhaqdhaqaaqa cudurka / xaaladda ku saabsan wax soo saarka cytokines la doortay [95,173]; iyo 3) saamaynta wakiilada nafsaaniga ah ee wax soo saarka cytokines [52]. Nolosha nuska ah ee gaaban iyo isbeddelka degdega ah ee serum cytokines [181] (tusaale ahaan, 18 daqiiqo ee TNF-? [182] iyo 60 daqiiqo ee IL-10 [183]), waxay sii xaddidi kartaa isku halaynta tarjumaada Heerarka lagu cabiray muunad sera random.

MDD, waxaa jira la isku raacsan yahay in proinflammatory Th1 jawaab-celinta immunophenotype ay ka badan tahay (Shaxda 2) [17,29]. Heerarka sare ee quinolinic acid ee maskaxda MDD ee dhimashada kadib [53], waxay soo jeedinayaan joogitaanka jawaabta Th1 ee kor loo qaaday (Jaantus 1) [21,29]. Aashitada CNS quinolinic acid waxay kor u qaadi kartaa qulqulka calcium ee dhexdhexaadinta apoptosis ee astroglia bini'aadamka [184]Jawaabta astroglia-derived Th2 [29], tirinta Th1 iyo Th2 seesaw dheelitirka ee u roon jawaabta microglial Th1. CNS hyposerotonergia [29] waxay ku darsataa taageero dheeraad ah jawaabta Th1 ee xad-dhaafka ah, taas oo lagu muujiyay in la yareeyo isku-darka CNS serotonin [185] iyo in la kordhiyo hoos-u-dhaceeda (Jaantus 1) [21,29].

CNS hyperglutamatergia waxa kale oo laga yaabaa inay gacan ka geysato jawaab-celinta Th1 ee maskaxda (Jaantuska 2). Daraasad ku jirta vitro waxay soo jeedinaysaa in nasashada durugsan ee T-lymphocytes ay si guud u muujinayaan metabotropic glutamate reseptor 5 (mGluR5) [164], kaas oo ku xidhidhiyaha glutamate uu joojinayo sii-deynta lymphocytic IL-6, taas oo hoos u dhigaysa kororka unugyada T-af-soo-celinta tooska ah [164]. T-lymphocytes firfircoon, laakiin aan nasanin T-lymphocytes, waxay ka gudbi karaan BBB [37].

Xogta tijaabadu waxay soo jeedinaysaa in isdhexgalka ka dhexeeya kuwa qaata unugyada T-yada ee T-lymphocytes firfircoon iyo unugyadooda soo bandhiga antigen-ka ay hoos u dhigi karaan mGluR5 oo ay keenaan mGluR1 tibaaxaha [164]. Noocyada xayawaanka, ku-xidhka glutamate-ka xad-dhaafka ah ee soo-dhoweeyayaasha mGluR1 lymphocytic waxay kor u qaadaan wax soo saarka cytokines Th1, oo ay ku jiraan IFN-? [164].

Waxaan qiyaasaynaa in bukaannada MDD qaarkood, oo barbar socda xogta tijaabada ah [164], isku-xidhka xad-dhaafka ah ee CNS glutamate si ay u kiciso lymphocytic mGluR1 reseptors ay gacan ka geysan karto jawaab-celinta Th1 ee dheeraadka ah, oo ay ku jiraan IFN-? (Jaantuska 2). Waxaan qiyaaseynaa in IFN-? tiro yar, oo la mid ah saameynteeda in vitro ee microglia [166], waxay dhalin kartaa muujinta microglial ee MHC-II iyo EAAT2 [163,166], taas oo u oggolaanaysa microglia inay u adeegto unugyada soo bandhigaya antigen-ka iyo inay bixiso shaqada dib u soo celinta glutamate [163,164,166], taas oo u beddelaysa microglia waxyeellada leh oo loo beddelo phenotype neuroprotective [163,166] oo ka qaybqaata baabi'inta glutamate-ka-ka-soo-baxa ah [163,164,166]. Sidaa darteed, waxaan sidoo kale qiyaasi karnaa in jawaabta Th1 ee dheeraadka ah ee koox-hoosaadyada bukaanada MDD ay tahay seef laba af leh, kor u qaadida caabuqa waxyeelada leh iyo u adeegida habka ka-hortagga faa'iido-darrada ah ee xaddidaya xad-dhaafka ah ee neuroexcitotoxicity glutamate (Jaantus 2).

Shisoofrani, halka qaar ka mid ah daraasaadka cytokine ee durugsan ay soo jeedinayaan sarraynta antiinflammatory Th2 immunophenotype/jawaab [52], kuwa kale waxay beeninayaan tan [173,174]. Si kastaba ha ahaatee, waxaanu ku raacsanahay qorayaasha qiyaasay in jawaabta Th2 ay tahay phenotype ugu weyn ee shisoofrani [52]. Maskaxda sare, CSF, iyo heerarka serum ee KYNA [21,52] waxay soo jeedinayaan hoos u dhigista micro-glial IDO iyo KMO, taas oo ah shaqada jawaabta Th2 taas oo u beddesha astroglial KYN catabolism xagga isku dhafka KYNA (Jaantus 1) [21,52]. Dhaqdhaqaaqa KMO oo la dhimay iyo muujinta KMO mRNA ee maskaxda shisoofrani ee dhimashada kadib [73] waxay la socotaa jawaabta Th2 ee dheeraadka ah (Jaantuska 1). Kordhinta faafitaanka difaaca kaftanka ee dhexdhexaadka ah ee Th2-dhexdhexaadin aan caadi ahaynsoo saarida autoantibodies oo ay ku jiraan unugyada ka hortagga fayraska [76] iyo korodhka immunoglobulin E [52] waxay ku kordhinaysaa taageero dheeraad ah qiyaasta jawaabta Th2.

Caabuqa neerfaha & Habacsanaanta Glutamate ee CNS

Glutamate waxay dhexdhexaadisaa garashada iyo dhaqanka [186]. Heerarka glutamate-ka Synaptic waxaa nidaamiya isku xirnaanta sare ee sodium-ku-tiirsan glial iyo neuronal EAATs, kuwaas oo ah, nidaamka XAG-ka mas'uul ka ah glutamate reuptake / aspartate sii deynta [137,164] iyo sodium-independent astroglial glutamate / cystine antiporter system (Xc-) mas'uul ka ah sii-deynta glutamate/cystine reuptake [164]. Astroglial EAAT1 iyo EAAT2 waxay bixiyaan in ka badan 90% dib-u-qaadista glutamate [79].

Neuroinflammation waxay bedeli kartaa dheef-shiid kiimikaadka glutamate iyo shaqada gaadiidleyda [15,29,187,188], soo saarista garashada, dabeecadda, iyo cilladaha dhimirka [15,21,29,79,186,188,189]. Waxqabadyada aan caadiga ahayn ee EAATs ee shaqada / muujinta iyo dheef-shiid kiimikaadka glutamate ee MDD, BPD, schizophrenia, iyo OCD ayaa lagu soo koobay Shaxda 2.

MDD, waxaa jira caddayn loogu talagalay hyperglutamatergia cortical (Shaxda 2). Heerarka glutamate-ka cortical ayaa si togan ula xiriira darnaanta calaamadaha niyad-jabka, iyo koorsada shan toddobaad ee daawada niyad-jabka ayaa hoos u dhigtay uruurinta glutamate serum [85,86]. Hal qiyaas oo ketamiin ah, oo ah NMDAR antagonist oo awood leh, ayaa dib u celin kara MDD dib u celinta toddobaadka [17,21,29,85]. Heerarka glutamate ee CNS ee xad-dhaafka ah waxay keeni karaan caabuqa dhexdhexaadinta neurotoxicity [163,164,188], oo ay ku jiraan jawaabta proinflammatory Th1 (Jaantus 2) [164].

Caddaynta xaddidan ee vitro waxay soo jeedinaysaa in caabuqa / cytokines proinflammatory ay kordhin karto heerarka CNS glutamate [188] ee wareegga quudinta iyada oo loo marayo dhowr habab oo suurtagal ah: 1) cytokines proinflammatory waxay joojin kartaa [15,17,168] ​​oo ay ka noqoto [45,137] astroglial EAAT-dhexdhexaadinta glutamate shaqada dib u soo celinta; 2) Cytokines proinflammatory waxay kor u qaadi kartaa isku-dhafka quinolinic acid microglial [53], kaas oo si tijaabo ah loo muujiyay si kor loogu qaado sii-deynta synaptosomal glutamate [15,17,29,190]; 3) kordhay COX-2/PGE-2 iyo TNF-? Heerarka waxay keeni karaan qulqulka kaalshiyamka [137], taas oo ku salaysan xogta vitro, waxay kordhin kartaa glutamate astroglial iyo sii-deynta D-serine [191]; iyo 4) Microglia firfircooni waxay muujin kartaa xad-dhaaf ah nidaamyada Xc-antiporter ee dhexdhexaadiya sii-deynta glutamate [164,192].

schizophrenia, prefrontal cortical hypoglutamatergia [87,90,193,194] (Shaxda 2) iyo hoos u dhaca shaqada NMDAR ayaa la helay [5]. Dhawaan H1 magnetic resonance spectroscopy (MRS) meta-falanqaynta (28 daraasaad, 647 schizophrenia, 608 xakamaynta) ayaa xaqiijiyay hoos u dhaca glutamate iyo korodhka heerarka glutamine ee kiliyaha hore ee dhexe [90]. Doorka wax ku biirinta caabuqa ee hypoglutamatergia lama xaqiijin. Kor u kaca KYNA ee maskaxda shisoofrani [21,52], sida caadiga ah shaqada jawaabta Th2 (Jaantuska 1), waxay joojin kartaa qaybta NR1 ee NMDAR iyo alfa 7 nicotinic�receptor acetylcholine (?7nAchR) [195], taasoo keentay hoos u dhaca shaqada NMDAR iyo hoos u dhigi ?7nAchR-dhexdhexaadinta glutamate sii daayo [195].

Gudaha BPD iyo OCD, xogtu waxay soo jeedinaysaa CNS cortical hyper-glutamatergia ee labada xanuun (Shaxda 2) [78,84,88,131]. Wax ku biirinta caabuqa (BPD iyo OCD) iyo autoantibodies (OCD) [7,77,84,88,130] ee kordhinta heerarka glutamate ee CNS waxay u baahan tahay baaritaan dheeraad ah.

Doorka S100B

S100B waa borotiinka calcium-ku-xidha 10 kDa oo ay soo saartay astroglia, oligodendroglia, iyo choroid plexus ependymal cells [196]. Waxay dhexdhexaadinaysaa saamaynta ay ku leedahay neerfayaasha ku xeeran iyo glia iyada oo loo marayo soo-dhoweeyaha loogu talagalay soo-saarka glycation horumarsan [196]. Heerarka S100B ee ka baxsan unugyada Nanomolar waxay bixiyaan saameyno neurotrophic faa'iido leh, xaddidaya dhaawaca neuronal ee la xiriira walbahaarka, waxay joojiyaan microglial TNF-? sii daayo, oo kordhiso dib u soo celinta astroglial glutamate [196]. Isku-darka Micromolar S100B, oo ay inta badan soo saarto astroglia firfircoon iyo lymphocytes [196,197], waxay leeyihiin saameyn waxyeello leh oo ay u beddelaan soo-dhoweeyaha badeecada dhammaadka glycation sare oo ay ku jiraan apoptosis neuronal, soosaarka COX-2 / PGE-2, IL-1? iyo noocyada nitric oxide ee aan duci karin, iyo kor u qaadida monocytic/microglial TNF-? qarsoodi [21,196,198].

Serum iyo, gaar ahaan, CSF iyo unugyada maskaxda S100B heerarka ayaa ah tilmaamayaasha firfircoonida glial (badanaa astroglial) [199]. MDD iyo cilmi nafsiga, heerarka serum S100B waxay si togan ula xiriiraan darnaanta isdilka, oo ka madax banaan ogaanshaha cudurka dhimirka [200]. Falanqaynta dhimashada ka dib ee S100B waxay muujisay heerarka hoos u dhaca ee kiliyaha hore ee dorso-lateral ee MDD iyo BPD, iyo heerarka korodhay ee kortex parietal ee BPD [196].

Falanqaynta Meta-Analysis (193 niyadda xanuunka, 132 kontaroolada caafimaadka leh) ayaa xaqiijiyay serum sare iyo heerarka CSF S100B ee xanuunka niyadda, gaar ahaan inta lagu jiro xaaladaha murugada daran iyo waallida [201].

Shisoofrani, maskaxda, CSF iyo serum S100B heerarka ayaa sare loo qaaday [199,202]. Meta-falanqaynta (12 daraasadood, 380 schizophrenia, 358 kontaroolo caafimaad leh) ayaa xaqiijiyay heerarka serum S100B ee schizophrenia [203]. Maskaxda dhimashada ka dib ee maaddooyinka shisoofrani, S100B-immunoreactive astroglia waxaa laga helaa meelaha lagu lug leeyahay shisoofrani, oo ay ku jiraan kortex cingulate hore, kortex hore ee dorsolateral, kortex orbitofrontal iyo hippocampi [154]. Heerarka sare ee S100B waxay la xiriiraan paranoid [154] iyo cilmu-nafsiga negativistic [204], garashada daciifka ah, jawaab-celinta daaweynta liidata iyo muddada jirrada [202]. Polymorphisms-ka hidde-sidaha ee S100B [32] iyo soo-dhoweynta hiddo-wadaha-soo-saarka glycation-ka sare ee schizophrenia cohorts (Shaxda 2) [32,33,205] waxay soo jeedinayaan cilladahan inay u badan tahay kuwa aasaasiga ah / cudur-sidaha halkii ay ka ahaan lahaayeen kuwa sare / biomarkers. Runtii, hoos u dhaca heerarka serum S100B ka dib daawaynta daawoyinka lidka diiqadda [201] iyo antipsychotics [196] ayaa soo jeedinaya�Qaar ka mid ah khusaynta kiliinikada ee S100B ee pathophysiology ee xanuunada dhimirka.

Caabuqa neerfaha & Cadaadiska Oxidative oo Kordhay

Cadaadiska Oxidative waa xaalad taas oo xad-dhaaf ah oksaydhiyeyaasha ay waxyeeleeyaan ama wax ka beddelaan macromolecules noolaha sida lipids, borotiinnada iyo DNA [206-209]. Natiijooyinka xad-dhaafka ah ee ka yimaada wax soo saarka oksaydhiyeyaasha oo kordhay, baabi'inta oksidheerta oo yaraatay, difaacayaasha antioxidant-ka cilladaysan, ama isku-darka qaarkood [206-209]. Maskaxdu waxay si gaar ah ugu nugul tahay diiqada oksaydhisku sababta oo ah: 1) xaddi sare oo asiidh dufan ah oo polyunsaturated peroxidizable ah; 2) Macdanta raad-raaceed ee xad-dhaafka ah oo aad u sarreeya oo keena peroxidation lipid iyo xag-jirrada ogsijiinta (tusaale, birta, naxaasta); 3) isticmaalka oksijiinta sare; iyo 3) hababka anti-oxidation xaddidan [206,207].

Cadaadiska oksaydhka ee xad-dhaafka ah wuxuu ku dhici karaa MDD [206], BPD [206,207], schizophrenia [207,209], iyo OCD [206,208]. Calaamadaha durugsan ee khalkhal abuurka oksaydhiyeyaasha waxaa ka mid ah badeecooyinka lipid peroxidation oo kordhay (tusaale, malondialdehyde iyo 4-hydroxy-2-nonenal), korodhka nitric oxide (NO) metabolites, antioxidants hoos u dhaca (tusaale, glutathione) iyo isbeddelka heerarka enzyme antioxidant [206,207].

MDD gudaheeda, korodhka soosaarka anion-ka xagjirka ah ee superoxide wuxuu xidhiidh la leeyahay kororka oksaydhaynta-dhexdhexaadinta apoptosis neutrophil [206]. Heerarka serum ee enzymes-ka antioxidant (tusaale ahaan, superoxide dismutase-1) ayaa sare loo qaadaa inta lagu jiro marxaladaha niyad-jabka ba'an waxayna caadi ka dhigaan ka dib daawaynta serotonin reuptake inhibitors (SSRIs) [206]. Tani waxay soo jeedinaysaa in MDD, heerarka enzyme antioxidant serum ay yihiin calaamad dawladeed, taas oo laga yaabo inay ka tarjumayso hab magdhow ah oo ka hortagaya kororka ba'an ee diiqada oksida. [206]. Shisoofrani marka la barbardhigo, heerka CSF milmay superoxide dismutase-1 ayaa si aad ah hoos ugu dhacay bukaanada schizophrenic ee bilawga hore marka loo eego bukaanada schizophrenic ee raaga iyo kontaroolada caafimaadka qaba. Tani waxay soo jeedinaysaa in heerarka enzyme antioxidant ee maskaxda laga yaabo inay gacan ka geystaan ​​waxyeelada oksaydhka ee shisoofrani ba'an [210], inkastoo daraasado waaweyn loo baahan yahay si loo xaqiijiyo natiijadan.

Dhowr tijaabo oo dheeri ah iyo daraasado bini-aadmi ah ayaa si faahfaahsan u baadhay hababka hoos yimaada pathophysiology ee korodhka cadaadiska oksaydhka ee xanuunka dhimirka [206-262]. Noocyada xayawaanka ee niyad-jabka, heerarka maskaxda ee glutathione waa la dhimay halka lipid peroxidation iyo NO heerarka la kordhiyo [206,262].

Daraasadaha dhimashada ka dib waxay muujinayaan hoos u dhaca heerarka maskaxda ee wadarta glutathione ee MDD, BPD [206] iyo maaddooyinka schizophrenic [206,207]. Fibroblasts oo ka soo jeeda bukaannada MDD waxay muujinayaan kororka cadaadiska oksaydhka ee ka madaxbannaan heerarka glutathione [262], iyaga oo ka doodaya doorka aasaasiga ah ee hoos u dhaca glutathione oo ah habka ugu weyn ee cadaadiska oksaydhka ee niyad-jabka.

Dhaqdhaqaaqa Microglial wuxuu kordhin karaa diiqada oksaydhka iyada oo loo marayo soo saarideeda cytokines proinflammatory iyo NO [206-209]. Cytokines Proinflammatory iyo heerar sare oo NO ah ayaa laga yaabaa inay kor u qaadaan samaynta noocyada ogsijiinta falcelinta (ROS), taas oo iyana dardargelisa lipid peroxidation, waxyeelada phospholipids xuubka iyo receptors monoamine neurotransmitter xuubka iyo baabi'inta antioxidants endogenous. Kordhinta alaabada ROS waxay kor u qaadi kartaa firfircoonida microglial waxayna kordhisaa wax soo saarka proinflammatory iyada oo loo marayo kicinta NF-?B [208], taas oo markaa sii wadi doonta dhaawaca oksaydhka [208], taas oo abuuraysa suurtagalnimada jawaab celinta saxda ah ee pathological ee qaar ka mid ah xanuunada dhimirka [206-209]. In kasta oo xanuunka neuroinflammation uu kordhin karo heerarka glutamate ee maskaxda [85,86], doorka glutamatergic hyperactivity oo ah sababta walaaca oksaydhka ayaa ah mid aan la xaqiijin [207].

Cilad la'aanta mitochondrial waxay gacan ka geysan kartaa korodhka cadaadiska oksaydhka ee MDD, BPD iyo schizophrenia [206]. Daraasadaha dhimashada ka dib ee cudurradan ayaa muujinaya cillado aan caadi ahayn oo ku jira DNA-da mitochondrial, oo la jaan qaadaya faafitaanka sare ee khalkhalgelinta dhimirka ee xanuunada mitochondrial aasaasiga ah [206]. Daraasadaha xayawaanka ee vitro waxay muujinayaan in cytokines proinflammatory, sida TNF-?, ay yareyn karto cufnaanta mitochondrial iyo daciifinta dheef-shiid kiimikaadka mitochondrial [211,212], taasoo keentay kororka wax soo saarka ROS [206,213]. Natiijooyinkan tijaabada ah ayaa laga yaabaa inay muujinayaan isku xirnaanta makaanikada ee ka dhexeeya neuroinflammation, cillad mitochondrial iyo walbahaarka oksaydhka [206,213], taas oo u qalanta baaritaan dheeri ah oo ku saabsan waddooyinkan is-goysyada cudur-sidaha ee cudurrada dhimirka ee aadanaha.

U nuglaanshaha unugyada neerfaha ee waxyeelada oksaydhisku way ku kala duwan yihiin xanuunada dhimirka ee kala duwan oo ku salaysan neuroanatomical, neurochemical iyo dariiqyada molecular ee ku lug leh cilladda gaarka ah [207]. Saamaynta daawadu waxay sidoo kale noqon kartaa mid muhiim ah, sida caddaynta hordhaca ah waxay soo jeedinaysaa in antipsychotics, SSRIs iyo xasiliyeyaasha niyadda ay leeyihiin sifooyinka antioxidant [206,207,262]. Doorka daawaynta ee antioxidants adjuvant (tusaale, fiitamiinnada C iyo E) ee xanuunka dhimirka ayaa weli ah in lagu caddeeyo tijaabooyin caafimaad oo la kala soocay oo awood sare leh. N-acetylcysteine ​​​​ayaa muujinaya natiijooyinka ugu rajo-gelinta badan ee maanta, iyada oo dhowr tijaabo oo la xakameynayo placebo-la kala soocay oo muujinaya waxtarkeeda MDD, BPD iyo schizophrenia [207].

Dhiiga �Brain Barrier Disfunction

BBB-du waxay xaqiijisaa heerka difaaca maskaxda ee mudnaanta leh iyadoo xaddidaysa gelitaanka dhexdhexaadiyeyaasha bararka durugsan, oo ay ku jiraan cytokines iyo unugyada difaaca kuwaas oo wax u dhimi kara neurotransmission [214,215]. Fikradda burburka BBB iyo doorka ay ku leedahay qaar ka mid ah bukaannada dhimirka [60,214,216,217] waxay la socotaa korodhka korodhka cudurrada dhimirka ee cudurrada la xidhiidha cilladdeeda, oo ay ku jiraan SLE [97], stroke [11], �suuxdin [218] iyo autoimmune encephalitides (Shaxda 1). Kor u kaca CSF: saamiga albumin-ka ee bukaanada qaba MDD iyo schizophrenia waxay soo jeedinaysaa korodhka BBB [214].

Hal daraasad (63 maadooyinka dhimirka, 4,100 kontaroolada), CSF aan caadi ahayn oo tilmaamaya dhaawaca BBB ayaa lagu ogaaday 41% maadooyinka dhimirka (14 MDD iyo BPD, 14 schizophrenia), oo ay ku jiraan isugeynta intrathecal ee IgG, IgM, iyo / org pleocytosis CSF khafiif ah (5 ilaa 8 unug halkii mm3) iyo joogitaanka ilaa afar IgG oligoclonal bands [216]. Mid ka mid ah daraasadda ultrastructural ee dhimashadii ka dib ee shisoofrani ayaa shaaca ka qaaday cilladaha BBB ee ultrasructural ee kortika hore iyo kuwa muuqaalka ah, oo ay ku jiraan xummad-xumida unugyada endothelial, geeddi-socodka astroglial-end-foot-, iyo dhumuc iyo aan caadi ahayn ee lamina basal [60]. Si kastaba ha ahaatee, daraasaddan, qorayaashu kama faalloon wax ku biirinta suurtagalka ah ee isbeddelada dhimashada ka dib natiijooyinkooda. Daraasad kale oo lagu baarayay transcriptomics ee unugyada endothelial BBB ee maskaxda schizophrenic ayaa aqoonsaday farqi weyn oo u dhexeeya hidde-sideyaasha saameeya shaqada difaaca jirka, kuwaas oo aan laga helin kontaroolada [217].

Cilladaha xuubka-dhexdhexaadinta oxidation-dhexdhexaadinta ayaa laga yaabaa inay gacan ka geysato pathophysiology ee cillad la'aanta BBB ee xanuunada dhimirka. Caddaynta aan tooska ahayn ee daraasadaha kiliinikada iyo tijaabada ah ee niyad-jabka [219] iyo, ilaa xad ka yar, schizophrenia [220] waxay soo jeedinaysaa in oksaydhka kordhay ay gacan ka geysan karto cillad la'aanta endothelial. Xanuunka endothelial wuxuu matali karaa habka la wadaago ee xisaabinta xiriirka caanka ah ee u dhexeeya niyad-jabka iyo cudurrada wadnaha iyo xididada [219,221], taas oo laga yaabo inay la xiriirto heerarka hoos u dhaca vasodilator NO [221-223]. Daraasadaha tijaabada ah waxay soo jeedinayaan in hoos u dhigista heerarka endothelial NO ay si farsamaysan ugu xiran yihiin isku-dhafka endothelial nitric oxide synthase (eNOS) oo ka soo jeeda tetrahydrobiopterin (BH4) oo muhiim ah, iyada oo ka beddelaysa substrate-ka L-arginine ilaa oksijiin [224-226]. eNOS aan la isku dhejin waxay kor u qaadaa isku-dhafka ROS (tusaale ahaan, superoxide) iyo noocyada nitrogen ee fal-celinta (RNS) (tusaale ahaan, peroxynitrite; wax soo saarka isdhexgalka superoxide ee NO) 227-224].

Xogta xayawaanku waxay muujisay in SSRIs ay dib u soo celin karaan yaraanta endothelial NO heerarka [219], taas oo soo jeedinaysa in hababka anti-oxidative ay gacan ka geysan karaan saameyntooda lidka ku ah niyad-jabka. Bini'aadamka, L-methylfolate waxay xoojin kartaa saameynta ka-hortagga niyad-jabka ee SSRIs [228], iyada oo la sii daayo iyada oo la kordhinayo heerarka BH4, taas oo ah cofactor lagama maarmaan u ah eNOS dib-u-celinta-dhexdhexaadinta anti-oxidation [229], iyo sidoo kale heerka - xaddidaya enzymes-ka monoamine (taas oo ah, serotonin, norepinephrine, dopamine) synthesis [228].

Isku soo wada duuboo, labadaba hawshii ugu dambaysay ee xoogga saaraysa doorka eNOS-ku-soo-baxa oksidheerka ee aan la isku qabsanayn ee cudurada xididada xididada [230,231] iyo �Daraasadaha epidemiological ee dejiya niyad-jabka sida khatarta ku-tiirsanaanta ee cudurrada xididdada xididdada, sida istaroogga iyo cudurrada wadnaha [219,221], waxay ku daraan taageero dheeraad ah ku habboonaanta bukaan-socodka ee eNOS-dhexdhexaadinta dhaawaca oksijiinta ee niyad-jabka. In kasta oo ay jiraan caddayn badan oo ku saabsan cilladaha cytokine ee cudurrada dhimirka ee bini'aadamka iyo xogta tijaabada ah ee muujinaysa in cytokines proinflammatory ay yareyn karto muujinta eNOS [212] iyo kordhinta BBB permeability [215], caddaynta bini'aadamka ee si toos ah ugu xirta cytokines-ka-soo-baxa proinflammatory ee eNOS cillad la'aanta iyo / ama BBB naafanimada waa maqan.

Sawirka & Daawaynta bararka Xanuunka Dhimirka

Sawirka Xanuunka Neuroinflammation ee Situ

Kiliinik ahaan, sawir-qaadista neuroinflammation ayaa laga yaabaa inay caddeyso inay muhiim u tahay aqoonsiga koox-hoosaadka bukaannada dhimirka ee qaba xanuunka neuroinflammation kuwaas oo ay u badan tahay inay si wanaagsan uga jawaabaan daawaynta immunomodulatory. Intaa waxaa dheer, sawir-qaadista noocan oo kale ah waxay u oggolaan kartaa dhakhaatiirta inay la socdaan dhaqdhaqaaqa xanuunka neuroinflammation ee la xidhiidha xanuunka iyo jawaabta ay ka bixiso daaweynta difaaca ee bukaannada dhimirka. Sawirka bararka maskaxda bini'aadamku wuxuu dhaqan ahaan ku tiirsan yahay MRI ama CT-ga muuqaalka ee wakiilada isbarbardhiga faleebada ee dheeraadka ah, taas oo muujinaysa burburka gudaha ee BBB. Gadolinium-kobcinta MRI waxay mararka qaarkood muujisaa burburka noocan oo kale ah ee gobollada limbic ee la xidhiidha habka shucuureed ee bukaanka qaba xanuunka dhimirka ee loo yaqaan 'paraneoplastic' ama encephalitides kale [107,109,113]. Aqoontayada, si kastaba ha ahaatee, kobcinta aan caadiga ahayn weligeed laguma muujin xanuunka dhimirka ee caadiga ah [21,214,232], in kasta oo shaqeyn [214,216] iyo cilladaha BBB ee aan caadiga ahayn [60].

Haddii xanuunka neuroinflammation-ka khafiifka ah lagu arki karo gudaha vivo iyo in kale xanuunnada dhimirka ee caadiga ah ayaan weli la garanayn. Mid ka mid ah farsamada rajo-gelinta leh waa sawir-qaadista positron emission (PET) iyadoo la adeegsanayo raadiyaha, sida C11-PK11195, kaas oo ku xiran borotiinka translocator, oo hore loogu yaqaanay xuubka benzodiazepine, oo lagu muujiyey microglia firfircoon [233,234].

Isticmaalka habkan, bukaanada qaba schizophrenia ayaa lagu muujiyay inay leeyihiin firfircooni weyn oo microglial ah oo dhan kortex [235] iyo hippocampus inta lagu jiro cilmi nafsiyeed ba'an [236]. Hal daraasad (14 schizophrenia, 14 kontaroolada) ma helin farqi weyn oo u dhexeeya [11C] DAA1106 oo ku xidhan schizophrenia iyo kantaroolka, laakiin xidhiidh toos ah oo u dhexeeya [11C] DAA1106 xidhitaanka iyo darnaanta calaamadaha togan iyo muddada jirrada ee shisoofrani [236].

Baarayaasha ka socda machadkeena waxay adeegsadeen C11-PK11195 PET si ay u muujiyaan caabuqa bi-hippocampal ee bukaanka qaba cillad maskaxeed oo maskaxeed, oo ay ku jiraan MDD maskaxiyan, suuxdin, iyo amnesia anterograde, oo la xidhiidha unugyada difaaca-GAD [237]. Si kastaba ha ahaatee, PK11195 PET waxay leedahay �calaamadaha hoose ee guryaha oo u baahan cyclotron goobta.

Sidaas awgeed, cilmi-baaris ayaa loo heellan yahay horumarinta isku-xirnaanta borotiinka beddelka ee PET iyo SPECT. Daraasadaha unugyada maskaxda ee mustaqbalka ee awoodda sare leh ee ka dambeeya dhimashada iyada oo la adeegsanayo qiyaasta borotiinka ee loogu talagalay in lagu caddeeyo hababka dheef-shiid kiimikaadka iyo bararka, CNS cytokines iyo soo-qabayaashooda xidhitaannada, cudurrada dhimirka ayaa loo baahan yahay si loo horumariyo fahamkayaga pathophysiology autoimmune.

Doorka Dawooyinka Kahortagga caabuqa ee Cudurada Dhimirka

Daraasado dhowr ah oo dadka iyo xayawaanka ah ayaa soo jeedinaya in daawooyinka anti-bararka qaarkood laga yaabo inay door muhiim ah ka ciyaaraan daaweynta xanuunada dhimirka (Shaxda 3). Daawooyinka caadiga ah waa inhibitors cyclooxygenase (Shaxda 3) [238-245], minocycline (Shaxda 3) [240-245], omega-3 fatty acids [246,247], iyo neurosteroids [248].

Daraasado dhowr ah oo bini-aadmi ah ayaa muujiyay in COX-2 inhibitors ay hagaajin karaan calaamadaha dhimirka ee MDD, BPD, schizophrenia iyo OCD (Shaxda 3) [248]. Taas bedelkeeda, daaweynta isku dhafan ee COX-inhibitors-ka aan la dooran (taas oo ah, daawooyinka aan anti-inflammatory ahayn ee aan steroid ahayn (NSAIDs)) waxay yareyn kartaa waxtarka SSRIs [249,250]; Laba tijaabo oo waaweyn ayaa sheegay in soo-gaadhista NSAID-yada (laakin aan ahayn kuwa la xushay COX-2 inhibitors ama salicylates) ay la xiriirto murugo sii xumaanaysa oo ka mid ah qayb-hoosaadyada daraasadaha [249,250].

Tijaabadii ugu horeysay, oo ku lug leh 1,258 bukaan oo niyadjabsan oo lagu daaweeyay citalopram 12 toddobaad, heerka cafisku aad ayuu uga hooseeyaa kuwa qaatay NSAIDs ugu yaraan hal mar marka loo eego kuwa aan haysan (45% oo ka soo horjeeda 55%, OR 0.64, P = 0.0002) [249]. Tijaabada kale, oo ku lug leh maadooyinka 1,545 MDD, ayaa muujisay heerka niyad-jabka daaweynta u adkaysta ayaa aad uga sarreeya kuwa qaata NSAIDs (OR 1.55, 95% CI 1.21 ilaa 2.00) [231]. Ka sii daridda niyad-jabka ee kooxaha NSAID-yada waxaa laga yaabaa inaanay si farsamaysan ugu xidhnayn daawaynta NSAID, laakiin waxay la xidhiidhaa xaalado caafimaad oo daba-dheeraaday [10,12-18] kuwaas oo u baahan NSAID-yada muddada-dheer oo la og yahay inay si madax-bannaan ula xiriiraan. khatarta sii kordheysa ee niyad-jabka u adkaysta daaweynta [249,251]. Daraasadaha mustaqbalka ee baaraya saameynta NSAID-yada ee niyad-jabka iyo ka jawaabista daawooyinka niyad-jabka ee bini'aadamka ayaa loo baahan yahay.

Daraasado kale oo tijaabo ah oo la adeegsanayo jaangooyooyin cadaadis ba'an si ay u kiciyaan xaalad niyad-jab ah oo la mid ah jiirarka, citalopram waxay kordhisay TNF-?, IFN-?, iyo p11 (cutubka molecular ee ku xiran dabeecadda niyad-jabka ee xayawaanka) ee kiliyaha hore, halka NSAID ibuprofen molecules kuwaas oo hoos u dhacay; NSAIDs waxay sidoo kale hoos u dhigtay saameynta antidepressant ee SSRIs laakiin maaha kuwa kale ee ka hortagga niyad-jabka [249]. Natiijooyinkani waxay soo jeedinayaan in cytokines proinflammatory laga yaabo inay si aan caadi ahayn u sameeyaan saameyn liddi ku ah niyad-jabka inkastoo caddayn aad u badan laga helayDaraasadaha bini'aadamka ee liddi ku ah (sida kor lagu eegay), taas oo lagu yarayn karo NSAIDs [249]. Ugu yaraan laba tixgelin ayaa laga yaabaa inay ku xisaabtamaan isbarbardhiggan muuqda: 1) xaaladaha tijaabada ah, cytokines proinflammatory ayaa lala xiriiriyay doorka neuroprotective, [251; (waayotusaale, IFN-? heerarka hooseeya waxay keeni karaan microglia neuroprotective (Jaantus 2) [163,166,251]; iyo 2) haddii jawaabahaas lagu arkay macnaha guud ee cadaadiska ba'an ee qaabka xayawaanka ayaa lagu dabaqi karaa MDD endogenous ee bini'aadamka weli ma cadda [251].

Saamaynta daaweynta COX-2 inhibitors ee xanuunada dhimirka waxaa laga yaabaa inay ku lug yeelato habaynta biosynthesis ee COX-2-derived prostaglandins, oo ay ku jiraan proinflammatory PGE2 iyo antiinflammatory 15-deoxy-?12,14-PGJ2 (15d- PGJ2) [252,253]. COX-2 inhibitors waxay yareyn kartaa bararka dhexdhexaadka ah ee PGE2, kaas oo gacan ka geysan kara pathophysiology ee xanuunada dhimirka [252,253]. Waxa kale oo laga yaabaa in ay beddelaan heerarka 15d-PGJ2, iyo dhaqdhaqaaqa nukliyeerkeeda receptor peroxisome proliferator-activated gamma receptor nuclear (PPAR-?) [252,253].

Daraasado dhowr ah ayaa soo jeedinaya in 15d-PGJ2 iyo qaboojiyaha nukliyeerka PPAR-? waxay u adeegi kartaa calamadaha noolaha ee shisoofrani [253]. Bukaannada schizophrenic, heerarka serum PGE2 waa la kordhiyaa, halka heerarka serum ee 15d-PGJ2 ay hoos u dhaceen, sida muujinta soo-dhoweeyaha nukliyeerka PPAR-? ee PBMC [252]. Iyadoo COX-2 inhibitors ay xaddidi karaan saamaynta faa'iidada leh ee ka hortagga caabuqa ee COX-2-ku-tiirsan �15d-PGJ2/PPAR-? Jidka-way, waxaa laga yaabaa inay si faa'iido leh u yareeyaan saameyntooda waxyeelada leh, oo ay ku jiraan 1) khatarta sii kordheysa ee wadnaxanuun myocardial iyo caabuqyada qaarkood (tusaale, cytomegalovirus iyo Toxoplasma gondii) ee bukaanka schizophrenic [254] iyo 2) saameynteeda pro-apoptotic ee lagu arkay unugyada kansarka dadka iyo xoolaha [255]. Hababka kale ee suurtogalka ah ee COX-2 inhibitors saamaynta daaweynta waxay ku lug yeelan kartaa awooddooda si loo yareeyo heerarka cytokine proinflammatory [163], xaddid quinolinic acid excitotoxicity (sida MDD) iyo hoos u dhigista heerarka KYNA (sida schizophrenia) [128].

Minocycline waxay waxtar u yeelan kartaa xanuunada dhimirka (Shaxda 3) [248]. Xogta gudaha vitro waxay soo jeedinaysaa in minocycline ay joojiso MAP, dheecaanka cytokine, COX-2/PGE-2 muujinta, iyo nitric oxide synthase [256]. Minocycline waxay sidoo kale ka hortagi kartaa glutamatergic dysregulated iyo dopaminergic neurotransmission [256].

Waxtarka omega-3 fatty acid ee xanuunka dhimirku ma cadda [248]. 2011-ka falanqaynta meta-falanqaynta ee 15 tijaabooyinka la kantaroolay (916 MDD), omega-3 supplements ka kooban eicosapentaenoic acid daawaynta isku xidhan ee SRIs (P <60) [200]. Si kastaba ha ahaatee, falanqaynta xigtay, si kastaba ha ahaatee, waxay soo gabagabaysay in aysan jirin faa'iido muhiim ah oo ku jirta omega-2,200 fatty acids ee niyad-jabka iyo in waxtarka la sheegay ay tahay kaliya natiijada eexda daabacaadda [0.001]. Falanqaynta 246-ka ee 3 tijaabo oo la kala soocay oo ay ku jiraan 247 ka qaybgalayaasha BPD waxay ogaadeen in niyad-jabka, laakiin aan ahayn manic, calaamadaha ayaa si weyn u wanaajiyey kuwa loo aqoonsaday omega-2012 fatty acids marka loo eego kuwa qaata placebo (Hedges g 5, P = 291) [3]. Tijaabada la kala soocay ee maaddooyinka schizophrenic ee la socda ilaa bilaha 0.34, labadaba dhibcaha calaamadaha togan iyo kuwa taban ayaa si weyn hoos ugu dhacay kaqeybgalayaasha 0.025 ee loo kala soocay omega-257 (12 g / maalintii toddobaadyada 66; P = 3 iyo 1.2, siday u kala horreeyaan) [12]; ahQorayaashu waxay soo gabagabeeyeen in kordhinta omega-3 inta lagu jiro koorsada hore ee schizophrenia ay sidoo kale ka hortagi karto soo noqoshada iyo horumarka cudurada [258].

Falanqaynta maadada 2012 ee toddobo tijaabo oo la kantaroolay oo la kala soocay oo lagu qiimeeyay korodhka omega-3 ee 168 bukaannada schizophrenic ayaa helin wax faa'iido ah daawaynta [259]. Qorayaasha falanqaynta-meta waxay si gaar ah u sheegeen in aan wax gunaanad ah laga soo saari karin ka hortagga soo noqoshada ama dhammaadka horumarka cudurka [259]. Xogta tijaabadu waxay soo jeedinaysaa in eicosapentaenoic acid iyo docosahexaenoic acid ay dhexdhexaadiyaan saameyntooda anti-bararka iyaga oo kor u qaadaya isku-dhafka resolvins iyo protectins, taas oo joojin karta faleebada leukocyte waxayna yaraynaysaa wax soo saarka cytokine [248].

Neurosteroids, oo ay ku jiraan pregnenolone iyo dheef-shiid kiimikaadka hoose ee allopregnanolone, ayaa laga yaabaa inay door faa'iido leh ku yeeshaan qaar ka mid ah xanuunada dhimirka [248,260]. MDD, cilmi-baarisyo dhowr ah ayaa laga helay heerarka plasma / CSF allopregnanolone oo hoos u dhacay oo la xidhiidha darnaanta calaamadaha, taas oo caadi ka dhigtay ka dib daawaynta lagu guuleystay ee antidepressants qaarkood (tusaale, SSRIs), iyo daaweynta korantada [261]. Shisoofrani, heerarka pregnenolone ee maskaxda waa la bedeli karaa [248] iyo heerarka serum allopregnanolone ayaa laga yaabaa inay kordhaan ka dib qaar ka mid ah dawooyinka nafsiga ah (tusaale, clozapine iyo olanzapine) [260]. Saddexda tijaabo ee la kala soocay ee la kantaroolay (100 schizophrenia (lagu daray); muddada daawaynta, qiyaastii sagaal toddobaad) calaamadaha togan, taban, iyo garashada, iyo sidoo kale waxyeellooyinka ka baxsan pyramidal ee antipsychotics ayaa si weyn loo hagaajiyay hal ama dhowr tijaabo oo ka mid ah kuwa la kala soocay pregnenolone marka loo eego kuwa qaata placebo [248]. Hal tijaabo, horumarinta ayaa lagu sii waday daawaynta pregnenolone ee muddada-dheer [248]. Pregnenolone waxay nidaamin kartaa garashada iyo dhaqanka adoo xoojinaya shaqada NMDA iyo GABAA reseptors [248]. Intaa waxaa dheer, allopregnanolone waxaa laga yaabaa inuu sameeyo saameyn neuroprotective iyo anti-bararka [248]. Daraasado badan oo RCT ah ayaa loo baahan yahay si loo xaqiijiyo doorka faa'iidada leh ee steroids neuroactive ee xanuunka dhimirka ee bilawga hore ee bini'aadamka.

Waxaan sugeynaa natiijooyinka dhowr tijaabo oo caafimaad oo socda oo baaraya saameynta daaweynta ee wakiilada kale ee ka-hortagga caabuqa, oo ay ku jiraan salicylate, horjoogaha NF-?B (NCT01182727); acetylsalicylic acid (NCT01320982); pravastatin (NCT1082588); iyo dextromethorphan, antagonist NMDAR aan tartan lahayn oo xaddidi kara bararka ku dhaca dopaminergic neuronal dhaawaca (NCT01189006).

Xeeladaha Daaweynta Mustaqbalka

Inkasta oo daawaynta difaaca ee hadda jirta (tusaale ahaan, IVIG, plasmapheresis, corticosteroids iyo wakiilada difaaca jirka) ayaa inta badan waxtar u leh daaweynta encephalitides autoimmune halkaas oo caabuqu yahay mid ba'an, aad u daran oo asal ahaan ka soo jeeda asalka la qabsiga, waxtarkooda xanuunka dhimirka ee qadiimiga ah ee caabuqa uu yahay mid daba-dheer.aad u fudud, oo u badan asal ahaan asal ahaan, waa xaddidan yahay [2]. Horumarinta daawaynta cusub waa inay ujeedadeedu tahay dib u celinta luminta glial [46,138], hoos u habeynta MAP waxyeelada leh, iyadoo la wanaajinayo endogenous neuroprotective T regs iyo MAP faa'iido leh, halkii ay si aan kala sooc lahayn u xakameyn lahaayeen caabuqa sida ku dhaca wakiilada difaaca jirka ee hadda jira. Intaa waxaa dheer, horumarinta antioxidant-ka-adjuvant-ka-adjuvant-ka ah ee awoodda leh oo wax ka beddeleysa dhaawaca oksaydhka ee cudurrada dhimirka ayaa loo baahan yahay.

Gabagabada

Is-difaacidnimadu waxay sababi kartaa cudurro maskaxeed oo maskaxeed oo badan oo laga yaabo inay marka hore la yimaadaan calaamado go'doonsan. Caabuqa/iska-ilaalinta gudaha ayaa laga yaabaa inay la xiriirto cudur-sidaha calaamadaha dhimirka ee qayb ka mid ah bukaannada qaba xanuunnada dhimirka ee caadiga ah. Caabuqa gudaha ku jira waxa laga yaabaa inuu si farsamaysan ugu xidhan yahay monoaminergic-ka caadiga ah iyo cilladaha glutamatergic-ka iyo dhaawaca oksaydhka ee kordhay ee laga soo sheegay cudurrada dhimirka.

Souhel Najjar1,5*, Daniel M Pearlman2,5, Kenneth Alper4, Amanda Najjar3 iyo Orrin Devinsky1,4,5

Soo Gaabiyey

3-OH-KYN: 3-hydroxy-kynurenine; ?7nAchR: Alpha 7 nicotinic acetylcholine reseptors; AMPAR: Amino-3-hydroxy-5-methyl-l-4-isoxazolepropionic acid reseptors; APC: Unug soo bandhigaya Antigen; BBB: Dhiiga xannibaadda maskaxda;
BH4: Tetrahydrobiopterin; BPD: Cudurka laba-cirifoodka; CI: Muddada kalsoonida;
CNS: habka dhexe ee neerfayaasha; COX-2: Cyclooxegenase-2; CSF: dareeraha maskaxda ee maskaxda; DSM-IV: Buugga Baadhista iyo Tirakoobka ee Cudurrada Maskaxda Daabcaaddii 4aad; EAATs: Gaadiidleyda amino acid ee xiisaha leh; eNOS: Endothelial nitric oxide synthase; GABAB: Gamma aminobutyric acid-beta; GAD: Glutamic acid decarboxylase; GFAP: Glial fibrillary acidic protein; GLX: 1H MRS glutamate la ogaan karo, glutamine, gamma aminobutyric acid composite;
IDO: Indoleamine 2,3-dioxygenase; Ig: Immunoglobulin; IL: Interleukin; IL-1RA: Interleukin 1 antagonist receptor; IFN-?: Interferon gamma;
KAT: Kynurenine aminotransferase; KMO: Kynurenine 3-monooxygenase; KYN: Kynurenine; KYNA: kynurenic acid; LE: limbic encephalitis;
LPS: Lipopolysaccharide; MAP: Dhaqdhaqaaqa Microglial iyo faafinta;
MDD: xanuunka weyn ee niyad-jabka; mGluR: Qaboojiyaha glutamate-ka-metabotropic; MHC: II Fasalka adag ee iswaafajinta histo ku habboon ee labaad; MRI: Sawir-qaadista magnetic; MRS: spectroscopy resonance magnetic; NF-?B: Qodobka Nukliyeerka kappa B; NMDAR: N-methyl-D-aspartate receptor; NR1: Goobta Glycine;
OCD: Xanuunka waswaaska ah; AMA: Saamiga khayaaliga; PANDAS: Xanuunada difaaca jirka ee neerfaha maskaxda ee carruurta ee la xiriira caabuqyada streptococcal; PBMC: Unugyada mononuclear-ka ee dhiigga ku wareegsan; PET: Sawir-qaadista positron; PFC: Kortex hore; PGE-2: Prostaglandin E2; PPAR-
?: Peroxisome proliferator-firfircoonay gamma qaboojiyaha nukliyeerka; QA: Quinolinic acid; RNS: Noocyada nitrogen ee firfircoon; ROS: Noocyada ogsijiinta falcelinta;
sIL: interleukin milmaya; SLE: lupus erythematosus habaysan; SRI: Dib-u-qaadista Serotonin; TNF-?: Tumor necrosis factor alpha; T-regs: CD4 + CD25 + FOXP3+ T unugyo nidaamsan; TDO: Tryptophan-2,3-dioxygenase; Th: T-caawiye; VGKC: Kanaalka potassium-gated-gated; XAG-: Glutamate aspartate transporter; Xc-: Astroglial glutamate/cystine-ka madax-bannaan ee Sodium
nidaamka xamaaliga

Meelaha xiisaha leh

Qorayaashu waxay caddeeyeen in aysan jirin danahooda tartanka.

Qorayaasha
SN iyo DMP waxay sameeyeen dib u eegis suugaaneed ballaaran, xog la turjumay, waxay diyaariyeen qoraal-gacmeedka, tirooyinka, iyo miisaska. KA waxay diyaarisay qaybta la xidhiidha hababka oksaydhka waxayna gacan ka gaysatay dib u eegisyada qoraal-gacmeedka. AN iyo OD ayaa si aad ah u dib u eegay oo hagaajiyay naqshadaynta iyo tayada qoraal-gacmeedka. Dhammaan qorayaashu way akhriyeen oo oggolaadeen qoraal-gacmeedka ugu dambeeya.

Mahadnaq

Waxaan u mahadcelineynaa Drs. Josep Dalmau, MD, PhD, Tracy Butler, MD, iyo David Zazag, MD, PhD, si ay u bixiyaan khibradooda encephalitides autoimmune, imaging neuroinflammation, iyo neuropathology, siday u kala horreeyaan.

Qoraaga�Faah-faahin

1Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. 2Geisel School of Medicine ee Dartmouth, Machadka Dartmouth ee Siyaasadda Caafimaadka iyo Ku-dhaqanka Caafimaadka, 30 Lafayette Street, HB 7252, Lubnaan, NH 03766, USA. 3Waaxda Cilmi-nafsiga, Qaybta Neuropathology, Dugsiga Caafimaadka ee Jaamacadda New York, 550 First Avenue, New York, NY 10016, USA. 4Waaxda Dhimirka, Dugsiga Caafimaadka ee Jaamacadda New York, New York, NY, USA. 5Jaamacadda New York University Comprehensive Papilepsy, 550 First Avenue, New York, NY 10016, USA.