Nezhadi, Akram

Simorgh Research Repository

,(,},! 5 r(,1,'.1.1,-L, .l prJr. C;, u--,af: cS;iS; ttL <-li ;L[:,llJr..l f.r-,tiJl"l .+l-r d"flii- c5;4* ,J<,i, ;r ,gl.r.K+olI ;t lJtt-4rJtL :,r-rl;,s.a cgt( ,i._r. ;,y-:51! ,Srt+ cCJ+ J- _,, tXS+*^cEjslol*o>Sll .r Jo<l+" ,69;S;1gJlji 151 :t-"o-,dlrL ,r+L.-l Ji-*;,-,(.1 :t--,419 .lt:*,idL5-}, Ja--Eo j(.1 ,it+.'& ..rt^3 ;iS.l :;3Li-o .lt':,,.1\Y1o - \Y11 :,J*^^-i JLIKerman University of Medical SciencesFaculty of MedicineIn Partial Fulfillment of the Requirements for the Degree(PhD)Iitle:Study the effect of allopurganolone on synaptic plasticity in striatum andhippocampus regions of experimental model of parkinsonism rats:behavioral, molecular and electrophysiological studyBy: Akram l{ezhadiSupervisor:Dr. Saeed Esmaeili mahaniAdvisors:1- Dr. Vahid Sheibani2-Dr. Mohammad ShabaniYear: 2017Of V a-l ;Lr; csLo or$ , c-l *;lr;;r:,r.y csl4a.;i^* #-p_U ;l n<- ;9*"{rL. .rr1^: :it,ral 9 4"JL,,1 eo I -Sr- sYV;l;l e" Olrt*;,l 4t u,-lr1;l .c";.r;5 p[i9 o.:9, L,l.j,a::;l:;99 SsV* *.1 O';q LS)9)- 7 plV -r;n )i.-k 1,, i:YV;l ;yl ,r-: 9) )b 4t ;Lr: 01, ,r,5 l+; ,J,, cs, e,, *sb -y!;,,) .r-,|;, 7lL- ; aJ ;-l j'1r**J c-Y)&l ;l ,J- d.)^.4d a.l c-l ot1; ;L;j o1-c.i;>t] .b; ,r" _E.$l ..r,,;1;'l ;l,t^,;l .J9,.-o ) f i\.*.il t+;*^ ;* q 4t dl dJtt^ Jl u|or.,i olL;l l^rJrl-lr,,y y*Siy.l,y .;.t; q sU1t 1l ..grlu.r:O.z;. b,.:rl.rj )9", Jui! $.f cr-sl, oyr$r\ cS,rL*,,) or.l).:b.,1 ,_r-"! gVVil ,tlrGx:9;-19r.;l ":y u.u19,,)G !. r srl:.5rll ,tyr$*jl **lL,r:;[-i I GSt oYV:;l y.\eyt*;l L1 al:9-titr-lsty c,l;l nrr. aJlt" .1,1 ;l ju ,v.l.rl* l,;s sF* oySh,,l .,;L s-.q- oy!;.c.^-1 iy;SrL Jr",_r,lrx-,_r[cif ,,),r-"f- 6t.+, #; yQtl*)lX.st4*Jfb ;l);ly6rii,rol,,i,J;5 o9f Lr, q f S o.:la::,ul 1L;"+.9 >l; ; ullg-,SttJf )1 ,_s.F allt erl ,': :Q^i91 g )llo*) ,tlyYxel'l Y'mg/kg 19.: L ou.rLr:q--p,, ol.F I b mglkg;9r L o-ri rLl;..,-g. oyf ,*-pf F#* A ,i.;i L u,.lg-,sl4.ir ;: uy-..{r\,srt* ,r"K4.t;1 Jr" rb.,1 .sr; e,.; [!119,- -r*{l*;;-q(d,1t'-l r-l r-1;.1.\ 6eVr-r:./1 aJtJ/-" A$*y1.:o,u}) 6-OHDAJr" rt-,1 )1 4 )y ;l ,tlySxll ;lrf y* .u; are- u3t:y.*1 jy ! .,-L ,:,0_.r ot*,., ,y*.>.-(hc,,\c ,sF>\.1 b-,f., l;-11 a"^o ,r .c-.sL- a"lrl atr A -r" 4 ,F .i )y 4. rtf {. t 4.>.F Url:S;'i9sti9;.rkrr.,I I uioy"y,l.srb xj ,-y.;y L-i or;,UiJl .Jq-;p 6-)y. ) o:14;l [,r5'>9 J,-r+ i*- .-,,-LL- ,Ljr.)r,,,r,1 ;L.51t,:..;r 11 olti;1 !,i.tl, .S[,,f,, L-rr)N 9 tL. rtl")i I al ,,_ri,, Jr-;PSD-) postsynaptic density protein 95 .r-*lf- S\b *::rt d-.."f j:t ,r"ty. r-oo'or.; b-.-->,slb 6*9x 9 D1 ;-19: ,srS eb-,#+^A :.Jr-" r ti!.,;l a*.1 ,,)Neuroligin gNeurexinl ,(9Jc-_:. ,.y-l y o9V' ..*f )f ,S\)j >ty J\. ,-t*,1 ,yy L-i f y\.pl {o1,,) Caspase-3 9 COX-:in vivo L->* )r.r'I+" L(t.o ,_ll,*;b" 4 lo-y orr ui i:..- -J9,--o CAl a,-L 1r (LTp) r:,-r, ;\'-.fi ,snSl:.,.6-OHDA t-e; o-r; ,61 .;St.5b;19,U d),*d e*\ AlySXli y* al:lr;L; 3_'-'r :to +:!!_,.-,1-.,? o\: Sss rrlL ;r '*.lfl ,*;yy,l A-i ol; 'l-oJl ,sk*i.'t .:lr.;' ";-o15 d.ct 4t S;* 0,. :-t.* ,u.l.r or[ .:; ;\, ,tl.)i 1l .r*-JL'l-( or; ,;+15 9 .4ij 4l*. e y )l y* et 9 J.:l;' L; ,r) ci-.-;L 1: atllo 9,s;r\.,co aS sr* 4,$ 6-OHDA t-9, o:r.i,1ll LstL; Fly €t *\ rtly6..:.-.rt ,;-l;l .r, hl+ , r,-+ irj .;Lh c.El+J'1; ,r,-LLtilL d.r;L; dl.4ol 9 &!p. )9.e J4.)r" --gNeurexinl ,PSD-95 Lr-"U 6\-a 6";9y, Ct- r: (P<0.001)11>** r,.:bll o-r;-o$V r)#y e--..r*"L,f) S\eyy.",_F ..r_1 2, ogVc .ty *_.fl.9ri :,Ulr,-' :""S*r g piU.;-l o+'U l) r: neurolic:of ,;t r'> -u fy[Fl ,: Caspase-3 t COX-2 d1{4i'9, Ct- 1; 1l: ,r;* u4.l;!l e.rt 6-OHDA t*;,srS eb- 1: rl":. * o91;'Ll -r*;>r, r9r,1., l, "u r-l: J#r ol*; ,-y.l ;lySxli tisi-\l;y .r.f;*.* oZfl ,sjly.*t#l C,_b d"Ll ,.-r; o.u_": ri_L;i )tt, Slptf i ri\.i-\r> Dl ,r:-"-.,-,ss\ssL 9 '1-oJ1 1.:.-tutt e-! Ll c;ls .,,-"q- "ir./" J.kJ I {"!,.e-"f- Jhl,r s}b ,-<*\l) cj[-,,--+.:.:1; J)&1 ,uSf o;li "-\ &-l .x ogVo .r-,19r crQl.:,ry tp.t * 1l al rlr .rLi e.L: :rg2S a;)u u,.|r-- rsQ,ir,,, rr!.1-l +iib rr )y-,y,i s t,\Jl d1{.i1- ra.lrsl 9 .,-,l4- sla r-y.::ly" e-ait.i. r:,J-"1+ 's\h ,:;9X *- i rp',,r:;L;.r[,,r,, 1.) J),L;l c-^cL;;-7-.o,).,j cl J#.-ti1*ll_,y y* I ;1; ;Li 6_,-1i 69*." .)t- ,_,- ;; LTP ,g;\?s\ 9 ,liiJl 1> ._i^K I Z*S:-;CL- 1; or; .:b,1 oVV;1 ;l -ulr; .r, .g;L-; -r-' l; ,s)y-"y.\$ i a\Jl t; ,rlf q d?p \ ,rrly\S.-:I ir" ,.5! .5"- Aly* + sl.r .r t tS sF* *J*" 9 f iV-"\ .lll .,r .,,-"tp .gto ;:.-;..q1 :L' + gy-$;\.s,,L* jl -;U *rtlt; t ;S:. o)')'>..1 .. \/\1...1 ...1r,,, p - .: -^^>r r,r,>Li.i i:Y)4;l ,Olils y,li ,.r-,q- .<f"t Jft ,uyr$ ,\,.r,,t * :iJ.rS ,3Ll r,, ,.UAbstractBackground and Objectives: According to prevalence of Parkinson's disease, as one of themost common neurodegenerative disease and the fact that treatment options for the disease sofar have been insufficient and not convincing. Since these patients also suffer from movementdisorders and cognitive impairment, so find ways to improve treatment of both disorders seemnecessary. Research has shown that the main cause of these disorders is abnormality insynaptic levels in the striatum and hippocampus that occur in these patients. Neuroprotectiverole of neurosteroids mentioned in a number of studies, but there is not any directly onsynaptic disorders caused by Parkinson's disease.Whether these hormones have effect onmotor and cognitive disorders associated with Parkinson's disease or will be able to stopsynaptic alterations? The aim of this study was to evaluate the effect of allopregnanolone(A1lo: the metabolite of progesterone) on synaptic plasticity in the rat model of Parkinson'sdisease.Methods: In this study were used of male Wistar that they have been divided into five groups:control, sham, lesion, lesion group treated with Allo5 mg/kg and lesion group treated withAllo20 mg/kg. To simulate PD, rats received 8 pg 6-OHDA (dissolved in 3 pl of 0.9o/o NaCl,supplemented with 0.02% ascorbic acid) in the right substantia nigra pars compacta (SNc) bystereotaxic surgery. Allo (5 and 20 mglkg, orally) was administered on the day after the 6-OHDA injection and continued every other day for 8 weeks. Motor behaviors and motor-skillleaming were assessed by the apomorphine induced rotation, accelerating rotarod, beam-balance (BB), beam-walk (BW) and bar test and cognitive behaviors were assessed by theNovel object recognition (NOR), the object recognition tasks and Morris water maze. Thelevels of striatal postsynaptic density protein 95 (PSD-95), neurexinl and neuroligin weredetermined in the regions of the striatum and hippocampus and the levels of dopaminereceptor D1 as well as COX-2 and Caspas-3 proteins were determined in the striatum byimmunoblotting. Furthermore, hippocampal long-term potentiation (LTP) was assessed usingin vivo field potential recordings.Results: The data indicated that A11o significantly improved the 6-OHDA-induced motorimpairment which revealed by decrease in number of apomorphine-induced rotation, increasein the ability to remain on a rotating rod and the increase in balancing and crossing on beamand also with decrease in degree of catalepsy in bar test. ln addition, Allo significantlyimproved the 6-OHDA-induced cognitive impairment which revealed by the reduction ofleaming and memory impairment in MWM test and with increase in the exploration index inNOR and object location tasks. Furthermore, PSD-95, neurexinl and neuroligin levels weresignificantly decreased (P<0.001) in the striatum and hippocampus of 6-O}IDA-lesionedanimals, while the levels of COX-2 and caspase-3 were increased (P<0.001) in the striatum of6-OHDA-treated animals. The mentioned molecular changes were attenuated by Allotreatment. There was no significant in the level of dopamine receptor Dl in the experimentalgroups. Although, dopamine denervation does not alter basal synaptic transmission and pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials but the induction andmaintenance of long-term potentiation (LTP) were impaired in the CAl and Alloadministration overcame the 6-OHDA-induced impairment in LTP generation in thehippocampus.Conclusion: The results showed that the loss of dopamine neurones leads to motor disabilitiesand disruptions in the protein level of synapses and increased levels of inflammation andapoptosis marks in the striatum in the rat model of Parkinson's. It also leads to cognitivedefects, changes in syraptic protein levels in the hippocampus and reduction in the inductionand maintenance of LTP. Our results demonstrated that A11o, due to its anti-inflammatory andanti-apoptotic properties, improves the mentioned deficiencies and preserves pre- and post-synaptic proteins in striatum and hippocampus area. So it may be an effective factor to protectmotor and cognitive disabilities wich are symptom of parkinson's disease'Key words: Parkinson's disease, synaptic plasticity, allopregnanolone, cognitive impairment,motor disability

مطالعه اثر آلوپرگنانولون بر شکل پذیری سیناپسی نواحی استریاتوم و هیپوکمپ در مدل تجربی بیماری پارکینسون موشهای صحرایی : مطالعه رفتاری ، مولکولی و الکتروفیزیولوژی

مطالعه اثر آلوپرگنانولون بر شکل پذیری سیناپسی نواحی استریاتوم و هیپوکمپ در مدل تجربی بیماری پارکینسون موشهای صحرایی : مطالعه رفتاری ، مولکولی و الکتروفیزیولوژی

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