郭煒,李優(yōu)偉,常春然

北京市垂楊柳醫(yī)院放射科,北京 100022

郭煒#,李優(yōu)偉,常春然

北京市垂楊柳醫(yī)院放射科,北京 100022

癲;動(dòng)物模型;應(yīng)用;制備

#【通訊作者】郭煒,Tel:86-013681373183,E-mail:guow ei1205@126.com。

1 急性簡(jiǎn)單部分性癲模型

這類模型是一組急性皮質(zhì)損傷所致的驚厥放電。臨床上顱內(nèi)膿腫、腫瘤、血腫等可引發(fā)驚厥,然后發(fā)展為慢性隱匿性反復(fù)性發(fā)作。而動(dòng)物模型只出現(xiàn)單次驚厥,不發(fā)展為慢性驚厥。制備這類模型的方法較多,如給予大腦皮質(zhì)表面致驚劑青霉素、荷包牡丹堿,直接急性電刺激皮質(zhì)組織,減少或消除抑制性神經(jīng)遞質(zhì)γ-氨基丁酸(GABA),化學(xué)致驚劑誘發(fā)新皮質(zhì)腦片放電等。其中應(yīng)用最廣泛的是以青霉素涂于動(dòng)物大腦皮質(zhì)表面的方法。此模型適合研究驚厥活動(dòng)的播散和癲產(chǎn)生的神經(jīng)元基礎(chǔ)等問(wèn)題。研究表明低劑量的青霉素置于培養(yǎng)中的神經(jīng)元、麻醉動(dòng)物的大腦皮質(zhì)或海馬腦片中可選擇性阻斷GABA介導(dǎo)的抑制性突觸后電位(IPSPs),而高劑量的作用則缺乏特異性[1,2]。近年來(lái)被廣泛使用的毛果蕓香堿致大鼠模型,具有制作簡(jiǎn)便、性發(fā)作潛伏期短、致率高等特點(diǎn),其所產(chǎn)生的慢性癲模型具有與人類顳葉癲相似的行為、腦電與神經(jīng)病理改變,是研究急性癲的理想模型。最近,Sanjiay等[3]等對(duì)雄性的 SD大鼠注射毛果蕓香堿(380 mg/kg)誘發(fā)癲發(fā)作,在海馬的內(nèi)嗅皮質(zhì)也記錄到自發(fā)的性發(fā)作波。Peng等[4]對(duì)由毛果蕓香堿誘導(dǎo)的大鼠癲模型的研究發(fā)現(xiàn),海馬齒狀回GABAA受體δ亞單位表達(dá)的增強(qiáng)可引起神經(jīng)元興奮性的提高及GABAA受體表達(dá)的減少。而 Yogendrasinh等[5]發(fā)現(xiàn)齒狀回GABAA受體α1亞單位表達(dá)水平的增加可以抑制癲發(fā)作的頻率。Wei等[6]研究發(fā)現(xiàn)齒狀回藍(lán)狀細(xì)胞的減少可以有效促發(fā)異常環(huán)路的形成。Sun等[7]用電刺激的方法,將一組雙極電極植入大鼠的海馬,給予一定的電流量(400m s)和刺激頻率(50H z),經(jīng)過(guò)4～6周的刺激,在動(dòng)物的邊緣葉可以檢測(cè)到自發(fā)的性放電。癲患者的齒狀回顆粒細(xì)胞中突觸神經(jīng)類固醇受體減少,δ亞單位受體表達(dá)增加,兩者共同調(diào)節(jié)突觸傳遞功能,兩者調(diào)節(jié)的失常,必然導(dǎo)致神經(jīng)元傳導(dǎo)功能的紊亂,進(jìn)而誘發(fā)癲。

急性模型的缺點(diǎn)是:①每種藥物有各自選擇的特異性,此特性與癲產(chǎn)生的關(guān)系甚少,如青霉素酶可拮抗青霉素所致的癲,但不能拮抗其它類型的癲產(chǎn)生;②急性模型的建立是依靠強(qiáng)烈的刺激,病灶中許多細(xì)胞參與癲活動(dòng),其參與程度大大超過(guò)人類病灶的實(shí)際神經(jīng)元數(shù)量;③急性模型僅持續(xù)數(shù)分鐘到數(shù)小時(shí),而不導(dǎo)致反復(fù)性驚厥,并且模型無(wú)臨床患者組織常見(jiàn)的神經(jīng)元、樹突、膠質(zhì)細(xì)胞和局部神經(jīng)環(huán)路形態(tài)學(xué)的病理改變,代表性不足;④建立此模型時(shí),動(dòng)物需要麻醉,而麻醉可能對(duì)實(shí)驗(yàn)造成一定的影響。

2 慢性簡(jiǎn)單部分性癲模型

此類模型的建立方法包括:在貓或猴的腦皮質(zhì)注入二價(jià)金屬離子(氫氧化鎂、鈷、鋅、鎢等)、冷凍損傷、注射神經(jīng)節(jié)苷脂抗體、靜脈給予致驚劑等,其中最有效的和實(shí)際的癲模型是在腦內(nèi)注入二價(jià)金屬離子產(chǎn)生“自發(fā)性”放電狀態(tài)的簡(jiǎn)單部分性驚厥。此類癲模型的發(fā)作行為、發(fā)作間和發(fā)作后腦電圖、病理改變及抗藥物效果均近似人類簡(jiǎn)單部分性癲,如:鎂離子損傷可誘發(fā)對(duì)側(cè)的面部或肢體末端抽搐,偶爾也發(fā)展成為全身性強(qiáng)直-陣攣性驚厥,發(fā)作期與間歇期的腦電圖特征與臨床患者類似,神經(jīng)病理顯示膠質(zhì)細(xì)胞增生、神經(jīng)樹突扭曲[8]。該模型的優(yōu)點(diǎn)是適于研究從腦病理?yè)p傷,癲產(chǎn)生,直至發(fā)展全過(guò)程中的機(jī)制。

3 復(fù)雜部分性癲模型

4 全身性強(qiáng)直-陣攣性驚厥模型

這類模型包括遺傳性全身性驚厥動(dòng)物模型、最大電休克模型、化學(xué)藥物致驚模型。目前應(yīng)用較多的是遺傳性動(dòng)物,但迄今尚未發(fā)現(xiàn)與人類的全身強(qiáng)直-陣攣性癲近似的動(dòng)物模型。從各種遺傳突變種系中所選動(dòng)物,其誘發(fā)癲發(fā)作所用的刺激,以及它們伴有的非驚厥性異常均與人類不同。理想的對(duì)25次/秒間歇閃光刺激敏感的狒狒癲模型,因價(jià)格昂貴難于管理而不實(shí)用。目前多用遺傳性癲易感小鼠及大鼠模型,并已有專門的實(shí)驗(yàn)室進(jìn)行同種近親繁殖的種系(如美國(guó) Jackson實(shí)驗(yàn)室)。Noebels等[18,19]近年已證實(shí)在1種伴自發(fā)驚厥及5種對(duì)感官刺激驚厥易感的小鼠系中,每種均由單基因位點(diǎn)突變引起,如聽源性驚厥(12～16 Hz鈴聲誘發(fā))易感的 DBA/2J(audiogenicseizures,AGS)、Totterer小鼠系等。DBA/2J的易感性在出生后2～4周最高,按發(fā)作行為不同評(píng)分,腦電圖因奔跑跳躍不易記錄,近年通過(guò)廣泛神經(jīng)生化研究發(fā)現(xiàn)可能缺少鈣依賴的ATP酶。Totterer(tg/tg)小鼠表現(xiàn)出癲及腦電圖異常并同時(shí)有遺傳性共濟(jì)失調(diào),已證實(shí)其海馬及藍(lán)斑等區(qū)NA的濃度及神經(jīng)末梢數(shù)量增多。在大鼠中,遺傳性癲 易感大鼠(geneti-cally epilepsy-prone rat,GEPR)對(duì)聽源性刺激、高溫、電、化學(xué)及點(diǎn)燃等刺激誘發(fā)的癲均易感,較小鼠更適宜于電生理研究?，F(xiàn)今國(guó)際常用的GEPR是從SD大鼠中分離出的,分為高度易感的GEPR-9及中度易感的GEPR-3,均以出生后2～4周易感性最高。遺傳性動(dòng)物模型較人工致癲更符合自然性,并有助于探討驚厥活動(dòng)的產(chǎn)生及傳播通路及各腦區(qū)神經(jīng)遞質(zhì)、調(diào)質(zhì)的變化情況。

5 全身失神性癲模型

6 體外培養(yǎng)的腦組織、腦片或細(xì)胞癲模型

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R741;R742.1

A

1001-117X(2010)03-0213-04

10.3870/sjsscj.2010.03.011

2009-09-30