Ceftriaxone對MPTP所誘發巴金森氏症失智大鼠模型之行為與神經新生的效果

Ceftriaxone Reverses Deficits of Behavior and Neurogenesis in MPTP-induced Rat Model of Parkinson’s Disease Dementia

蒙宛筠(Wan-Yun Meng)

指導教授 ： 何應瑞

中山醫學大學/醫學科技學院/心理學系暨臨床心理學碩士班/碩士(2017年)

摘要

帕金森氏症（Parkinson's disease, PD）是一種高盛行率的神經退化性疾病，病人不只會出現運動障礙，還會出現失智症，又稱做帕金森氏症失智（Parkinson's disease dementia, PDD）。Ceftriaxone（CEF）是一種beta-lactam類的抗生素，藉由增加glutamate轉運子（glutamate transporter 1, GLT-1）以促進回收突觸間隙過多的glutamate達到神經保護效果。本篇研究實驗一，探討CEF治療是否可以恢復1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）誘發之PD大鼠模型的行為和認知功能缺陷；實驗二，探討CEF是否會影響MPTP誘發之PD大鼠模型的神經新生功能。
本研究使用雄性Wistar大鼠為實驗動物。所有大鼠皆接受立體定位手術，在雙側黑質體緻密區注入MPTP，以誘發PD的大鼠模型。實驗一，在MPTP誘發手術後當天開始給予大鼠進行CEF (5 mg/kg/day, i.p.)治療15天。MPTP誘發手術後第0~7天使用橫桿測驗評估大鼠的動作缺損，手術後第8~10天使用T型迷宮測驗評估大鼠的工作記憶能力，手術後第12~14天使用物件辨識測驗評估大鼠的辨識能力。研究結果顯示：PD大鼠有工作記憶和辨識能力的缺損，經CEF治療後可以恢復其能力。實驗二，在MPTP誘發手術後當天開始進行CEF（5或100 mg/kg/day, i.p.）治療15天，而後進行犧牲取下腦組織，以測量大鼠的海馬回齒狀回和黑質體緻密區與網狀區內被溴脫氧尿苷(bromodeoxyuridine, BrdU)標定的新生之細胞數量。研究發現PD大鼠在海馬回齒狀回和黑質體網狀區內新生的神經數量比假手術組的大鼠少，經過CEF（100 mg/kg）治療的PD大鼠其海馬回齒狀回和黑質體緻密區與網狀區內新生的神經數量顯著的增加。這些結果顯示，PD會干擾神經新生及認知功能，CEF治療可以增加PD大鼠的神經新生且恢復認知功能缺損。因此，CEF可能具有治療帕金森氏症失智的潛力。

關鍵字

帕金森氏症 ； 失智症 ； 頭孢曲松 ； 神經新生 ； 神經保護 ； 溴脫氧尿苷

並列摘要

Parkinson’s disease (PD) is a neurodegenerative disease with high prevalence. Patients with PD have not only movement but also cognitive deficits, known as Parkinson’s disease dementia (PDD). Ceftriaxone (CEF), a beta-lactam antibiotic, has neuroprotective effect mediated by increasing the glutamate transporter 1 (GLT-1) expression and glutamate clearance in the synapse. The aims of the study were：(1) in the experiment 1：To investigate whether CEF treatment can reduce cognitive deficit in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model ; (2) in the experiment 2：To determine the effects of ceftriaxone on neurogenesis in the hippocampus and substantia nigra (SN) in the MPTP-induced PD rat model.
MPTP was stereotaxically injected into the SN pars compacta (SNc) to induce PD rat model in male Wistar rats. In the experiment 1, Starting on the day of MPTP lesioning (day 0), the rats were treated with CEF (5 mg/kg/day, i.p.) or saline for 15 days and underwent a bar test on days 0-7, a T-maze test on days 8–10, and an object recognition test on days 12–14. MPTP-lesioned rats showed impairment of working memory in the T-maze test and deficit of recognitive function in the object recognition test. Treatment of CEF decreased the above MPTP-induced cognitive deficits. In the experiment 2, Starting on the day of MPTP lesioning (day 0), the rats were treated with CEF (5 or 100 mg/kg/day, i.p.) or saline for 15 days, then the brain was taken for histological evaluation. Newborn cells in the dentate gyrus of hippocampus and in the SNc and SN reticulata (SNr) were labeled by bromodeoxyuridine immunohistochemistry (BrdU).The results showed that MPTP lesioning reduced neurogenesis in the dentate gyrus of hippocampus and in the SNr. Treatment of CEF, at the dosage of 100 mg/kg/day, increased the number of newborn cells in the dentate gyrus of hippocampus and in the SNc and SNr. In conclusion, these data suggest that CEF improves neurogenesis and reduces cognitive impairment in the PD rats. CEF may therefore has clinical potential for the treatment of PDD.

並列關鍵字

parkinson’s disease ； dementia ； ceftriaxone ； neurogenesis ； neuroprotection ； bromodeoxyuridine

參考文獻

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