生物體內因代謝反應、紫外線或放射線照射等現象所產生的自由基 (free radicals) 或 巴金森氏症 (Parkinson's disease) 是一種慢性神經病變的疾病，其主
要是因為腦部多巴胺神經細胞退化，導致大腦基底核細胞失去平衡性的調 節控制。臨床上有證據顯示巴金森氏症病患除運動障礙外，常合併其他自 主神經機能障礙以及憂鬱等症狀出現，並且發現病患血液中促腎上腺皮質 激素 (ACTH) 及腎上腺皮質素 (cortisol) 的濃度偏低，此意味著下視丘─
腦下垂體─腎上腺神經荷爾蒙迴路受持久性的影響。在動物實驗有證據說 明利用 NMDA (N-methyl-D-aspartate) 受體拮抗劑可以阻斷由 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 所產生之巴金森氏
症候群 (parkinsonism) 的運動障礙。這些皆顯示促腎上腺皮質釋放激素 ( CRF) 及 NMDA 受體之神經傳導系統在巴金森氏症的病理機轉中扮演某種程度 的角色。本研究是利用連續 7 天腹腔注射 MPTP (25mg/kg) 的 C57BL/6J 小黑 鼠來建立一個巴金森氏症候群的動物模式，分別在停止注射後之第一天、
第三天、第七天、第十四天及第三十天抽血及犧牲取腦後分兩部份實驗進 行。第一部份實驗是測定血液中 ACTH 是否有顯著的變化，用以間接反映出 下視丘 CRF 之分泌狀態。結果發現小黑鼠在接受 MPTP 注射後之第一天、第 三天及第三十天，其血清中 ACTH 的濃度有顯著降低 (32% 、 47% 及 43%) ，而 只注射一次劑量的小黑鼠其血清中 ACTH 的濃度在注射後之第一天、第三天
、第七天及第十四天並無顯著變化，顯示慢性 MPTP 中毒的小黑鼠，可能發 生下視丘與腦下腺體功能之異常。第二部份實驗，則是利用試管內接受體 結合實驗 (receptor ligand binding assay) 、受體結合自動放射顯影實
驗 (slide autoradiography) 及原位雜交實驗 (in situ hybridization) 來
觀察大腦各部位中 NMDA 接受體數目變化與其基因轉錄的調控情形。結果發 現在大腦皮質、紋狀體及中腦的 NMDA 受體數目有短暫且顯著的減少，杏仁 核的 NMDA 受體數目則呈現較長時期的減少，但在海馬迴並無變化，顯示長 期給與 MPTP 可以調控腦部 NMDA 接受體之表現。而上述改變可能都是巴金森 氏症致病機轉之一部份。
長期給予 MPTP 對小黑鼠血液中促腎上腺皮質素
(ACTH) 濃度及腦部 NMDA 受體 表現的影響
Parkinson's disease is a chronic neurodegenerative disorder, the most prominent morphological feature of which is progressive loss of dopaminergic nigrostriatal neurons. Recent
investigations have implicated an important role of
corticotrophin releasing factor(CRF) and N-methyl-D-aspartate (NMDA) receptor in dopaminergic neurotoxicity of Parkinson disease. Reduced ACTH(adrenocorticotrophic hormone), cortisol in blood have been found in human subjects and reduced CRF in hypothalamus, paraventricular nucleus has been shown in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animal model of parkinsonism. NMDA receptor antagonists significantly attenuated the toxic effect of MPTP. Therefore, we investigated : 1) whether the reduced CRF will stimulate the hypothalamic-pituitary-adrenal axis, manifested by reducing in serum (ACTH) level; 2) whether chronic application of MPTP will alter the expression of the NMDA receptor, manifested by
alteration in the ligand binding to this receptor. We used C57 BL/6J black mice treated with 25 mg/kg MPTP for seven
consecutive days as a model of Parkinsonism. Blood were drawn by cardiac puncture and animal were sacrificed on the 1st, 3th,
7th, 14th and 30th day. ACTH concentration in plasma was
determined by radioimmunoassay and the density of NMDA receptor in the brain was determined by [3H]TCP binding assay, slide autoradiography and quantification of NMDA receptor mRNA by in situ hybridization. The results indicated that ACTH were
significantly reduced at 1 days, 3 days and 30 days after MPTP treatment. The number of [3H]TCP binding site in cortex, striatum and midbrain were transient reduced after MPTP treatment.; in amygdala, [3H]TCP binding site were long-time reduced after MPTP treatment; and in hippocampus, [3H]TCP binding site were no significantly change. These results
suggested a functional change in the hypothalamic-pituitary axis and an alteration of the expression of NMDA receptor in brain,
which might contribute to the mechanism of Parkinson's disease.
The effect of MPTP on the plasma
concentration of ACTH and the expression of brain NMDA receptor in C57BL/6J mice.
