| 摘要: | 憂鬱症是一種常見的精神疾病。在我們先前的研究發現，給予大鼠NMDA受體致效劑(D-serine和Sarcosine)，具有類似抗憂鬱之效果。Sodium benzoate是一種右旋胺基酸氧化酵素抑制劑，能減少NMDA受體致效劑 (D-alanine和D-serine)的代謝。Sodium benzoate亦有增強NMDA受體功能的特性。此外，早期在Sodium benzoate相關的研究都集中於精神分裂症患者之治療。截至目前，Sodium benzoate在精神疾病之動物實驗方面的研究仍是有限。為了進一步瞭解NMDA和AMPA受體在憂鬱情形下調控神經傳導過程的病理機轉，我們使用不同劑量之Sodium benzoate，觀察大鼠在強制游泳測試(憂鬱症動物行為模式)、高腳十字迷宮實驗(動物焦慮行為模式)以及前脈衝抑制行為(精神分裂症動物行為模式)進行研究。除了動物行為模式外，我們也以免疫分析方式探討大鼠在海馬迴內NMDA、AMPA受器變化及下游因子一氧化氮合成酶、P-mTOR與P-PTEN相關的病理機制。
在我們的實驗結果發現，施予Sodium benzoate可減少大鼠游泳靜止不動的時間，以及改善K他命誘導的PPI功能缺失。而在高腳十字迷宮試驗與正常老鼠組相較之下，並無焦慮行為(偽陽性之行為)產生。這意味著Sodium Benzoate可能具有改善憂鬱症以及改善精神分裂症之症狀。在免疫分析結果亦顯示海馬迴NMDA受體、AMPA受體與P-mTOR蛋白含量，於零小時犧牲後，相較於正常老鼠組有明顯增加，P-PTEN蛋白表現相較於正常老鼠組則有明顯減少。然而，在nNOS與eNOS蛋白含量相較於正常老鼠組並無顯著差異。期望經由研究的結果能有助於了解憂鬱環境下AMPA受體和NMDA受體活化的病理機轉，並且提供一種具潛能的新穎療法，未來可透過AMPA受體活化和影響NMDA受體以迅速改善憂鬱症及精神分裂症之症狀。
Major depression is a common disorder. In our previous studies, we found NMDA-enhancing agents, D-serine and sarcosine, exert antidepressant-like effect in rats. Sodium benzoate is an inhibitor of D-amino acid oxidase (DAO), which metabolizes the co-agonist of NMDA receptor, D-alanine or D-serine. Indirectly, sodium benzoate also has the property of NMDA enhancement. Nevertheless, until now, the investigation for the effects of sodium benzoate on rat models of psychiatric disorders is lack. We conducted this study to investigate the effect of sodium benzoate at different doses in forced swimming test (FST, behavioral model of depression), elevated plus-maze tests (EPM, behavioral model of anxiety) and prepulse inhibition test (PPI, behavioral model of schizophrenia) to evaluate the potential action of sodium benzoate in psychiatric disorders. Additionally, we also conduct the biochemical analysis to explore the alteration of NMDA, AMPA receptor, nitric oxide synthase, P-mTOR and P-PTEN in the hippocampus that is related to the pathogenesis of psychiatric disorders.
Our results showed that sodium benzoate could reduce the duration of immobility in FST and reverse ketamine-induced deficit in PPI significantly. But, no significant difference is noted in EPM when comparing with that control group. It implies that sodium benzoate may have therapeutic efficacy for depression and schizophrenia. Additionally, the biochemical results showed that the levels of NMDA receptor, AMPA receptor and P-mTOR proteins were increased and the levels of P-PTEN proteins were decreased of the sodium benzoate treated in the hippocampus of rats when comparing with those control group. But no significant change was noted for the levels of nNOS and eNOS proteins. Hence, we hope that results of this study may conducive to better understanding the mechanism of NMDA and AMPA receptor in the pathogenesis of depression and schizophrenia, and offered the possibilities of potential therapeutic use of NMDA agonists for improvement of the efficacy of depression and schizophrenia. |
