Mao Yu, Xing Yao, Li Jie, Dong Dong, Zhang Shoude, Zhao Zhenjiang, Xie Jingli, Wang Rui, Li Honglin
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology Shanghai 200237, China.
State Key Laboratory of Plateau Ecology and Agriculture, Department of Pharmacy, Medical College of Qinghai University, Qinghai University Qinghai 810016, China.
Am J Transl Res. 2021 May 15;13(5):4040-4054. eCollection 2021.
Schizophrenia is a serious mental disorder characterized by hallucinations, delusions, and extremely disordered thinking and behavior. There are several hypotheses of pathogenesis in schizophrenia: dopaminergic, glutamatergic, or serotonergic hyperfunction. Guanosine reportedly protects the central nervous system by modulating the glutamatergic system. Thus, we assumed that guanosine may exert a positive effect on the pathophysiology of schizophrenia. Herein, we demonstrated that guanosine significantly reduced MK-801-induced hyperlocomotion and stereotyped behaviors, but showed no effect on hyperlocomotion induced by d-amphetamine, indicating that guanosine may directly affect the glutamatergic system. Guanosine dose-dependently reduced 5-HTP-induced wet dog shakes (WDS) and other serotonin syndromes (SS) behaviors, indicating that it might block serotonin 5-HT or 5-HT receptors. Finally, we confirm that that guanosine modulates serotonin 5-HT and 5-HT receptors and it might be anti-schizophrenic partly through pertussis toxin-sensitive G-coupled PI3K/Akt signaling. Collectively, this study provides possible compounds and mechanisms for therapeutic effects on schizophrenia.
精神分裂症是一种严重的精神障碍，其特征为幻觉、妄想以及极度紊乱的思维和行为。精神分裂症的发病机制有多种假说：多巴胺能、谷氨酸能或血清素能功能亢进。据报道，鸟苷通过调节谷氨酸能系统来保护中枢神经系统。因此，我们推测鸟苷可能对精神分裂症的病理生理学产生积极影响。在此，我们证明鸟苷能显著降低MK - 801诱导的运动亢进和刻板行为，但对d - 苯丙胺诱导的运动亢进没有影响，这表明鸟苷可能直接影响谷氨酸能系统。鸟苷剂量依赖性地减少5 - 羟色氨酸诱导的湿狗摇晃（WDS）和其他血清素综合征（SS）行为，表明它可能阻断血清素5 - HT或5 - HT受体。最后，我们证实鸟苷调节血清素5 - HT和5 - HT受体，并且它可能部分通过百日咳毒素敏感的G偶联PI3K/Akt信号传导发挥抗精神分裂症作用。总的来说，这项研究为精神分裂症的治疗效果提供了可能的化合物和机制。
