Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India.
Department of Pharmacy, Amritsar Group of Colleges, Punjab, India; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA.
Eur J Pharmacol. 2023 May 5;946:175648. doi: 10.1016/j.ejphar.2023.175648. Epub 2023 Mar 8.
Depression is the most common mental health disorder worldwide; however, the exact cellular and molecular mechanisms of this major depressive disorder are unclear so far. Experimental studies have demonstrated that depression is associated with significant cognitive impairment, dendrite spine loss, and reduction in connectivity among neurons that contribute to symptoms associated with mood disorders. Rho/Rho-associated coiled-coil containing protein kinase (ROCK) receptors are exclusively expressed in the brain and Rho/ROCK signaling has gained considerable attention as it plays a crucial role in the development of neuronal architecture and structural plasticity. Chronic stress-induced activation of the Rho/ROCK signaling pathway promotes neuronal apoptosis and loss of neural processes and synapses. Interestingly, accumulated evidence has identified Rho/ROCK signaling pathways as a putative target for treating neurological disorders. Furthermore, inhibition of the Rho/ROCK signaling pathway has proven to be effective in different models of depression, which signify the potential benefits of clinical Rho/ROCK inhibition. The ROCK inhibitors extensively modulate antidepressant-related pathways which significantly control the synthesis of proteins, and neuron survival and ultimately led to the enhancement of synaptogenesis, connectivity, and improvement in behavior. Therefore, the present review refines the prevailing contribution of this signaling pathway in depression and highlighted preclinical shreds of evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.
抑郁症是全球最常见的精神健康障碍；然而，到目前为止，这种重度抑郁症的确切细胞和分子机制还不清楚。实验研究表明，抑郁症与认知功能显著受损、树突棘丧失以及神经元之间的连接减少有关，这些都导致了与情绪障碍相关的症状。Rho/Rho 相关卷曲螺旋蛋白激酶（ROCK）受体仅在大脑中表达，Rho/ROCK 信号转导备受关注，因为它在神经元结构和结构可塑性的发展中起着至关重要的作用。慢性应激诱导的 Rho/ROCK 信号通路的激活促进神经元凋亡和神经过程及突触的丢失。有趣的是，越来越多的证据将 Rho/ROCK 信号通路确定为治疗神经紊乱的潜在靶点。此外，抑制 Rho/ROCK 信号通路已被证明在不同的抑郁症模型中是有效的，这表明 Rho/ROCK 抑制的临床应用具有潜在的益处。ROCK 抑制剂广泛调节与抗抑郁相关的通路，显著控制蛋白质的合成、神经元的存活，并最终导致突触发生、连接的增强以及行为的改善。因此，本综述阐述了该信号通路在抑郁症中的主要作用，并强调了 ROCK 抑制剂作为疾病修饰靶点的临床前研究证据以及应激相关抑郁症的潜在机制。
