Advances in molecular mechanisms and therapeutic strategies for central nervous system diseases based on gut microbiota imbalance.

BACKGROUD: Central nervous system (CNS) diseases pose a serious threat to human health, but the regulatory mechanisms and therapeutic strategies of CNS diseases need to be further explored. It has been demonstrated that the gut microbiota (GM) is closely related to CNS disease. GM structure disorders, abnormal microbial metabolites, intestinal barrier destruction and elevated inflammation exist in patients with CNS diseases and promote the development of CNS diseases. More importantly, GM remodeling alleviates CNS pathology to some extent. AIM OF REVIEW: Here, we have summarized the regulatory mechanism of the GM in CNS diseases and the potential treatment strategies for CNS repair based on GM regulation, aiming to provide safer and more effective strategies for CNS repair from the perspective of GM regulation. KEY SCIENTIFIC CONCEPTS OF REVIEW: The abundance and composition of GM is closely associated with the CNS diseases. On the basis of in-depth analysis of GM changes in mice with CNS disease, as well as the changes in its metabolites, therapeutic strategies, such as probiotics, prebiotics, and FMT, may be used to regulate GM balance and affect its microbial metabolites, thereby promoting the recovery of CNS diseases.

Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat.

Spinal cord injury (SCI) is a devastating neurological disorder that often results in loss of motor and sensory function. Diabetes facilitates the blood-spinal cord barrier (BSCB) destruction and aggravates SCI recovery. However, the molecular mechanism underlying it is still unclear. Our study has focused on transient receptor potential melastatin 2 (TRPM2) channel and investigated its regulatory role on integrity and function of BSCB in diabetes combined with SCI rat. We have confirmed that diabetes is obviously not conductive to SCI recovery through accelerates BSCB destruction. Endothelial cells (ECs) are the important component of BSCB. It was observed that diabetes significantly worsens mitochondrial dysfunction and triggers excessive apoptosis of ECs in spinal cord from SCI rat. Moreover, diabetes impeded neovascularization in spinal cord from SCI rat with decreases of VEGF and ANG1. TRPM2 acts as a cellular sensor of ROS. Our mechanistic studies showed that diabetes significantly induces elevated ROS level to activate TRPM2 ion channel of ECs. Then, TRPM2 channel mediated the Ca2+ influx and subsequently activated p-CaMKII/eNOS pathway, and which in turn triggered the ROS production. Consequently, over-activation of TRPM2 ion channel results in excessive apoptosis and weaker angiogenesis during SCI recovery. Inhibition of TRPM2 with 2-Aminoethyl diphenylborinate (2-APB) or TRPM2 siRNA will ameliorate the apoptosis of ECs and promote angiogenesis, subsequently enhance BSCB integrity and improve the locomotor function recovery of diabetes combined with SCI rat. In conclusion, TRPM2 channel may be a key target for the treatment of diabetes combined with SCI rat.