Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran.
Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Neurosci Biobehav Rev. 2022 Oct;141:104860. doi: 10.1016/j.neubiorev.2022.104860. Epub 2022 Sep 7.
Transient receptor potential (TRP) channels are highly expressed in cells of the cerebellum including in the dendrites and somas of Purkinje cells (PCs). Their endogenous activation promotes influx of Ca and Na, resulting in depolarization. TRP channels can be activated by endogenous endocannabinoids (eCBs) and activity of TRP channels has been shown to modulate GABA and glutamate transmission. Ataxia is caused by disruption of multiple intracellular pathways which often involve changes in Ca homeostasis that can result in neural cellular dysfunction and cell death. Based on available literature, alteration of transmission of eCBs would be expected to change activity of cerebellar TRP channels. Antagonists of the endocannabinoid system (ECS) including enzymes which break eCBs down have been shown to result in reductions in postsynaptic excitatory activity mediated by TRPC channels. Further, TRPC channel antagonists could modulate both pre and postsynaptically-mediated glutamatergic and GABAergic transmission, resulting in reductions in cell death due to excitotoxicity and dysfunctions caused by abnormal inhibitory signaling. Accordingly, TRP channels, and in particular the TRPC channel, represent a potential therapeutic target for management of ataxia.
瞬时受体电位 (TRP) 通道在小脑细胞中高度表达，包括浦肯野细胞 (PC) 的树突和胞体。它们的内源性激活促进 Ca 和 Na 的流入，导致去极化。TRP 通道可被内源性大麻素 (eCBs) 激活，并且已经证明 TRP 通道的活性可以调节 GABA 和谷氨酸的传递。共济失调是由多种细胞内途径的破坏引起的，这些途径通常涉及 Ca 稳态的变化，可能导致神经细胞功能障碍和细胞死亡。基于现有文献，预计 eCBs 的传递改变将改变小脑 TRP 通道的活性。已经表明，内源性大麻素系统 (ECS) 的拮抗剂，包括分解 eCBs 的酶，可导致由 TRPC 通道介导的突触后兴奋性活性降低。此外，TRPC 通道拮抗剂可以调节谷氨酸能和 GABA 能传递的突触前和突触后，从而减少由于兴奋性毒性和异常抑制信号引起的细胞死亡和功能障碍。因此，TRP 通道，特别是 TRPC 通道，代表了治疗共济失调的潜在治疗靶点。
