Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6

Now we just need someone competent that can create a protocol to deliver suppression of TRPC6 channel degradation. But with NO STROKE LEADERSHIP, nothing will occur. You, your children and grandchildren are fucking screwed.  

Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6

Lu Liu¹, Lijuan Gu², Manli Chen¹, Yueying Zheng¹, Xiaoxing Xiong^1,2* and Shengmei Zhu^1*

• ¹Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
• ²Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China

Stroke remains a leading cause of death, disability, and medical care burden worldwide. However, transformation from laboratory findings toward effective pharmacological interventions for clinical stroke has been unsatisfactory. Novel evidence has been gained on the underlying mechanisms and therapeutic potential related to the transient receptor potential (TRP) channels in several disorders. The TRP superfamily consists of a diverse group of Ca²⁺ permeable non-selective cation channels. In particular, the members of TRP subfamilies, TRP canonical (TRPC) channels and TRPC6, have been found in different cell types in the whole body and have high levels of expression in the central nervous system (CNS). Notably, the TRPCs and TRPC6 channel have been implicated in neurite outgrowth and neuronal survival during normal development and in a range of CNS pathological conditions. Recent studies have shown that suppression of TRPC6 channel degradation prevents ischemic neuronal cell death in experimental stroke. Accumulating evidence supports the important functions of TRPC6 in brain ischemia. We have highlighted some crucial advancement that points toward an important involvement of TRPCs and TRPC6 in ischemic stroke. This review will make an overview of the TRP and TRPC channels due to their roles as targets for clinical trials and CNS disorders. Besides, the primary goal is to discuss and update the critical role of TRPC6 channels in stroke and provide a promising target for stroke prevention and therapy.

Introduction

Ischemic stroke is induced by the obstruction of an artery or multiple arteries leading to the brain. Focal impairment or occlusion of blood circulation to the brain impairs the normal function of neurons. The mechanisms underlying ischemic stroke are complex, and include excitotoxicity, oxidative and nitrosative stress, Ca²⁺ overload, inflammation, and apoptosis (Szydlowska and Tymianski, 2010; Khoshnam et al., 2017). Among these mechanisms, intracellular Ca²⁺ overload remains a vital role in neuronal injury associated with ischemic stroke (Choi, 1995). Glutamate receptors, such as N-methyl-D-aspartate receptor (NMDAR), are thought to be major pathways for intracellular Ca²⁺ influx in the central nervous system (CNS) after cerebral ischemia-reperfusion (IR) injury. Excessive NMDARs activation and the following Ca²⁺ influx through NMDARs are crucial steps required for initiating ischemic cell death (Szydlowska and Tymianski, 2010; Lai et al., 2011). To date, pre-clinical studies have provided substantial evidences for the neuroprotective effect of NMDAR antagonists in experimental ischemic stroke (Ginsberg, 2008). However, for several decades, clinical trials of NMDAR antagonists have all ended up with failure to show beneficial effects due to their narrow therapeutic windows and adverse effects (Wu and Tymianski, 2018). Thus, effective therapeutic interventions for ischemic stroke are urgently required.

Despite the pivotal functions of NMDARs, non-glutamate mechanisms have drawn attention as promising Ca²⁺ influx pathways involved in brain ischemia. In this respect, researchers shifted focus toward the transient receptor potential (TRP) channels (Szydlowska and Tymianski, 2010). TRPs are non-selective cationic channels which have key functions in different disorders (Moran, 2018). The TRP canonical (TRPC) subfamily was proved to be extensively distributed in CNS and have important functions in neuronal development (Tai et al., 2009). Understanding of these channels may drive the researchers to make a significant breakthrough in CNS diseases therapy. Recently, growing evidence indicates that TRPC6 channel has been involved in Ca²⁺ homeostasis and shown to participate in the molecular pathophysiology of ischemic stroke. TRPC6 was reported to have an critical role in neuroprotection in both in vitro and in vivo models of ischemic stroke (Du et al., 2010). In this review, we present a general description of the current understanding of TRPs and TRPC subfamily, with an emphasis on their involvement in clinical trials and CNS dysfunctions. Furthermore, this review concentrates on evidence-based advancements of TRPC6 in CNS disorders and cerebral ischemia. The primary aim is to clarify the relationship between TRPC6 and ischemic stroke and discuss future perspectives.

More at link.