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

Abstract

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 Ca 2+ 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.

Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia

“…Ca 2+ overload is one of the main molecular mechanisms involved in ischemic cell damage and death [56]. TRPC6, along with a few other prominent members of the family, has recently gained considerable attention as a promising target for the prevention of Ca 2+ overload [23]. Dysregulation of TRPC6 activity has been implicated in ischemic stroke [23,57], as well as retinal ischemia [58], and renal hypoxia following cerebral ischemia [59].…”

“…Recent studies have shown that TRPC6-mediated signaling promotes neuronal survival [60], the brain-derived neurotrophic factor-mediated axonal growth cone guidance [61], dendritic outgrowth and branching [17], and excitatory synapse formation [13]. In addition, positive modulation of TRPC6 activity allows for the sustained activation of the CREB/CaMK-IV and Ras/MEK/ERK pathways, which is vital for neuronal development, survival, and proper functioning [23]. Blocking CREB signaling hinders post-stroke recovery [62], and CaMK-IV inhibition impairs blood-brain barrier integrity and exacerbates ischemic injury [63].…”

“…To date, two strategies have been proposed for the pharmacological modulation of TRPC6 activity for the treatment of Alzheimer's disease and cerebral ischemia: (1) TRPC6 activation to allow Ca 2+ influx via neuronal SOCE and sustain the stability of postsynaptic contacts (for AD) and to attenuate NMDAR activity and prevent calcium-dependent excitotoxicity [15,16] (for ischemia); (2) inhibition of TRPC6 in order to prevent calcium overload and the subsequent cell damage [23,64] (for AD and ischemia). Although apparently mutually exclusive, both of these strategies are aimed to keep the intracellular Ca 2+ concentration within the normal range, which requires limiting its entry via transmembrane channels and/or release from intracellular stores [75].…”

“…Given the pivotal role of NMDAR in excitotoxic neuronal damage, NMDAR blockers have been proposed as potential neuroprotective agents, although most of them have failed to show substantial effectiveness in human patients so far [76]. Due to that fact, TRPC6 has emerged as an alternative therapeutic target for AD and ischemic stroke [23].…”

“…Current prevalent evidence suggests that the TRPC6 channel function is downregulated in AD and cerebral ischemia [14,[21][22][23]. However, there are reports in the literature that observe TRPC6 overactivation in AD [24] and cerebral ischemia models [25,26].…”