Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke

Abstract

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates the cAMP (adenosine 3’,5’-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-D-aspartate (NMDA) receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells, such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood–brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.

Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

“…There are two types of strokes: ischemic and hemorrhagic. Ischemic stroke occurs more commonly (87% of stroke patients) due to an occlusion of blood vessels [30][31][32][33][34]. In humans, the middle cerebral artery is the most common location of occlusion caused by a buildup of plaque in the artery (thrombosis) or plaque that originates from other locations (embolism) [30].…”

“…Similarly, neuroprotectin D1 (NPD1), which can also be produced by neutrophils, elicits similar protective effects through transient receptor potential cation 6 (TRPC6) pathways when administered by i.v. in the rat MCAO model, leading to a reduction in infarct volume [31,109]. Since resolvins and protectins are generated through omega-3 fatty acid metabolism, dietary fatty-acid supplementation has been investigated for both stroke prevention and intervention but has generated inconsistent results in human clinical trials [110].…”

Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

“…Ischemic stroke is associated with high morbidity and mortality [ 1 , 2 , 3 ]. It also contributes to the social burden of disability that persists after strokes.…”

Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in Trap1-Deficient Drosophila melanogaster Is Abrogated by Metformin

“…Hypoxia is a key underlying condition of various devastating diseases including pulmonary hypertension, ischemic heart failure as well as global and focal cerebral ischemia [1][2][3]. Acute ischemic stroke is one of the main causes of death and disability in adults worldwide [3][4][5]. Here, occlusion of a cerebral artery results in a rapid deprivation of oxygen and nutrients leading to neuronal cell death [3,5].…”