Abstract
Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia.
Highlights
Due to increased life expectancies, neurodegenerative diseases (NDD), such as Alzheimer’s disease (AD), dementia, and cerebrovascular diseases, are considered by WHO the main cause of disability in the coming decades
The present review summarizes current knowledge on the role of TRPC6 channels in the development of two neurological disorders: Alzheimer’s disease and cerebral ischemia
Cerebral ischemia serves as a risk factor for AD, and vice versa
Summary
Due to increased life expectancies, neurodegenerative diseases (NDD), such as Alzheimer’s disease (AD), dementia, and cerebrovascular diseases, are considered by WHO the main cause of disability in the coming decades. The pathophysiological mechanisms causing AD and cerebral ischemia may differ, cerebral ischemia serves as a risk factor for AD development [4], and vice versa [5,6], indicating that a common intracellular mechanism may be disrupted in these two distinct pathologies Such a common mechanism may be associated with Ca2+ dyshomeostasis. Multiple factors might have contributed to the unsuccessful clinical trials, it is possible that the disruption of neuroprotective pathways, which precedes NMDA receptors hyperactivation, could be responsible for either AD and/or ischemic brain damage. One of such neuroprotective pathways is the transient receptor potential cation channel, subfamily C, member 6 (TRPC6)-dependent regulation of excitatory synapse formation. In order to keep the review focused, this Ca2+ -independent process observed in AD and brain ischemia pathogenesis is omitted
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