Impact of TRPV1 on Pathogenesis and Therapy of Neurodegenerative Diseases

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a transmembrane and non-selective cation channel protein, which can be activated by various physical and chemical stimuli. Recent studies have shown the strong pathogenetic associations of TRPV1 with neurodegenerative diseases (NDs), in particular Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS) via regulating neuroinflammation. Therapeutic effects of TRPV1 agonists and antagonists on the treatment of AD and PD in animal models also are emerging. We here summarize the current understanding of TRPV1’s effects and its agonists and antagonists as a therapeutic means in neurodegenerative diseases, and highlight future treatment strategies using natural TRPV1 agonists. Developing new targets and applying natural products are becoming a promising direction in the treatment of chronic disorders, especially neurodegenerative diseases.

TRPV1 Channels in the Central Nervous System as Drug Targets

“…Beneficial effects of capsaicin have been reported in animal models of neurodegenerative diseases and stroke; see [ 46 , 47 ]. In transgenic mice with mutated amyloid precursor protein, a model of Alzheimer’s disease, capsaicin [ 48 ] and the selective TRPV1 agonist, vanillin [ 49 ], reversed the impairments of hippocampal LTP, spatial learning, and memory.…”

“…In animal models of Parkinson’s disease, capsaicin, acting via TRPV1 channels, reduced neurodegeneration and improved behavioural outcomes, reportedly by reducing oxidants and proinflammatory cytokine production by activated microglia [ 50 ]. However, TRPV1 antagonists have also been found to have neuroprotective effects in animal models of Parkinson’s disease (see [ 47 ]), indicating that further understanding of the importance of a balance of agonist, antagonist and desensitisation properties of TRPV1 channel modulators is required.…”

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“…Activation of TRPV1 can rescue microglial dysfunction, restore metabolic impairments, and enhance immune responses, thereby reducing amyloid pathology and memory deficits in AD models 82,83 . On the other hand, TRPA1 channels, predominantly expressed in astrocytes, are activated by Aβ and mediate Ca2+ influx, which in turn triggers the production of pro-inflammatory cytokines and activation of transcription factors such as NF-κB and NFAT.…”

“…The regulation of these channels by inflammatory mediators underscores their potential as therapeutic targets. Pharmacological modulation of TRP channels, such as using TRPV1 agonists, has shown promise in alleviating AD symptoms by reducing neuroinflammation and improving cellular functions 82,83 .…”