Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson’s Disease: An Insight Into Role of Pharmacological Interventions

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the symptoms of motor deficits and cognitive decline. There are a number of therapeutics available for the treatment of PD, but most of them suffer from serious side effects such as bradykinesia, dyskinesia and on-off effect. Therefore, despite the availability of these pharmacological agents, PD patients continue to have an inferior quality of life. This has warranted a need to look for alternate strategies and molecular targets. Recent evidence suggests the Transient Receptor Potential (TRP) channels could be a potential target for the management of motor and non-motor symptoms of PD. Though still in the preclinical stages, agents targeting these channels have shown immense potential in the attenuation of behavioral deficits and signaling pathways. In addition, these channels are known to be involved in the regulation of ionic homeostasis, which is disrupted in PD. Moreover, activation or inhibition of many of the TRP channels by calcium and oxidative stress has also raised the possibility of their paramount involvement in affecting the other molecular mechanisms associated with PD pathology. However, due to the paucity of information available and lack of specificity, none of these agents have gone into clinical trials for PD treatment. Considering their interaction with oxidative stress, apoptosis and excitotoxicity, TRP channels could be considered as a potential future target for the treatment of PD.

Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model

“…Considering that the changes in the calcium homeostasis and oxidative stress are associated with the degeneration of dopaminergic neurons in substantia nigra, it has been suggested that TRP channels could mediate some of the mechanisms that lead to the development of the PD [ 53 ]. It has been reported that TRPV1 activation triggers Ca 2+ -dependent cell death [ 54 ] and NADPH-oxidase-mediated ROS production in microglia [ 55 ].…”

A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson’s disease

“…The TRPV1 agonist capsaicin was shown to prevent degeneration of dopaminergic neurons by inhibiting oxidative stress and neuroinflammation caused by activation of glia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD [ 14 ]. Capsaicin was also shown to restore rotarod performance, as well as dopaminergic signaling, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD [ 15 ]. It was further demonstrated that the neuroprotective effects of TRPV1 activation using capsaicin were mediated through endogenous ciliary neurotrophic factor and its receptors [ 12 ].…”

Kunitz-Type Peptides from Sea Anemones Protect Neuronal Cells against Parkinson’s Disease Inductors via Inhibition of ROS Production and ATP-Induced P2X7 Receptor Activation

“…Indeed, these peptides interacted with free radicals, which may be one of the reasons for the reduced ROS levels. On the other hand, it is known that ion channels such as Kv and TRP and cell receptors such as P2X7 are actively involved in the regulation of neuronal processes, including inflammation, and are considered potential therapeutic targets for PD [61][62][63]. Recently, we showed that Kunitz-type peptides, namely HCRG1 and HCRG2, which are blockers of Kv channels, maintained ROS production in 6-OHDA-treated cells at the reference level [50].…”