Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases

Abstract

Central nervous system (CNS) inflammation is a potential therapeutic target for neurodegenerative diseases. In recent years, a number of studies have focused on the links between neurodegenerative diseases and CNS glial cells, especially microglia. Microglia are the main resident immune cells in the CNS and represent approximately 10-15% of all CNS cells. Microglia play an important role in maintaining brain homeostasis at rest by surveying the environment, and engulfing apoptotic cells and debris in the healthy brain. However, under certain pathological conditions, microglia can generate neurotoxic factors, such as pro-inflammatory cytokines and molecules like nitric oxide (NO), which lead to CNS inflammatory diseases. In this review, we discuss the evidence that regulation of microglial ion channels may modulate CNS inflammation and subsequent tissue damage in neurological disorders. In particular, we discuss the role of transient receptor potential (TRP) channels in microglia in both acute and chronic inflammatory conditions, and describe the physiological and pathophysiological roles of TRP channels in CNS inflammatory pathways. Additionally, we describe the benefits of stimulation/inhibition of TRP channels in animal models of microglia-related CNS inflammatory diseases.

Development of a Potential Therapeutic Small Volume Resuscitative Fluid against Hemorrhagic Shock in Rat Model

“…Neurotoxicity of NO overproduction in the brain has also been shown by several studies [16][17][18]. NO may play an important role in secondary neuronal damage after ischemia [19].…”

TRP Channels Role in Pain Associated With Neurodegenerative Diseases

“…The increase [Ca 2+ ]i then induces mitochondrial dysfunction that leads to caspase activation, ROS and RNS production, microglia activation, and production of pro-inflammatory mediators (yellow arrows). cell death (Kim et al, 2006) and NADPH-oxidase-mediated production of ROS in microglia (Shirakawa and Kaneko, 2018), suggesting that a similar mechanism could operate in death of DNs in PD. For instance, TRPV1 antagonists such as capsazepine and iodo-resiniferatoxin inhibit DNs death in vivo and in vitro (Kim et al, 2005).…”

“…It has been demonstrated that LPC increases phosphorylation of p38 MAPK in microglia, which was eliminated in TRPM2-KO. From these results, it is feasible to propose TRPM2 channels as potential therapeutic targets to inhibit excessive microglial activation, neuroinflammation, and, therefore, pain through modulation of p38 MAPK phosphorylation (Miyake et al, 2014;Jeong et al, 2017;Shirakawa and Kaneko, 2018).…”

“… Kim et al (2005) showed that capsaicin, a TRPV1 agonist, elicits cell death of mesencephalic DNs. Additionally, it has been reported that TRPV1 activation triggers Ca 2+ -dependent cell death ( Kim et al, 2006 ) and NADPH-oxidase-mediated production of ROS in microglia ( Shirakawa and Kaneko, 2018 ), suggesting that a similar mechanism could operate in death of DNs in PD. For instance, TRPV1 antagonists such as capsazepine and iodo-resiniferatoxin inhibit DNs death in vivo and in vitro ( Kim et al, 2005 ).…”

“…It has been recently shown that cannabinoids provide promising multitarget approach for the treatment of pain and neurodegeneration since they regulate the activity of TRP channels, which are considered non-cannonical endocannabionoid receptors. In this vein, it has been shown that cannabidiol, cannabinol, cannabigerol, or cannabidiolic acid binds TRPs, including TRPV1–4, TRPA1, and TRPM8 ( Shirakawa and Kaneko, 2018 ; Muller et al, 2019 ; Starkus et al, 2019 ).…”