TRPM2 channel: A novel target for alleviating ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemic brain damage

Abstract

The transient receptor potential melastatin-related 2 (TRPM2) channel, a reactive oxygen species (ROS)-sensitive cation channel, has been well recognized for being an important and common mechanism that confers the susceptibility to ROS-induced cell death. An elevated level of ROS is a salient feature of ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxia-ischaemia. The TRPM2 channel is expressed in hippocampus, cortex and striatum, the brain regions that are critical for cognitive functions. In this review, we examine the recent studies that combine pharmacological and/or genetic interventions with using in vitro and in vivo models to demonstrate a crucial role of the TRPM2 channel in brain damage by ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemia. We also discuss the current understanding of the underlying TRPM2-dependent cellular and molecular mechanisms. These new findings lead to the hypothesis of targeting the TRPM2 channel as a potential novel therapeutic strategy to alleviate brain damage and cognitive dysfunction caused by these conditions.

Keywords: TRPM2 channel; brain damage; chronic cerebral hypo-perfusion; ischaemia-reperfusion; neonatal hypoxia-ischaemia; reactive oxygen species.

Figure 1

TRPM2‐dependent cellular mechanisms for brain damage. Elevated generation of reactive oxygen species (ROS) is a common feature of ischaemia‐reperfusion, chronic cerebral hypo‐fusion and neonatal hypoxia‐ischaemia. A, Activation of the TRPM2 channel in hippocampal neurons mediates delayed neuronal cell death, contributing to ischaemia‐reperfusion or ischaemic stroke brain damage. B‐C, Activation of the TRPM2 channel in microglia initiates microglial activation in chronic cerebral hypo‐fusion and neonatal ischaemia‐hypoxic brain damage. TRPM2‐mediated infiltration of peripheral immune cells and astrocyte activation also contribute to brain damage by ischaemia‐reperfusion and neonatal hypoxia‐ischaemia, respectively (not depicted). See text for more details

Figure 2

TRPM2‐dependent molecular mechanisms for delayed neuronal death. Two distinctive TRPM2‐mediated molecular mechanisms for delayed neuronal death leading to ischaemia‐reperfusion brain damage have been proposed. A, Elevated generation of reactive oxygen species (ROS) during ischaemia‐reperfusion and subsequent activation of the TRPM2 channel in hippocampal neurons induce down‐regulation of the GluNA2‐containing NMDAR‐mediated survival signalling pathway and up‐regulation of the GluNB2‐containing NMDAR‐mediated death‐promoting signalling pathways, resulting in neuronal death. B, Elevated ROS during reperfusion following transient ischaemia stimulates NADPH‐dependent oxidases (NOX)‐mediated ROS generation. ROS causes lysosomal loss and dysfunction and release of Zn²⁺, elevating the cytosolic Zn²⁺ level. ROS also induces activation of the TRPM2 channel in the mitochondria as well as on the cell surface via promoting ADPR generation catalysed by poly(ADPR) polymerase (PARP) and poly(ADPR) glycohydrolase (PARG) in the nucleus. Activation of the TRPM2 channel in the mitochondria increases mitochondrial uptake of Zn²⁺ that triggers mitochondrial loss and dysfunction and mitochondrial ROS generation. Therefore, activation of the TRPM2 channel sets in motion a positive feedback mechanism ultimately drives lysosomal and mitochondrial dysfunction and neuronal death