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Advanced Neurology TRPM2 in neurological disorders

TRPM2 mice may not be solely attributed to TRPM2. The 2-VO-induced global ischemia in terms of reduced
-/-
mechanisms underlining the neuroprotection in TRPM2 - hippocampal cornu ammonis 1 (CA1) pyramidal neuronal
/- mice are mediated by increased phosphorylation of ERK death and memory impairment compared with wild-
1/2 and AKT and by the inhibition of glycogen synthase type controls . Neuroprotection in TRPM2 mice is
-/-
[86]
kinase 3 (GSK3)-β by Akt. associated with the absence of a delayed, ROS-induced,
2+
In addition to promoting neuronal death, TRPM2 has TRPM2-dependent accumulation of cytosolic Zn , which
[86]
also been implicated to act in peripheral immune cells promotes CA1 neuronal death . This is consistent with
and glial cells post-stroke. Using bone marrow chimeric a more recent study showing that modulation of TRPM2
[87]
mice, Gelderblom et al. demonstrated a contribution of prevents 2-VO-induced cell death .
TRPM2 to immune cell invasion after tMCAO . They Last, genetic ablation and inhibition of TRPM2 with
[77]
found that besides reduced infarction and improved tatM2NX both prevent hippocampal CA1 cell death in
cognitive outcome, TRPM2 -/- mice exhibited reduced mice after CA/CPR-induced global ischemic stroke . The
[88]
invasion of peripheral neutrophils and macrophages effect was again only observed in males, which is consistent
to the injury site and reduced inflammation . Similar with the previous studies [88,89] . Surprisingly, TRPM2
[77]
effects were observed using the TRPM2 inhibitor, N-(p- inhibition with tatM2NX at delayed time points post-stroke
amylcinnamoyl)anthranilic acid. In microglia, TRPM2 reversed synaptic plasticity and hippocampal-dependent
activation has been suggested to induce inducible nitric memory impairments in males and females 1 week after
oxide synthase post-stroke, and the time course of TRPM2 CA/CPR . Electrophysiology confirmed that delayed
[88]
mRNA upregulation in the cortex is consistent with the inhibition of TRPM2 reverses the ischemia-induced
temporal profile of microglial activation after tMCAO. long-term potentiation deficits in the hippocampus.
This indicates a potential contribution of TRPM2 to post- Using a pharmacological approach, TRPM2 was shown
ischemic inflammation [74,78-80] . to mediate synaptic impairment through calcineurin-
[88]
A sex-dependent role of TRPM2 has been reported GSK3-β signaling following CA/CPR . These findings
in ischemic stroke . Jia et al. first demonstrated that the demonstrate that the TRPM2 channel mediates cell death
[81]
TRPM2 inhibitor, clotrimazole, was effective in reducing in neurons, glia, and immune cells in models of both focal
infarction volume after tMCAO only in male mice . ischemic-reperfusion injury and global ischemia.
[20]
Accordingly, in vivo shRNA-targeted TRPM2 knockdown 3.4. TBI
reduced neuronal survival in male mice, indicating
that TRPM2 activation contributes to ischemic injury TBI represents the primary cause of mortality and
selectively in males . Similar findings were described neurological morbidity globally in individuals under the
[20]
[90]
by Shimizu et al. using aged animals with a more specific age of 45 . The estimated incidence of TBI is over 69
TRPM2 inhibitor, tatM2NX . This male-specific TRPM2 million per year worldwide and the most common reasons
[82]
activation is potentially caused by androgen signaling, for TBI include road traffic accidents, falls, and sports-
[91]
which can promote the activation of poly (ADP-ribose) related concussions . TBI is characterized by a primary
polymerase 1 (PARP1) and the formation of ADPR, which injury and manifests immediately after the mechanical
directly activates TRPM2. A 5-fold increase in ADPR insult, followed by a delayed long-lasting secondary injury.
activity and increased PARP1 activity were observed in TBI-induced brain damage has been associated with
male mice after tMCAO compared with either female excitotoxicity, oxidative stress, BBB dysfunction, edema,
[90]
mice or castrated male mice, while PARP knockout inflammation, hematoma, and diffuse axonal injury .
male mice exhibited reduced infarction . In contrast, Animal models recapitulate different aspects of TBI.
[83]
both ovariectomized and PARP1 female mice show Controlled cortical impact is commonly used to study
-/-
exacerbated ischemic injury after tMCAO compared with focal injury. In the controlled cortical impact model, a
intact female mice [84,85] . However, female mice treated craniotomy is performed and TBI is typically delivered
directly with the androgen dihydrotestosterone do not through a piston onto the exposed dura with a user-
show activation of PARP and no increase in the level of specified time, speed, and depth of the impact . In the
[92]
ADPR, indicating that circulating androgen alone is fluid percussion injury model, a pressure pulse generated
insufficient to promote TRPM2 activation and mediate from a fluid percussion device is delivered onto the
TRPM2-mediated ischemic injury in females . exposed dura . Fluid percussion injury, either lateral or
[85]
[92]
A similar detrimental role of TRPM2 has been midline, produces a mixed injury with combined focal
[93]
proposed in the global ischemia models, 2-VO and CA/ cortical contusion and a diffused subcortical injury .
CPR. Specifically, TRPM2 mice were protected from In the weight drop injury model, injury is induced by a
-/-
Volume 1 Issue 1 (2022) 7 https://doi.org/10.36922/an.v1i1.3