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Advanced Neurology TRPM2 in neurological disorders

and cognitive memory impairment present in wild-type Global ischemia models are characterized by reduced
mice relative to their younger (2 – 3 and 12 – 16 months blood supply to most regions or the entire brain. The
old) counterparts. These functional improvements 2-vessel occlusion (2-VO) model is one of the easiest
corresponded to reduced white matter and hippocampal methods to induce global ischemia in rodents [71,72] and
damage and reduced levels of microglia/macrophages and involves the transient occlusion of the bilateral common
pro-inflammatory cytokines relative to TRPM2 mice . carotid artery (typically 5 – 15 min) to reduce global blood
+/+
[63]
TRPM2 is present in multiple cell lines; therefore, supply. Due to the simplicity of the surgical procedure,
Aβ-generated ROS may act on several cell types, including it has been increasingly used as an alternative to the
microglia, neurons, and endothelia, in neurovascular 4-VO model developed earlier. Global ischemia can also
dysfunction . Therapeutic targeting of TRPM2 may thus be induced using the cardiac arrest/cardiopulmonary
[64]
alter multiple pathways involved in AD progression and resuscitation (CA/CPR) model, which is specifically
overcome limitations of current strategies targeting only a used to study transient ischemic brain injury following a
[71]
single pathway. sudden cardiac arrest . In the CA/CPR model, CA is first
induced by potassium chloride injection. After typically
3.3. Ischemic stroke 8 – 10 min of CA, CPR is provided to the animals to
[73]
Stroke is the second leading cause of death globally restore circulation . This model induces clear injury in
according to the World Health Organization. Ischemic regions such as the hippocampi that are more sensitive or
stroke, often caused by obstructed blood supply to the vulnerable to ischemic insult.
brain, accounts for approximately 87% of all strokes . TRPM2 has been increasingly studied in experimental
[65]
Due to the complex nature of ischemic stroke, various in models of ischemic stroke. TRPM2 plays a detrimental
vivo experimental models have been developed in the past role and contributes to cell death after ischemic stroke,
few decades to mimic the clinical pathology of human whereas inhibition or genetic ablation of TRPM2 is
strokes. These models are critical for understanding generally protective. In focal ischemia models, Trpm2
pathophysiological processes involved in ischemic stroke mRNA levels were significantly increased in a time-
and to develop or test therapeutic strategies. dependent manner after tMCAO in the rat cortex . This
[74]
Animal models of ischemic stroke are generally classified upregulation was observed at 24 h, peaked at 7 d (3 – 4-fold
as focal or global ischemia. One of the most widely used focal increase), and remained increased at 4 weeks post-stroke.
-/-
stroke models is the intraluminal middle cerebral artery Consistent with this finding, TRPM2 mice show an
occlusion (MCAO) model, where a suture is first introduced approximately 40% reduction in infarction volume at 48 h
[75]
into either the common carotid artery or external carotid after tMCAO when compared with wild-type controls .
artery and advanced further into the MCA to interrupt blood A similar effect was observed in mice treated with the
[76]
supply [66,67] . This model mimics the majority of ischemic TRPM2 inhibitor, duloxetine, after tMCAO . However,
strokes in humans and generates highly reproducible there were no differences in infarct volumes between
-/-
infarction in the MCA territory. Intraluminal MCAO models wild-type and TRPM2 mice when they were subjected
can be used to model either permanent or transient ischemic to pMCAO, indicating that the absence of TRPM2 is
strokes. In the transient MCAO (tMCAO) model, the suture neuroprotective against ischemic stroke only when
[75]
is withdrawn after typically 60 – 120 min to allow reperfusion. followed by reperfusion . One explanation is that the
In contrast, reperfusion is absent in the permanent MCAO injury induced by pMCAO is so severe that genetic ablation
(pMCAO) model. Embolic stroke models are another of TRPM2 alone is not sufficient to rescue damaged tissue.
commonly used experimental model of stroke, where an Another possible explanation is that TRPM2 is involved in
autologous blood clot or thrombin is injected into the internal reperfusion, where there is an increased production of ROS
carotid artery or MCA . The embolic model is typically used and subsequent activation of TRPM2 by H O ; therefore,
[68]
2
2
-/-
to study novel thrombolytic agents or the combined therapy TRPM2 mice might be protected more from H O -
2
2
of neuroprotective agents and tissue plasminogen activator, induced cell death during the period of reperfusion .
[75]
with micro- and nano-particles recently being investigated Interestingly, the same study also found that the
in thrombolytic research . Other focal ischemic stroke hippocampal expression of N-methyl-D-aspartate receptor
[69]
models include the photothrombotic model, which uses a subunits GluN2A and GluN2B was significantly altered
photosensitive dye followed by illumination of the targeted in neurons of TRPM2 mice. Specifically, after MCAO,
-/-
brain regions, and the vasoconstrictor endothelin-1 model. GluN2A expression was increased by ~43% while GluN2B
[75]
Although less commonly used, these models allow the expression was decreased by ~46% in TRPM2 mice .
-/-
induction of focal ischemia in virtually any brain region and As GluN2A is involved in cell survival and GluN2B is
are more suitable for modeling lacunar stroke [67,70] . involved in cell death, the neuroprotection observed in
Volume 1 Issue 1 (2022) 6 https://doi.org/10.36922/an.v1i1.3