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Advanced Neurology TRPM2 in neurological disorders

similar, with ADPR acting on the NUDT9-H domain 2. Wang Q, Liu N, Ni YS, et al., 2021, TRPM2 in ischemic stroke:
of TRPM2 and initiating Ca influx into the cytosol . Structure, molecular mechanisms, and drug intervention.
2+
[10]
Furthermore, because TRPM2 is highly expressed in the Channels (Austin), 15(1): 136–154.
brain in multiple cell types, inhibition of TRPM2 has the https://doi.org/10.1080/19336950.2020.1870088
potential to modulate multiple pathways contributing to 3. Steinman J, Cahill LS, Koletar MM, et al., 2019, Acute
disease. An overview of the mechanisms by which TRPM2 and chronic stage adaptations of vascular architecture and
activation induces brain injury or disease is illustrated in cerebral blood flow in a mouse model of TBI. Neuroimage,
Figure 2. 202: 116101.
As noted, our own findings concerning neonatal hypoxic- https://doi.org/10.1016/j.neuroimage.2019.116101
ischemic injury demonstrate that TRPM2 inhibition reduces 4. Bolton AN, Saatman KE, 2014, Regional neurodegeneration
infarct volume and microglial activation [11,12] . Inhibitors of and gliosis are amplified by mild traumatic brain injury
TRPM2 exist, such as flufenamic acid, 2-APB, and clotrimazole; repeated at 24-hour intervals. J Neuropathol Exp Neurol,
however, they are not specific to TRPM2 [16,40] . For example, 73(10): 933–947.
2-APB activates TRPV1 – 3 in addition to TRPM2 [138,139] . https://doi.org/10.1097/NEN.0000000000000115
Specific TRPM2 inhibitors have been synthesized, as recently
demonstrated by Luo et al. who generated two ADPR 5. Braidy N, Muñoz P, Palacios AG, et al., 2012, Recent
analogues (7i and 8a) that specifically inhibit the TRPM2 rodent models for Alzheimer’s disease: Clinical
channel [138] . Zn recruits DRP1 to mitochondria and induces implications and basic research. J Neural Transm
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(Vienna), 119(2): 173–195.
mitochondrial fission and dysfunction [58,60,140] ; therefore, zinc
chelators are a possible option for preventing Ca -mediated https://doi.org/10.1007/s00702-011-0731-5
2+
Zn release by lysosomes [141] . Antioxidant therapy has also 6. Wang Y, Kilic E, Kilic U, et al., 2005, VEGF overexpression
2+
been proposed to treat neurodegenerative diseases such as induces post-ischaemic neuroprotection, but facilitates
AD [142] . Surprisingly, in Chinese hamster ovary cell cultures, haemodynamic steal phenomena. Brain, 128(Pt 1): 52–63.
antioxidants do not reduce TRPM2 cation current upon https://doi.org/10.1093/brain/awh325
exposure to H O , indicating that there are mechanisms in
2
2
addition to TRPM2 activation by which ROS effects cell 7. Lange I, Yamamoto S, Partida-Sanchez S, et al., 2009,
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function in neurodegenerative disorders [143] . TRPM2 functions as a lysosomal Ca -release channel in
beta cells. Sci Signal, 2(71): ra23.
Research on TRPM2 will continue to examine the https://doi.org/10.1126/scisignal.2000278
mechanisms discussed in this review and to develop
TRPM2-specific inhibitors that will lead to new treatments 8. Fleig A, Penner R, 2004, The TRPM ion channel subfamily:
for a variety of diseases. Molecular, biophysical and functional features. Trends
Pharmacol Sci, 25(12): 633–639.
Acknowledgments https://doi.org/10.1016/j.tips.2004.10.004
This work was supported by the Natural Sciences and 9. Belrose JC, Jackson MF, 2018, TRPM2: A candidate
Engineering Research Council of Canada (NSERC therapeutic target for treating neurological diseases. Acta
RGPIN-2016-04574) to H-S.S. and the Canadian Institutes Pharmacol Sin, 39(5): 722–732.
of Health Research (CIHR- PJT-153155) to Z-P.F. https://doi.org/10.1038/aps.2018.31

Conflict of interest 10. Ji D, Luo ZW, Ovcjak A, et al., 2021, Role of TRPM2 in brain
tumours and potential as a drug target. Acta Pharmacol Sin,
The authors have no competing interest to declare. online ahead of print.

Author contributions https://doi.org/10.1038/s41401-021-00679-4
11. Huang S, Turlova E, Li F, et al., 2017, Transient receptor
Conceptualization: Hong-Shuo Sun and Zhong-Ping Feng potential melastatin 2 channels (TRPM2) mediate neonatal
Writing – original draft: Joe Steinman, Andrea Ovcjak, and hypoxic-ischemic brain injury in mice. Exp Neurol, 296: 32–40.
Zhengwei Luo
Writing – review and editing: All authors https://doi.org/10.1016/j.expneurol.2017.06.023
12. Li F, Wong R, Luo Z, et al., 2019, Neuroprotective effects
References of AG490 in neonatal hypoxic-ischemic brain injury. Mol
Neurobiol, 56(12): 8109–8123.
1. Steinman J, Sun HS, Feng ZP, 2020, Microvascular alterations
in Alzheimer’s disease. Front Cell Neurosci, 14: 618986. https://doi.org/10.1007/s12035-019-01656-z
https://doi.org/10.3389/fncel.2020.618986 13. Allen Institute for Brain Science, 2004, Allen Mouse Brain

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