2. Academic Validation
  3. TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome

TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome

  • Neurobiol Dis. 2021 Dec;160:105534. doi: 10.1016/j.nbd.2021.105534.
Yu Shao 1,  Chen Chen 2,  Tao Zhu 3,  Zengxian Sun 4,  Shufen Li 4,  Lifen Gong 2,  Xinyan Dong 2,  Weida Shen 5,  Linghui Zeng 5,  Yicheng Xie 6,  Peifang Jiang 7
Affiliations

Affiliations

  • 1 Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China; Department of Pediatrics, Wenling First People's Hospital, Wenling 317500, China.
  • 2 Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China.
  • 3 Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.
  • 4 Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China; Department of Pediatrics, Lishui Central Hospital, Lishui 323000, China.
  • 5 Department of Pharmacy, Zhejiang University City College School of Medicine, Hangzhou 310015, China.
  • 6 Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China. Electronic address: [email protected].
  • 7 Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, China. Electronic address: [email protected].
PMID: 34673151 DOI: 10.1016/j.nbd.2021.105534
Abstract

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is characterized by demyelination, axonal injury and neurological deterioration. Few medications are available for progressive MS, which is associated with neuroinflammation confined to the CNS compartment. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in a wide range of neuroinflammatory diseases; however, the underlying molecular mechanisms of TRPM2 remain elusive. Here, we established a cuprizone model that presents hallmark MS pathologies to investigate the role of TRPM2 in progressive MS. We demonstrated that genetic deletion of TRPM2 yields protection from the cuprizone-induced demyelination, synapse loss, microglial activation, NLRP3 inflammasome activation and proinflammatory cytokines production and ultimately leads to an improvement in cognitive decline. Furthermore, we showed that the pharmacological inhibition of NLRP3 ameliorated the demyelination, neuroinflammation and cognitive impairment in the model with no additive effects on the TRPM2 KO mice. Taken together, these results indicated that TRPM2 plays important roles in regulating neuroinflammation in progressive MS via NLRP3 inflammasome, and the results shed LIGHT on TRPM2's potential role as a therapeutic target for MS.

Keywords

Cognitive dysfunction; Multiple sclerosis; NLRP3 inflammasome; Neuroinflammation; TRPM2 channel.

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