2. Academic Validation
  3. Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy

Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy

  • EMBO Mol Med. 2024 Jan;16(1):185-217. doi: 10.1038/s44321-023-00014-w.
Surendra K Prajapat 1,  Laxmi Mishra 1,  Sakshi Khera 1,  Shadrack D Owusu 1 2,  Kriti Ahuja 3,  Puja Sharma 1,  Eira Choudhary 1,  Simran Chhabra 1,  Niraj Kumar 4,  Rajan Singh 5 6,  Prem S Kaushal 4,  Dinesh Mahajan 7,  Arup Banerjee 1,  Rajender K Motiani 3,  Sudhanshu Vrati 1,  Manjula Kalia 8
Affiliations

Affiliations

  • 1 Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 2 Institut de Biologie Moléculaire et Cellulaire (IBMC), Université de Strasbourg, 67000, Strasbourg, France.
  • 3 Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 4 Structural Biology & Translation Regulation Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 5 Advanced Technology Platform Centre, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 6 Department of Life Sciences, Shiv Nadar University, Greater Noida, 201314, India.
  • 7 Chemistry and Pharmacology Lab, Centre for Drug Design and Discovery, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 8 Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India. manjula@rcb.res.in.
PMID: 38177535 DOI: 10.1038/s44321-023-00014-w
Abstract

Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce Autophagy for Antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent Autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked Autophagy and Antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent Antiviral effect by inhibiting JEV replication complexes. Drug-induced Autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined Antiviral and anti-inflammatory effect in JEV Infection, and has therapeutic potential for JE treatment.

Keywords

Antipsychotic; Microglia; Neuroinflammation; Phenothiazines; Trifluoperazine.

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