論文 - 詳細
| RRC ID | 82592 |
|---|---|
| 著者 | Prajapat SK, Mishra L, Khera S, Owusu SD, Ahuja K, Sharma P, Choudhary E, Chhabra S, Kumar N, Singh R, Kaushal PS, Mahajan D, Banerjee A, Motiani RK, Vrati S, Kalia M. |
| タイトル | Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy. |
| ジャーナル | EMBO Mol Med |
| 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. |
| 巻・号 | 16(1) |
| ページ | 185-217 |
| 公開日 | 2024-1-1 |
| DOI | 10.1038/s44321-023-00014-w |
| PII | 10.1038/s44321-023-00014-w |
| PMID | 38177535 |
| PMC | PMC10897192 |
| MeSH | Animals Anti-Inflammatory Agents / therapeutic use Antiviral Agents / pharmacology Antiviral Agents / therapeutic use Autophagy Encephalitis Virus, Japanese* / physiology Encephalitis, Japanese* / drug therapy Encephalitis, Japanese* / pathology Methotrimeprazine / pharmacology Methotrimeprazine / therapeutic use Mice Neuroinflammatory Diseases |
| IF | 8.821 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711) |