T817MA protects against inflammation and pyroptosis in response to brain ischemia via activating Sirt1 signaling

Ischemic stroke remains a leading cause of death and disability worldwide, yet effective neuroprotective therapies are lacking. Neuroinflammation and pyroptosis, a lytic and inflammatory form of programmed cell death, exacerbate secondary brain injury post-ischemia. This study investigated the neuroprotective effects of T817MA, a neurotrophic agent, in a rat model of transient middle cerebral artery occlusion (MCAO), focusing on its anti-pyroptotic mechanisms via Sirtuin1 (Sirt1) signaling. Animals were pretreated orally with T817MA at 30 mg/kg for 20 days, and brain edema was evaluated by brain water content. Neurological dysfunction was determined by modified neurological severity score (mNSS) and rotating pole test, and neuroinflammatory markers were assayed by immunostaining. Pyroptosis and potential molecular mechanisms were detected by measuring related proteins using western blot. T817MA treated rats exhibited reduced brain edema, improved neurological recovery, and attenuated motor-coordination deficits post-MCAO. T817MA suppressed neuroinflammation, evidenced by decreased activation of microglia (ionized calcium binding adapter molecule 1, Iba-1) and astrocytes (glial fibrillary acidic protein, GFAP). Mechanistically, T817MA inhibited caspase-1 cleavage, IL-1β release, and Gasdermin D (GSDMD)-mediated pyroptosis in neurons. Notably, T817MA prolonged Sirt1 activation up to 48 h post-ischemia, while Sirt1 inhibition with sirtinol reversed its protective effects on brain edema, caspase-1 activation, and IL-1β levels. These findings demonstrate that T817MA mitigates ischemic brain injury by suppressing neuroinflammation and pyroptosis through Sirt1-dependent pathways, highlighting its potential as a therapeutic candidate for ischemic stroke.

• Publication year

  2025

• Venue

  Scientific Reports

• Publication date

  2025-09-29

• Fields of study

  Medicine

• Identifiers
  DOI 10.1038/s41598-025-18871-5PMID 41023247PMCID 12480052
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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