ArticleCNS neuroscience & therapeutics2026
Restricting Synaptotagmin-3 Internalization Mitigates Cerebral Ischemia/Reperfusion Injury by Curtailed Neuronal Apoptosis and Microglial Re-Programming.
Article in CNS neuroscience & therapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
aimsIschemic stroke is a major global cause of disability and death. Synaptotagmin-3 (Syt3), a synaptic calcium sensor, exacerbates ischemic injury by promoting pathological glutamate release. This study investigated the potential neuroprotective effect of restriction of Syt3 internalization on neuronal apoptosis and microglial reprogramming following ischemia/reperfusion (I/R).
methodsThe effects of Tat-GluA2-3Y (3Y), a cell-permeable peptide inhibitor of Syt3 internalization, were studied in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 and BV2 cells.
resultsThe peptide 3Y treatment significantly reduced infarct volume, brain edema, and improved neurological deficits. Additionally, it reduced neuronal apoptosis and also inhibited neuroinflammation by down-regulating the level of IL-1b, TNF-a, and iNOS but up-regulating the level of TGF-b1 and Arg-1. Single-nucleus RNA sequencing of the peri-infarct region revealed a dual mechanism: 3Y suppressed pro-apoptotic gene programs in neurons and facilitated the transformation between different phenotypes of microglia via the cAMP pathway from a pro-inflammatory to an anti-inflammatory and immune-protective state. In vitro, 3Y attenuated oxygen-glucose deprivation-induced neuronal death and instructed microglia to adopt a protective, TGF-β1-secreting phenotype.
conclusionsCollectively, our findings establish the inhibition of Syt3 internalization as a novel therapeutic strategy that concurrently protects neurons and reprograms the microglial immune response, offering a promising dual-mechanism approach for acute stroke therapy.
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