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High glutamate accumulation and subsequent excitotoxicity after ischemia and hypoxia are important pathogenetic mechanisms of brain injury after ischemic stroke. Glutamate transporter 1 (GLT-1) on astrocyte membranes is responsible for 90% of glutamate clearance. The involvement of the mTOR\/Akt pathway in the upregulation of GLT-1 expression in astrocytes under oxygen-glucose deprivation and reoxygenation conditions has been demonstrated. Nevertheless, it is still unclear whether there is a negative feedback pathway from mTOR to Akt during cerebral ischemia\/reperfusion (I\/R). It has also not been elucidated whether the mTOR\/Akt pathway is involved in the expression of astrocyte GLT-1 in cerebral I\/R injury. In this study, we established a middle cerebral artery occlusion-reperfusion rat model to investigate the interactions and mechanisms of the mTOR\/Akt cascade with GLT-1 under cerebral I\/R conditions. These results provide evidence that brain I\/R injury activates the mTOR\/Akt pathway in the ischemic penumbra, increases astrocyte activation, and downregulates the expression of GLT-1. Inhibition of the mTOR pathway reversed GLT-1 downregulation and inhibited astrocyte activation by blocking the mTOR pathway, thereby attenuating neurological dysfunction, inflammatory response, and apoptosis caused by brain I\/R injury. In contrast, inhibiting the Akt pathway did not provide neuroprotection, with no significant decrease in the number of astrocytes, inflammatory response, or apoptosis in the model group. Additionally, the inhibition downregulated GLT-1 expression and promoted the lengthening and thickening of astrocyte processes in cerebral ischemic rats. Thus, the mTOR\/Akt cascade may be involved in regulating astrocyte growth and GLT-1 expression during brain I\/R injury. Furthermore, inhibiting the mTOR pathway may mitigate apoptosis and the release of inflammatory factors, thereby fostering neuronal survival and safeguarding the central nervous system.<\/jats:p>","DOI":"10.1371\/journal.pone.0351107","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:24:37Z","timestamp":1781285077000},"page":"e0351107","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["The mTOR\/Akt pathway is involved in regulating astrocyte growth and GLT-1 expression during cerebral 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