Neuroprotection (Chichester, England) · 2026
Post-recanalization administration of rapamycin improves functional outcome and reduces infarct size in a rat model of ischemic stroke.
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Schneider Anna M, Couch Yvonne, Larkin James, Buchan Alastair M, Beard Daniel J
Аннотация
AIM: Despite advances in endovascular recanalization for ischemic stroke, many patients experience poor outcomes. Adjunct cerebroprotective therapies are needed to improve recovery. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin has shown neuroprotective effects in preclinical stroke models. However, most studies administered rapamycin prior to or during stroke onset, limiting translational relevance. The aim of this study was to determine whether rapamycin administered immediately after recanalization improves infarct size and functional outcome, and whether these effects are associated with changes in cerebral blood flow (CBF) or blood-brain barrier (BBB) integrity.
METHODS: Male Wistar Han rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 90 min. Animals were randomized using the sealed envelope method to receive intravenous rapamycin (250 μg/kg, n = 9) or vehicle (n = 9) immediately after recanalization. Infarct volume, CBF, and BBB integrity were assessed using magnetic resonance imaging (MRI) at 72 h, alongside validated neurological tests. Group comparisons were performed using unpaired Student's t-tests.
RESULTS: Rapamycin significantly reduced infarct volume compared with vehicle (44.77 ± 30.93 mm³ vs. 113.44 ± 60.19 mm³, p = 0.0114) and improved Garcia neurological scores (12.78 ± 1.04 vs. 11.67 ± 0.87, p = 0.0295). In the adhesive removal test, rapamycin-treated animals showed shorter time to notice the stimulus (45.04 ± 11.91 s vs. 72.33 ± 12.17 s, p = 0.0002). Rapamycin had no significant effect on CBF, BBB disruption, or edema at 72 h (all p > 0.05). The p-mTOR/mTOR ratio did not differ significantly between groups at day 3 (0.55 ± 0.32 vs. 0.90 ± 0.41, p = 0.1880).
DISCUSSION: Rapamycin administered after recanalization improves functional outcomes and reduces infarct size, without altering sustained perfusion or BBB permeability. These findings highlight a perfusion-independent, time-sensitive cerebroprotective mechanism and support rapamycin's development as an adjunctive therapy in ischemic stroke.
METHODS: Male Wistar Han rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 90 min. Animals were randomized using the sealed envelope method to receive intravenous rapamycin (250 μg/kg, n = 9) or vehicle (n = 9) immediately after recanalization. Infarct volume, CBF, and BBB integrity were assessed using magnetic resonance imaging (MRI) at 72 h, alongside validated neurological tests. Group comparisons were performed using unpaired Student's t-tests.
RESULTS: Rapamycin significantly reduced infarct volume compared with vehicle (44.77 ± 30.93 mm³ vs. 113.44 ± 60.19 mm³, p = 0.0114) and improved Garcia neurological scores (12.78 ± 1.04 vs. 11.67 ± 0.87, p = 0.0295). In the adhesive removal test, rapamycin-treated animals showed shorter time to notice the stimulus (45.04 ± 11.91 s vs. 72.33 ± 12.17 s, p = 0.0002). Rapamycin had no significant effect on CBF, BBB disruption, or edema at 72 h (all p > 0.05). The p-mTOR/mTOR ratio did not differ significantly between groups at day 3 (0.55 ± 0.32 vs. 0.90 ± 0.41, p = 0.1880).
DISCUSSION: Rapamycin administered after recanalization improves functional outcomes and reduces infarct size, without altering sustained perfusion or BBB permeability. These findings highlight a perfusion-independent, time-sensitive cerebroprotective mechanism and support rapamycin's development as an adjunctive therapy in ischemic stroke.