Introduction: Qi-Lian-Gui-Shou Tang (QLGST) is a Chinese herb formula composed of Astragalus mongholicus, Coptis chinensiss, Radix Angelicae Sinensis, and Radix Polygoni Multiflori, and is normally used for treatment of patients with acute cerebral ischemic injury in Xuanwu Hospital, Capital Medical University, China. This study explores the efficacy and underlying mechanism of QLGST in a rat model with acute ischemic stroke. Methods: Male Sprague-Dawley rats (n=95) were subjected to sham operation or middle cerebral artery occlusion (MCAO) for 2 h to induce ischemia followed by 72 h reperfusion with or without administration of QLGST. QLGST at low (19.58 g/kg), moderate (39.16 g/kg) and high dosage (78.32 g/kg) (N=19 each group) was administrated by gavage starting 30 min after reperfusion, twice a day for 3 days. Behavioral deficit was tested after 72 h reperfusion, followed by infarct volume and cell apoptosis, detected by TTC and TUNEL staining, respectively. The expression of activated proteins in Akt/GSK3 beta pathway was assessed by western blot and immunofluorescence staining. Results: QLGST at all three dosages decreased neurological functional impairment, but the infarct volume was only significantly decreased by QLGST at the moderate dosage (clinic equivalent dose) compared to MCAO model without treatment. Furthermore, QLGST at moderate dosage inhibited neuronal apoptosis and increased the activation of Akt/GSK3 beta pathway as compared to MCAO model without treatment. Conclusion: Our results exhibited the neuroprotective effect of Chinese herb formula QLGST on acute ischemic brain injury in a rat model. We suggest this effect might be mediated by activation of the protective signaling Akt/GSK3 beta pathway. (C) 2014 Elsevier GmbH. All rights reserved.