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Abstract Aim: Heat shock proteins (HSPs) are important regulators of cellular survival and exert neuroprotective effects against cerebral ischemia. Both prostaglandin El (PGE1) and lithium have been reported to protect neurons against ischemic injury. The present study was undertaken to examine if lithium could potentiate the neuroprotection of PGE1 against cerebral ischemia, and if the synergetic effects take place at the level of HSPs. Methods: Brain ischemia was induced by a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were pretreated with subcutaneous injection of lithium for 2 d and a single intravenous administration of PGE1 immediately after ischemic insult. Cerebrocortical blood flow of each group was closely monitored prior to onset of ischemia, 5 min, 15 min, 30 min and 60 min after surgical operation. Body temperature was measured before, 5 min, 2 h and 24 h after the onset of pMCAO. The infarct volume, brain edema and motor behavior deficits were analyzed 24 h after ischemic insult. Cytoprotective HSP70 and heme oxygenase-1 (HO-1) in the striatum of the ipsilateral hemisphere were detected by immunoblotting. Brain sections from the striatum of the ipsilateral hemisphere were double-labeled with the anti-HSP70 antibody and 4,6-diamidino-2-phenylindole (DAPI). Results: Treatment with PGE1 (8 and 16 g/kg, iv) or lithium (0.5 mEq/kg, sc) alone reduced infarct volume, neurological deficits and brain edema induced by focal cerebral ischemia in rats. Moreover, a greater neuroprotection was observed when PGE1 and lithium were given together. Co-administration of PGE1 and lithium significantly upregulated cytoprotective HSP70 and HO-1 protein levels. Conclusion: Lithium and PGE1 may exert synergistic effects in treatment of cerebral ischemia and thus may have potential clinical value for the treatment of stroke.