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Background: Geranylgeranylacetone (GGA) has been recently reported to be centrally active after oral administration and protect against ischemic brain injury. This study was aimed to investigate the underlying mechanism of the protective effect of GGA. Methods: In this study, transient middle cerebral artery occlusion (tMCAO) was established. Neurological score and brain water content were adopted to investigate the role of GGA in vivo. Evans-blue (EB), western blot and immunofluorescence staining of tight junction proteins were performed to evaluate blood brain barrier (BBB) permeability. Inflammation response was assessed by immunofluorescence staining of MPO and Iba-1 and quantitative real-time polymerase chain reaction (qRT-PCR) of proinflammatory cytokines. In in vitro experiment, after oxygen-glucose deprivation (OGD), transepithelial electrical resistance (TEER) and endothelial cell monolayer permeability assay were conducted to examine the effects of GGA on barrier integrity. Furthermore, heat shock protein (HSP) 70 expression was knockdown by RNA interference in bEnd.3 cells to verify the involvement of HSP70 in the action of GGA. TEER, endothelial cell monolayer permeability, CCK8 and flow cytometry were performed. Expression of caspase-3 was detected by western blot and immunofluorescence staining. Results: Our results indicated that pretreatment with a single oral GGA dose (800 mg/kg) reduced the infarct volume and prevented the neurological impairments after tMCAO. Importantly, GGA ameliorated cerebral ischemia/reperfusion (I/R) induced BBB breakdown and rescued tight junction proteins (TJPs). GGA also profoundly decreased neutrophil infiltration, inhibited glial activation and reduced the expression of proinflammatory cytokines. Consistently, GGA significantly decreased OGD-induced BBB hyper-permeability in vitro. Consistent with the previous studies, GGA promoted HSP70 induction after I/R insult. Mechanistic study showed that GGA inhibited OGD-induced apoptosis of bEnd.3 cells. Genetic inhibition of HSP70 attenuated GGA’s anti-apoptotic effect and reversed the protective effects of GGA.