Alpha-lipoic acid (ALA), a natural antioxidant, is widely used for the treatment of some diseases including diabetes, and decursinol (DA), a constituent of root of Angelica gigas Nakai, has some pharmacological activities including anti-inflammatory function. In this study, we synthesized a novel synthetic alpha-lipoic acid-decursinol (ALA-DA) hybrid compound, and compared neuroprotective effects of ALA, DA or ALA-DA against ischemic damage in the gerbil hippocampal CA1 region induced by 5 min of transient cerebral ischemia. In the 10 and 20 mg/kg ALA-, DA- and 10 mg/kg ALA-DA-pre-treated-ischemia-groups, there were no neuroprotective effects against ischemic damage 4 days after ischemic injury. However, 20 mg/kg ALA-DA pre-treatment protected pyramidal neurons from ischemic damage in the CA1 region. In addition, 20 mg/kg ALA-DA pre-treatment markedly decreased the activation of astrocytes and microglia in the CA1 region 4 days after ischemic injury. On the other hand, post-treatment with the same dosages of them did not show any neuroprotective effect against ischemic damage. In brief, these findings indicate that pre-treatment with ALA-DA, not ALA or DA alone, can protect neurons from ischemic damage in the hippocampus induced by transient cerebral ischemia via the decrease of glial activation.