BACKGROUND: The neuroprotective effects of 1,25-dihydroxyvitamin D3 on neurotoxicity have already been documented. However, the mechanisms underlying these effects are not fully understood. Extracellular signal-regulated kinase (ERK), one of the mitogen-activated protein kinases (MAPKs), is a serine-threonine kinase activated by phosphorylation in response to a variety of extracellular mitogenic or stress signals. The ERK signaling cascade plays an important role in the regulation of several cellular processes that include mainly proliferation, but differentiation, survival and ERK activation has also been linked to neuroprotection. We explored whether 1,25-dihydroxyvitamin D3 protects against kainic acid-induced toxiticy on neurons and, if so, whether the 1,25-dihydroxyvitamin D3 protection is mediated by ERK. METHODS: Experiments were carried out on Sprague-Dawley rats. Under anesthesia, a solution containing the drug being investigated (e.g. 1.25-dihydoxyvitamin D3) was stereotaxically infused into the hippocampus or ventricle. In the rat hippocampus, brain slices were stained with cresyl violet for the visualization of neuronal cell bodies and ERK phophorylation was assayed. RESULTS: The injection of kainic acid into the hippocampi of male rats produced a loss of cresyl violet-stained neurons. Pretreatment with U0126, an inhibitor of MAPK/ERK kinase, inhibited the rapid activation of ERK by 1,25-dihydroxyvitamin D3 in the rat hippocampus. Moreover, the neuroprotective effects of 1,25-dihydroxyvitamin D3 against kainic acid toxicity were blocked by the pretreatment with U0126. CONCLUSIONS: These results indicate that ERK mediates 1,25-dihydroxyvitamin D3 neuroprotection after kainic acid toxicity in the rat hippocampus.