Bone morphogenetic protein-6 (BMP6) is a member of the TGF-beta superfamily. Expression of BMP6 and its receptors are increased when brain tissues of adult rats are injured, suggesting that BMP6 may have a neuroprotective function in the physiologic response to neurological damage. This research investigates the molecular mechanisms supporting a neuroprotective effect of BMP6 in neural cells traumatized by H(2)O(2). We demonstrate that presence of BMP6 either before or after H(2)O(2)-induced injury protects the cultured primary cortical cells from apoptosis. However, molecular mechanisms mediating the protective effects of either pre- or post-treatment with BMP6 are different. Cells pre-treated with BMP6 have attenuated MAPK activity induced by H(2)O(2), whereas the MAPK activity in cells post-treated with BMP6 remains unchanged. Further, pharmacological inhibitors of MAPKs, PD98059 and SB203580, block the protective effect of BMP6 in the cells pre-treated with BMP6 but not in the cells post-treated with BMP6. The protective effect of post-treatment with BMP6 appears to be mediated through regulation of p53 and Bax molecules, evidenced by decreased mRNA levels after BMP6 treatment. Taken together, these data suggest BMP6 protect cortical cells against oxidation stress induced by H(2)O(2) via two different mechanisms, where (1) pre-treatment with BMP6 acts through MAPK pathway and (2) post-treatment with BMP6 works by down-regulating p53 and Bax.