BACKGROUND To explore the theoretical basis for protecting the brain from ischemic stroke with tetramethylpyrazine, we studied whether and how tetramethylpyrazine could protect neurons against the oxygen-glucose deprivation (OGD)-induced death and whether transient receptor potential cation channel, subfamily C, member 6 (TRPC6) was involved. MATERIAL AND METHODS Primary rat cortical neurons were cultured and an OGD model was established in the presence or absence of tetramethylpyrazine. Neuronal death was assessed by measuring the uptake of membrane-impermeable PI. Western blot analysis was used to determine the protein expressions of TRPC6 and caspase-3. The involvement of TRPC6 was tested via RNAi against TRPC6. RESULTS OGD-induced neuronal death was decreased by tetramethylpyrazine in a concentration-dependent manner. The expression of TRPC6 protein was decreased by OGD. Furthermore, downregulating TRPC6 by RNA interfering mimicked the effect of OGD in neuronal death. Tetramethylpyrazine attenuated OGD-induced TRPC6 downregulation in a tetramethylpyrazine concentration-dependent manner. However, these effects of tetramethylpyrazine on attenuating OGD-induced neuronal death were abolished by TRPC6 RNAi. CONCLUSIONS Tetramethylpyrazine can protect neurons from oxygen-glucose deprivation-induced death, possibly via TRPC6.