The tachykinin endecapeptide substance P (SP) has been demonstrated to exert a functional role in neurodegenerative disorders, including Alzheimer's disease (AD). Aim of the present study was to evaluate the SP neuroprotective potential against apoptosis induced by the neurotoxic beta-amyloid peptide (A beta) in cultured rat cerebellar granule cells (CGCs). We found that SP protects CGCs against both A beta(25-35)- and A beta(1-42)-induced apoptotic CGCs death as revealed by live/dead cell assay, Hoechst staining and caspase(s)-induced PARP-1 cleavage, through an Akt-dependent mechanism. Since in CGCs the fast inactivating or A-type K(+) current (I(KA)) was potentiated by A beta treatment through up-regulation of Kv4 subunits, we investigated whether I(KA) and the related potassium channel subunits could be involved in the SP anti-apoptotic activity. Patch-clamp experiments showed that the A beta-induced increase of I(KA) current amplitude was reversed by SP treatment. In addition, as revealed by Western blot analysis and immunofluorescence studies, SP prevented the up-regulation of Kv4.2 and Kv4.3 channel subunits expression. These results indicate that SP plays a role in the regulation of voltage-gated potassium channels in A beta-mediated neuronal death and may represent a new approach in the understanding and treatment of AD.