Beta-amyloid peptide (A beta) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against A beta-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The A beta(25-35) (50 A mu M) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 A mu M EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented A beta(25-35)-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented A beta(25-35)-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from A beta(25-35) induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD.