title: 5-HT6 Receptor Agonist and Antagonist Against β-Amyloid-Peptide-Induced Neurotoxicity in PC-12 Cells.
abstract: Beta-amyloid peptide (Aβ) 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 Aβ-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 Aβ25-35(50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM 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 Aβ25-35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aβ25-35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aβ25-35induced 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.
authors.affiliation: Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, NandeVillage, Mulshi Taluka, Pune, 412 115, India.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Bokare
authors.affiliation: Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, NandeVillage, Mulshi Taluka, Pune, 412 115, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Praveenkumar
authors.affiliation: Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, NandeVillage, Mulshi Taluka, Pune, 412 115, India.
authors.forename: Mandar
authors.initials: M
authors.lastname: Bhonde
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, 576104, India. yogendra.nayak@manipal.edu.
authors.forename: Yogendra
authors.identifier: http://orcid.org/0000-0002-0508-1394
authors.initials: Y
authors.lastname: Nayak
authors.affiliation: Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, NandeVillage, Mulshi Taluka, Pune, 412 115, India.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Pal
authors.affiliation: Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, NandeVillage, Mulshi Taluka, Pune, 412 115, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Goel
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C534240:5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole; D016229:Amyloid beta-Peptides; D007211:Indoles; D010446:Peptide Fragments; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C074636:amyloid beta-protein (25-35); C097216:serotonin 6 receptor
keywords: 5-HT6 receptor; Alzheimer’s disease; Aβ25−35; Neuroprotection; PC-12 cells