title: A new target for Parkinson's disease: Small molecule SERCA activator CDN1163 ameliorates dyskinesia in 6-OHDA-lesioned rats.
abstract: Endoplasmic reticulum (ER) stress is intimately linked to Parkinson's disease (PD) pathophysiology. Disrupted intracellular calcium homeostasis is a major cause of the ER stress seen in dopaminergic neurons, leading to the cell death and subsequent loss of movement and coordination in patients. Dysfunctional calcium handling proteins play a major role in the promulgation of ER stress in PD. Specifically, compromised sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been identified as a major cause of ER stress and neuron loss in PD. We have identified a small molecule activator of SERCA that increases ER calcium content, rescues neurons from ER stress-induced cell death in vitro, and shows significant efficacy in the rat 6-hydroxydopamine (6-OHDA) model of PD. Together, these results support targeting SERCA activation as a viable strategy to develop disease-modifying therapeutics for PD.
authors: Neurodon LLC, 5700 Tanager St., Schererville, IN 46375, USA. Electronic address: rdahl@neurodon.net.
authors: Russell
authors: R
authors: Dahl
mesh_terms: D000634:Aminoquinolines / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D055808:Drug Discovery; D020820:Dyskinesias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020536:Enzyme Activators / Q000627:therapeutic use*; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; C000609635:CDN1163; D020536:Enzyme Activators; D016627:Oxidopamine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Drug discovery; ER stress; Endoplasmic reticulum; Medicinal chemistry; Parkinson’s disease; Small molecules