Astrocyte damage and the disorders of cytokine secretion induced by endoplasmic reticulum stress (ERS) are crucial pathological processes in ischemic injury of the central nervous system (CNS), (e.g., ischemic reperfusion injury of the brain and spinal cord). ERS stimulates damage to astrocytes and the release of pro-inflammatory cytokines, which deteriorates CNS injury. This current study investigates whether the overexpression of conserved dopamine neurotrophic factor (CDNF) alleviates ER stress-induced cell damage and inflammatory cytokine secretion. We found that primary astrocytes showed both a successful transduction and a significant overexpression of CDNF protein following lentivirus application. Our results show that the percentage of LDH released as a result of ER stress was significantly lower in astrocytes with an overexpression of CDNF than in the control groups without CDNF overexpression, indicating that CDNF alleviates ER stress-induced astrocyte damage. The secretion and mRNA expression levels of pro-inflammatory cytokines were increased by tunicamycin, and this stimulation was significantly suppressed by an overexpression of CDNF, demonstrating that CDNF plays an important role in astrocyte inflammation and functioning by resisting ER stress. These findings suggest that primary astrocytes can be efficiently transduced with CDNF lentiviral vectors and that the overexpression of CDNF in astrocytes shows the potential to alleviate cell damage and proinflammatory cytokine secretion, which may represent a promising strategy for neuroprotection in the CNS. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.