Cerebral dopamine neurotrophic factor and its functional fragments induce calcium signal through sigma-1 receptor and protect neurons against glutamate-induced excitotoxicity

Cerebral Dopamine Neurotrophic Factor (CDNF) is known to protect neurons in various pathologies. HER-096 is a CDNF-derived brain-penetrating peptidomimetic which also possesses neuroprotective properties. However, the mechanism underlying the cytoprotective effects is not fully understood. Using primary cortical co-culture of neurons and astrocytes we have found that both CDNF and HER-096 can induce intracellular calcium signals predominantly in astrocytes by release of Ca^{2 +} from endoplasmic reticulum to cytosol. This decrease in the ER Ca²⁺ pool activates store-operated calcium entrance (SOCE). Initial Ca²⁺ signal in these cells could be inhibited by the sigma-1 receptor antagonist BD-1047. CDNF and HER-096 reduced the glutamate-induced delayed Ca²⁺ deregulation and mitochondrial depolarisation which leads to significant protection against glutamate-induced excitotoxicity. Thus, the CDNF and HER-096 sigma-1 receptor mediated Ca²⁺ signal in astrocytes and neurons, from the ER, could modify the effects of high concentrations of glutamate that lead to neuroprotection.