Abstract
In addition to both the α1 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor antagonists, ifenprodil binds to the sigma receptor subtypes 1 and 2. In this study, we examined the effects of ifenprodil on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Ifenprodil significantly potentiated NGF-induced neurite outgrowth, in a concentration-dependent manner. In contrast, the α1 adrenergic receptor antagonist, prazosin and the NMDA receptor NR2B antagonist, Ro 25-6981 did not alter NGF-induced neurite outgrowth. Potentiation of NGF-induced neurite outgrowth mediated by ifenprodil was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist, NE-100, but not the sigma-2 receptor antagonist, SM-21. Similarly, ifenprodil enhanced NGF-induced neurite outgrowth was again significantly reduced by the inositol 1,4,5-triphosphate (IP3) receptor antagonists, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB) treatment. Furthermore, BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of ifenprodil on NGF-induced neurite outgrowth, indicating the role of intracellular Ca2+ in the neurite outgrowth. These findings suggest that activation at sigma-1 receptors and subsequent interaction with IP3 receptors may mediate the pharmacological effects of ifenprodil on neurite outgrowth.
Highlights
Recent findings reveal that the sigma-1 receptor is a novel endoplasmic reticulum (ER) chaperone, which regulates a variety of cellular functions, such as inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling, ion channel firing, protein kinase location/activation, cellular redox, neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis [1,2,3,4]
MAP-2 and growth-associated protein-43 (GAP-43) immunocytochemistry revealed that the addition of ifenprodil (10 mM) increased the number of cells with neurite outgrowth in PC12 cells compared with controls (Figure 2)
In order to determine the role of sigma receptor subtypes, we examined the effects of NE-100
Summary
Recent findings reveal that the sigma-1 receptor is a novel endoplasmic reticulum (ER) chaperone, which regulates a variety of cellular functions, such as inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling, ion channel firing, protein kinase location/activation, cellular redox, neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis [1,2,3,4]. Ifenprodil (CerocralH) has been used as a cerebral vasodilator in a limited number of countries, including Japan and France. It acts as a prototypical antagonist of the N-methyl-D-aspartate (NMDA) receptor, NR2B subunit [19,20]. There are no reports describing the effects of ifenprodil on neuronal plasticity. It remains unclear whether ifenprodil acts as an agonist or antagonist on the sigma receptor subtypes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
