Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons.
Neuronal loss and interruption of axonal pathways are occurring after spinal cord injury. This is initiated by the mechanical damage and propagated by secondary events that include the fast rise of glutamate concentration and the subsequent over-activation of glutamate receptors, triggering noxious processes to the cell. Excitotoxic processes are also observed in degenerative diseases that involve motoneuron loss. Sigma-1 receptors (Sig-1Rs) are expressed in the CNS and their ligands have been shown to prevent neuronal death associated to glutamate toxicity. In the present study, we used organotypic cultures of spinal cord slices and dorsal root ganglia (DRG) explants from 7-8 days old postnatal rats to assess whether the agonist of the Sig-1R, 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084), protects the spinal cord against glutamate excitotoxicity and promotes neurite elongation. The results showed that PRE084 exerted a bell-shape dose-dependent protective response of the motoneurons, with a significant neuroprotection obtained with 10 microM PRE084. PRE084 also caused an increase in the length of neurites in both motoneurons and neurons in DRG explants. Both effects were abrogated with the addition of BD 1063, an antagonist of Sig-1R, and the use of chelerythrine, a protein kinase C (PKC) pan-inhibitor indicating that PKC is implicated in the observed effects. These results suggest the use of PRE084 as a neuroprotective agent for spinal cord damage.
Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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Guzmán-Lenis
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Navarro
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D000818:Animals; D053119:Benzophenanthridines / Q000008:administration & dosage / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity; D066298:In Vitro Techniques; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology
C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010879:Piperazines; D017480:Receptors, sigma; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D018698:Glutamic Acid; C016299:chelerythrine; D011493:Protein Kinase C