Cellular NeuroscienceResearch PaperSelective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons
Section snippets
Organotypic spinal cord slice cultures
Organotypic slice cultures were prepared from Sprague–Dawley rats of postnatal day 7 (P7) using a modification (Guzman-Lenis et al., 2008) of previously described methods (Rothstein et al., 1993). Briefly, pups were over-exposed to CO2 and decapitated. The thoracic segment of their spinal cord was removed and placed in ice cold high glucose (6 mg/ml) Hanks' balanced salt solution (HBSS) (Sigma, St. Louis, MO, USA). Under sterile conditions, meninges and roots were removed and the spinal cord
Results
We first analyzed the expression of Sig-1R in the spinal cord organotypic culture by immunochemistry. Sig-1R was present in ventral (Fig. 1A) as well as in dorsal horn neuronal cells as confirmed by co-labeling with the neural marker PGP9.5 (Fig. 1B–D). Within the neurons, Sig-1R was mainly localized in the soma, with the highest density around the nucleus, and in minority along the neurites.
We assessed the potential of PRE084, a specific Sig-1R ligand, as neuroprotector against glutamatergic
Discussion
The results of this study show that the Sig-1R agonist PRE084 reduces the toxicity induced by glutamate to spinal cord organotypic cultures and promotes the elongation of neurites of both MNs and DRG neurons through PKC-mediated signaling.
Numerous studies have demonstrated neuroprotective properties of Sig-1R ligands in animal models of cerebral ischemia (Goyagi et al 2001, Goyagi et al 2003, Harukuni et al 2000, Takahashi et al 1995). Although the mechanisms involved are still unknown, several
Conclusion
In conclusion, the Sig-1R agonist PRE084 seems a promising drug to be tested for the treatment of SCI and other neurodegenerative diseases affecting the spinal cord in which excitotoxicity plays a central role. In addition to its neuroprotective effects, PRE084 has a significant pro-regenerative action, thus offering an interesting combination of actions in order to reduce neuronal damage and also to enhance re-growth of axonal pathways across the lesion site.
Acknowledgments
This research was supported by grants from the Ministerio de Ciencia y Tecnología (SAF2006-08682) and the Ministerio de Sanidad y Consumo (PI060201) of Spain, and funds from CIBERNED and TERCEL, Spain, and FEDER. We thank Dr. José M. Vela for fruitful discussions.
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