Neuroprotective effects of neurotrophins and melanocortins in spinal cord injury: an experimental study in the rat using pharmacological and morphological approaches.
Spinal cord injury (SCI) induces lifetime disability, and no suitable therapy is available to treat victims or to minimze their sufferings. Recently, neurotrophins and compounds acting at melanocortin receptors have been been identified as potential neuroprotective agents. In this investigation, the neuroprotective effects of neurotrophins and melanocortins on the pathophysiology of SCI were examined in a rat model. The SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anesthesia. In separate groups, neurotrophins [BDNF or IGF-1 (0.1-1 microg/10 microL in saline)] or melanocortins (ME10092, ME10354, ME10393, ME10431, and ME10501, having affinities to melanocortin receptors; 1-10 mug in saline) were applied topically over the traumatized cord segment within 5-10 min after SCI and the rats were allowed to survive for 5 h. A focal SCI resulted in widespread disruption of the blood-spinal cord barrier (BSCB) to Evans blue albumin (EBA), ([131])iodine, or lanthanum tracers and exhibited profound edema formation and cell or tissue destruction. Topical application of BDNF, IGF-1, or ME10501 (having high affinity to melanocortin-4 receptor, MCR-4) in high quantity markedly attenuated BSCB disruption, edema formation, and nerve cell, glial cell, and axonal injuries. On the other hand, low doses of neurotrophins or melanocortins were not effective in attenuating pathophysiology of SCI. These observations suggest that neurotrophins (BDNF and IGF-1) and melanocortins (with high affinity to MCR-4) are capable of inducing neuroprotection if applied shortly after trauma in high doses. Taken together, the results indicate that neurotrophins and melanocortins participate in the pathophysiology of spinal cord cell and tissue injury following trauma.
Sharma
Hari Shanker
HS
Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology, and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden. sharma@surgsci.uu.se
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001369:Axons / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I; D007811:Lanthanum; D009074:Melanocyte-Stimulating Hormones