Neuroprotective effects of melanocortins in experimental spinal cord injury. An experimental study in the rat using topical application of compounds with varying affinity to melanocortin receptors.
The possibility that local administration of low molecular weight non-peptide compounds with varying affinities at melanocortin receptors in the spinal cord will influence pathophysiological outcome of spinal cord injury (SCI) was examined in a rat model. Five new Melacure compounds ME10092, ME10354, ME10393, ME10431 and ME10501 were used in this investigation. Each compound was dissolved in saline and tested at 3 different doses, i.e. 1 microg, 5 microg and 10 microg total dose in 10 microl applied topically 5 min after SCI. The animals were allowed to survive 5 h and trauma induced edema formation, breakdown of the blood-spinal cord barrier (BSCB) and cell injuries were examined and compared with untreated injured rats. A focal SCI inflicted by an incision into the right dorsal horn of the T10-11 segments resulted in marked edema formation, breakdown of the BSCB to Evans blue albumin and caused profound nerve cell injury in the T9 and the T12 segments. Topical application of ME10501 (a compound with high affinity at melanocortin, MC-4 receptors) in high doses (10 microg) resulted in most marked neuroprotection in the perifocal spinal cord (T9 and T12) segments. On the other hand, only a mild or no effect on spinal cord pathology was observed in the traumatized animals that received ME10092, ME10354, ME10393 and ME10431 at 3 different doses. These observations suggest that non-peptide compounds with varying affinity to melanocortin receptors are able to influence the pathophysiology of SCI. Furthermore, compounds acting at melanocortin, MCR4 receptors are capable to induce neuroprotection in spinal cord following trauma.
Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Division of Anaesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, Uppsala, Sweden. Sharma@surgcsi.uu.se
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Sharma
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Skottner
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Lundstedt
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Flärdh
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Wiklund
D000287:Administration, Topical; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy / Q000209:etiology; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D044101:Receptors, Melanocortin / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000150:complications / Q000473:pathology* / Q000628:therapy*
D018696:Neuroprotective Agents; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones