MELANOCORTINS IN PERIPHERAL-NERVE REGENERATION - INFLUENCE OF DOSAGE FORMS AND ROUTES OF ADMINISTRATION

Neutrophic peptides derived from the melanocortin (ACTH/MSH) family stimulate both in vitro and in vivo the outgrowth of neuntes from developing neurones or damaged nerves. In medical biology the search for a new lead in the pharmacotherapy of brain and nerve lesions is tremendous as the incidence of especially aged related neurodegenerative diseases and nervous system trauma in a greying society is profound and currently little, if any, specific drug treatment seems to be at hand. In rats, the efficacy of melanocortins in accelerating functional recovery from sciatic nerve damage following various types of sub-cutaneous and oral administration was assessed. Rats bearing a crush lesion in the sciatic nerve and receiving melanocortins as a subcutaneous bolus injection every other day showed an accelerated recovery of function as tested in a foot withdrawal test or a walking pattern analysis. Sustained release from osmotic ALZET-minipumps or from lactate/glycolate biodegradable microspheres, both dosage forms implanted subcutaneously, were similarly effective. Although melanocortins have been shown to affect some CNS function following oral administration, both delivery via drinking water and via a stomach tube rendered the peptide ineffective in facilitating peripheral nerve repair. In the study on the pharmacotherapy of nerve trauma, local application of neurotrophic factors is both feasible as well as implicated by pathophysiological mechanisms governing post-lesion neurite outgrowth. In experiments concerning the repair of transected nerves we used microporous Accurel® polypropylene tubes to enclose the site of injury. The Accurel® can adsorb high quantities of peptides and this feature was used to deliver α-MSH at the repair site of sutured rat sciatic nerve. In studies on the crushed nerve, local application of the peptide was achieved by wrapping apeptideimpregnated biodegradable gelatine foam matrix (Willospon®) around the site of injury. Under both conditions local delivery leads to enhanced recovery of function following sciatic nerve damage. That local delivery and not leakage from the local site via systemic routes facilitated the recovery process was evident from control studies where the gelatine foam was wrapped around the contralateral nerve and no facilitated recovery could be established in the ipsilateral crushed nerve. Although currently there is little insight into the actual amount of peptide reaching the site of injury via the different routes of administration, it seems appropriate to conclude that a peak amount of peptide must be available in a short period following the nerve damage to faciliate the repair process. In the clinic different routes may be selected depending upon the nature of the nerve damage, i.e. mechanical trauma (local, biodegradable) or intoxication (bolus injection or biodegradable microspheres). © 1990.