RAPID NEUROTROPHIC ACTIONS OF AN ACTH MSH(4-9) ANALOG AFTER NIGROSTRIATAL 6-OHDA LESIONING

ACTH peptide fragments demonstrate potent neurotrophic effects on peri pheral nerves in situ, central neurons in culture, and have been impli cated to have effects on central neurons in vivo. Neurotoxic lesioning of the nigrostriatal system, which depletes the striatum of dopamine, provides a feasible model of central regeneration in which to test th ese peptides. Male Sprague-Dawley rats were lesioned unilaterally with 6-hydroxydopamine (8 mug/4 mul), infused into the substantia nigra. T hey were subsequently treated with 10 mug/kg IP of Org 2766 [ACTH/MSH( 4-9) analogue] or saline every 24 h starting immediately after the inf usion and were observed for 2 weeks. Rotational behavior data indicate that Org 2766 significantly decreases ipsiversive turning (p < 0.05), induced by amphetamine (2 mg/kg), as well as accelerating the onset o f denervation supersensitivity induced by apomorphine (0.05 mg/kg). Ev aluation of dopamine immunohistochemistry, using an anti-tyrosine hydr oxylase antibody, demonstrates an enhanced intensity of staining in th e ORG 2766-treated tissue compared to its saline counterpart. This dif ference is confirmed and quantified through specific high-affinity dop amine uptake. Dopamine uptake is about 17% higher in the striata of an imals treated with Org 2766. Higher dopamine uptake levels in these AC TH-treated animals correlate with greater fiber density in this group. Therefore, it appears that treatment with the ACTH/MSH(4-9) analogue Org 2766 (10 mug/kg/24 h) offers a protective effect from 6-OHDA lesio ns in the substantia nigra as well as accelerating various compensator y mechanisms involved in functional recovery.