The ACTH(4-9) analog ORG 2766 and recovery after brain damage in animal models--a review

Treatment with adrenocorticotrophic hormone (ACTH), as well as with ACTH fragments and analogues, can influence behaviour of animals and humans. Furthermore it facilitates recovery of damaged peripheral nervous tissue. The question whether ACTH/MSH peptides affect recovery processes after injury to the central nervous system as well is addressed in the present review. The effects of administration of the ACTH(4-9) analog ORG 2766 after brain lesions has been studied frequently. However, the interpretation of the available data is confused by the variability of the results. Several factors can be identified which influence the efficacy of the peptide: (i) not all behavioural tests are equally suitable to reveal a peptide effect on behavioural recovery; (ii) the affected brain area; (iii) whether cell bodies or terminals are affected; (iv) the post-operative housing conditions; and (v) the onset and duration of peptide administration. Two possible explanations of peptide efficacy on functional recovery are considered: first, the peptide may accelerate spontaneously occurring recovery processes and second, the peptide may induce compensatory mechanisms underlying functional recovery without recuperation of the damaged neurons. These compensatory mechanisms seem to rely mainly on enhanced non-selective attention by activation of limbic structures. It is as yet unknown to which receptor system ORG 2766 binds; the analog lacks affinity for the known melanocortin (MC) receptors in brain, yet ORG 2766 is able to modulate the activity of endogenous opioids and the NMDA-receptor. A modulating influence of the peptide on NMDA-receptor activity might indirectly account for both enhanced attention--with ensuing behavioural recovery--and the acceleration of spontaneous recovery.