Neurotrophic effects of ACTH/MSH neuropeptides

Abstract

Numerous experiments with peptides related to ACTH/MSH, and involving tests such as avoidance, approach, discrimination and rewarded behavior indicate that these peptides possess neuroactive effects on learning, motivation, attention, and concentration. In addition, ACTH/MSH neuropeptides affect social behavior, interact with opiate binding sites, and possess antiepileptic properties. Other CNS effects which can be demonstrated after intracranial administration only are grooming behavior, stretching, yawning and sexual behavior. The effects reside mainly in the N-terminal part of ACTH (ACTH-(4-10); ACTH-(7-16) and are dissociated from the peripheral corticotrophic effect. Several substitutions in the sequence ACTH-(4-9) led to a highly selective, potent and orally active neuropeptide with a marked loss of endocrine effects. Thus H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) appeared to be 1000 times more active on avoidance behavior than ACTH-(4-10) but to contain 1000 times less melanotrophic activity. It also had a markedly reduced steroidogenic, fat mobilizing and opiate-like activity. ACTH/MSH peptides also possess neurotrophic activities as derived from studies on regeneration of damaged nerve cells. Animal studies show beneficial effects of semichronic treatment of the ACTH-(4-9) analogue Org 2766 on nerve crush regeneration in animals. The activity for this effect resides in the sequence ACTH-(6-10). The neurotrophic influence is evident both at the sensory and the motor function level. The protective effect of Org 2766 is also found in other neuropathies as a result of diabetes mellitus and chemotherapy. It has been postulated that ACTH peptides mimic a signal as part of a regeneration program of the neurons similar to that found in developing nerves. Also recovery from lesions in the nucleus parafascicularis, nucleus accumbens and fimbria fornix can be facilitated by treatment with ACTH neuropeptides. In addition, long-term treatment of rats with Org 2766 reduces morphological correlates of brain aging such as neuronal loss and increased glial reactivity, neurochemical correlates such as corticosterone receptor loss and functional correlates such as emotionality, cognitive function and sociability.