Postnatal treatment with ACTH-(4-9) analog ORG 2766 attenuates N-methyl-D-aspartate-induced excitotoxicity in rat nucleus basalis in adulthood

It has been reported that the ACTH-(4-9) analog H-Met(O-2)-Glu-His-Phe-D-Ly s-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuron al tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early pos tnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. t he sensitivity of cholinergic neurons against excitotoxic damage. Wistar ra t pups received injections of ORG 2766 or saline on postnatal days 1, 3 and 5 and were then left undisturbed until adulthood. At the age of 6 months, the animals were subjected to unilateral lesion of magnocellular basal nucl eus by infusion of high dose of N-methyl-D-aspartate (NMDA). The effects of the excitotoxic insult were studied 28 hours and 12 days after the lesion by measuring both the acute cholinergic and glial responses, and the final outcome of the degeneration process. Twenty eight hours after NMDA infusion , postnatally ACTH-(4-9)-treated animals showed stronger suppression of cho line-acetyltransferase immunoreactivity and increased reaction of glial fib rillary acidic protein -immunopositive astrocytes in the lesioned nucleus c ompared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholin esterase -positive fibre projections in the cortex, were less in ACTH-(4-9) animals. Our data indicate that the early developmental effects of ACTH-(4 -9) influence intrinsic neuroprotective mechanisms and reactivity of neuron al and glial cells, thereby resulting in a facilitated rescuing mechanism f ollowing excitotoxic injury. (C) 2000 Elsevier Science B.V. All rights rese rved.