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

Eur J Pharmacol. 2000 Sep 29;405(1-3):33-42. doi: 10.1016/s0014-2999(00)00539-2.


It has been reported that the ACTH-(4-9) analog H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuronal tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early postnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. the sensitivity of cholinergic neurons against excitotoxic damage. Wistar rat 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 nucleus 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 choline-acetyltransferase immunoreactivity and increased reaction of glial fibrillary acidic protein -immunopositive astrocytes in the lesioned nucleus compared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholinesterase -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 neuronal and glial cells, thereby resulting in a facilitated rescuing mechanism following excitotoxic injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Adrenocorticotropic Hormone / analogs & derivatives*
  • Adrenocorticotropic Hormone / pharmacology*
  • Animals
  • Animals, Newborn / physiology*
  • Astrocytes / drug effects
  • Basal Nucleus of Meynert / drug effects*
  • Basal Nucleus of Meynert / enzymology
  • Basal Nucleus of Meynert / pathology
  • Cell Count
  • Choline O-Acetyltransferase / metabolism
  • Excitatory Amino Acid Agonists / toxicity
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry
  • N-Methylaspartate / antagonists & inhibitors*
  • N-Methylaspartate / toxicity
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Wistar


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Glial Fibrillary Acidic Protein
  • Peptide Fragments
  • Org 2766
  • ACTH (4-9)
  • N-Methylaspartate
  • Adrenocorticotropic Hormone
  • Choline O-Acetyltransferase
  • Acetylcholinesterase