1. First clinical impressions with an ACTH analog (HOE 427) in the treatment of Alzheimer's disease
K R Siegfried Ann N Y Acad Sci . 1991;640:280-3. doi: 10.1111/j.1749-6632.1991.tb00234.x.
Clinical studies of cognitive effects of ACTH fragments carried out so far with ACTH (1-10) and (4-9) (Org. 2766) brought about inconsistent and partly disappointing results. Efficacy could not be demonstrated in patients with Alzheimer's disease (AD). A possible reason for these results is the low metabolic stability and low lipophilicity of these compounds. HOE 427 has a considerably prolonged metabolic stability, has a high lipophilicity, and is much more potent than are existing compounds in pharmacologic models of memory and learning. It also was proven to have significant effects on ACh metabolism. Single dose studies in groups of mildly cognitively impaired elderly subjects and in patients with AD showed slight but significant effects on attention and mood. The effects were less consistent in patients than in healthy subjects.
2. C-terminal fragments of ACTH stimulate feeding in fasted rats
J K Chambers, K A Al-Barazanji, J R Arch, S Q Rice, J E Miller Horm Metab Res . 2001 Aug;33(8):480-5. doi: 10.1055/s-2001-16941.
Peptides derived from pro-opiomelanocortin, including alpha-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [alpha-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide alpha-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.
3. Acute influences of some ACTH-related peptides of fighting and adrenocortical activity in male laboratory mice
A E Evans, P F Brain Pharmacol Biochem Behav . 1977 Nov;7(5):425-33. doi: 10.1016/0091-3057(77)90210-6.
A number of corticotrophin preparations when given acutely enhanced fighting behavior, an event which may be consequent upon elevation of circulating corticosterone. A series of short ACTH analogues (ACTH 11-24, ACTH 4-10) had slight influences on circulating plasma corticosterone values and on fighting behavior. However, 20 microgram ACTH 1-10 given 12 hr before testing did increase fighting C.F. controls. As this compound only caused a slight stimulation of plasma corticosterone titers, the possibility exists of an extra-adrenal influence. One cannot, it appears, eliminate glucocorticoid influences using these preparations in the mouse. Acutely, ACTH 1-24 had virtually no influences on Animex-assessed motor activity but did enhance fighting in castrated mice maintained with either androgen or estrogen. It is tentatively concluded that the ACTH influences on aggression in the mouse are partially mediated via glucocorticoid influences on the CNS combined with an extra adrenal influence of part of the ACTH molecule. A possible reason for the differing acute and chronic influences of ACTH on fighting in mice is presented.
