Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones.
BACKGROUND
AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex).


OBJECTIVE
To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082.


METHODS
Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model.


RESULTS
As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082.


CONCLUSIONS
These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels.
Yan
Rongzi
R
NeoTherapeutics Inc, 157 Technology Drive, Irvine, CA 92618, USA.
Nguyen
Quang
Q
Gonzaga
James
J
Johnson
Mai
M
Ritzmann
Ronald F
RF
Taylor
Eve M
EM
D000315:Adrenalectomy; D000450:Aldosterone / Q000097:blood / Q000502:physiology*; D062365:Aminobenzoates; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood / Q000502:physiology*; D003513:Cycloheximide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004347:Drug Interactions; D007042:Hypoxanthines; D016015:Logistic Models; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010889:Piracetam / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D051381:Rats
D062365:Aminobenzoates; D007042:Hypoxanthines; D018696:Neuroprotective Agents; D011687:Purines; C086241:4-((3-(1,6-dihyro-6-oxo-9H-purin-9-yl)-1-oxopropyl)amino)benzoic acid; D000450:Aldosterone; D003513:Cycloheximide; D003345:Corticosterone; D010889:Piracetam