Neuroendocrine responses to intravenous infusion of physostigmine in patients with Alzheimer disease.
We have reported that physostigmine, a reversible cholinesterase inhibitor, enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the mechanism of cognition enhancement, plasma hormones were measured during high-dose acute and low-dose chronic steady-state intravenous infusions of physostigmine in nine subjects with AD. High-dose hormone responses were measured during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min. Chronic responses were measured during continuous intravenous infusions of physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or placebo administered in a randomized, double-blind, cross-over design. A replicable improvement in verbal memory was found in five subjects. High-dose physostigmine infusion that produced noxious side effects resulted in significant elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH) (p = 0.0001), cortisol (p = 0.0001), and beta-endorphin (p = 0.0001). Chronic physostigmine administration, in the absence of adverse effects, produced no significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or beta-endorphin (p = 0.82). These results indicate that high-dose physostigmine activates the hypothalamic-pituitary-adrenal (HPA) axis, likely representing a "stress response." In contrast, cognition-enhancing doses do not produce a peripheral corticosteroid response. Thus, physostigmine-induced memory improvement is independent of the activation of the HPA axis.
Asthana
S
S
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Raffaele
K C
KC
Greig
N H
NH
Schapiro
M B
MB
Blackman
M R
MR
Soncrant
T T
TT
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000187:drug effects; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy*; D000704:Analysis of Variance; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D016018:Least-Squares Analysis; D016014:Linear Models; D008568:Memory / Q000187:drug effects; D010153:Paired-Associate Learning / Q000187:drug effects; D010830:Physostigmine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D001615:beta-Endorphin / Q000097:blood / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D001615:beta-Endorphin; D000324:Adrenocorticotropic Hormone; D010830:Physostigmine; D006854:Hydrocortisone