Search

A cross-sectional survey was made in 56 exceptionally healthy males, ranging in age from 20 to 84 years. Measurements were made of selected steroidal components and peptidic hormones in blood serum, and cognitive and physical tests were performed. Of those blood serum variables that gave highly significant negative correlations with age (r > -0.6), bioavailable testosterone (BT), dehydroepiandrosterone sulfate (DHEAS), and the ratio of insulin-like growth factor 1 (IGF-1) to growth hormone (GH) showed a stepwise pattern of age-related changes most closely resembling those of the age steps themselves. Of these, BT correlated best with significantly age-correlated cognitive and physical measures. Because DHEAS correlated well with BT and considerably less well than BT with the cognitive and physical measures, it seems likely that BT and/or substances to which BT gives rise in tissues play a more direct role in whatever processes are rate-limiting in the functions measured and that DHEAS relates more indirectly to these functions. The high correlation of IGF-1/GH with age, its relatively low correlation with BT, and the patterns of correlations of IGF-1/GH and BT with significantly age-correlated cognitive and physical measures suggest that the GH-IGF-1 axis and BT play independent roles in affecting these functions. Serial determinations made after oral ingestion of pregnenolone and data from the literature suggest there is interdependence of steroid metabolic systems with those operational in control of interrelations in the GH-IGF-1 axis. Longitudinal concurrent measurements of serum levels of BT, DHEAS, and IGF-1/GH together with detailed studies of their correlations with age-correlated functional measures may be useful in detecting early age-related dysregulations and may be helpful in devising ameliorative approaches.

Immediate post-training, stereotactically guided, intraparenchymal administration of pregnenolone sulfate (PS) into the amygdala, septum, mammillary bodies, or caudate nucleus and of PS, dehydroepiandrosterone sulfate, and corticosterone into the hippocampus was performed in mice that had been weakly trained in a foot-shock active avoidance paradigm. Intrahippocampal injection of PS resulted in memory enhancement (ME) at a lower dose than was found with dehydroepiandrosterone sulfate and corticosterone. Intraamygdally administered PS was approximately 10(4) times more potent on a molar basis in producing ME than when PS was injected into the hippocampus and approximately 10(5) times more potent than when injected into the septum or mammillary bodies. ME did not occur on injection of PS into the caudate nucleus over the range of doses tested in the other brain structures. The finding that fewer than 150 molecules of PS significantly enhanced post-training memory processes when injected into the amygdala establishes PS as the most potent memory enhancer yet reported and the amygdala as the most sensitive brain region for ME by any substance yet tested.

Four peptides homologous to amyloid beta protein containing the Val-Phe-Phe (VFF) sequence administered intracerebroventricularly after training caused amnesia for footshock active avoidance training in mice. Results with VFF and other peptides containing VFF or portions thereof were used to generate a topographic map for a hypothetical binding surface for amnestic peptides, termed Z. Effects on retention of footshock active avoidance training were rationalized in terms of fit to Z, making possible design of potential memory-modulating peptidic and nonpeptidic substances. Three peptides that neither improved nor impaired retention blocked the amnestic effects of beta-(12-28), a peptide homologous to amyloid beta protein, opening the way to development of substances that can antagonize the neurotoxic effects of amyloid beta protein on neural structures and thus attenuate symptoms and progression of Alzheimer disease.

Immediate post-training intracerebroventricular administration to male mice of pregnenolone (P), pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, or aldosterone caused improvement of retention for footshock active avoidance training, while estrone, estradiol, progesterone, or 16 beta-bromoepiandrosterone did not. Dose-response curves were obtained for P, PS, DHEA, and testosterone. P and PS were the most potent, PS showing significant effects at 3.5 fmol per mouse. The active steroids did not show discernible structural features or known membrane or biochemical effects that correlated with their memory-enhancing capacity. The above, together with the findings that DHEA acted even when given at 1 hr after training and that P, PS, and DHEA improved retention over a much wider dose range than do excitatory memory enhancers, led to the suggestion that the effects of the active steroids converge at the facilitation of transcription of immediate-early genes. P and PS, for which receptors have not yet been demonstrated, may exert their effects by serving as precursors for the formation of a panoply of different steroids, ensuring near-optimal modulation of transcription of immediate-early genes required for achieving the plastic changes of memory processes. Low serum levels of P in aging and the increases of cancer and behavioral disorders in individuals receiving drugs that block synthesis of cholesterol, the immediate precursor of P, suggest possible clinical utility for P.

Immediate post-training intracerebroventricular administration of a synthetic peptide homologous to beta protein of brain amyloid, [Gln11]beta-(1-28), caused amnesia for footshock active avoidance training in mice in a dose-dependent fashion. This effect was specific to memory processing since the peptide did not cause amnesia when injected 24 hr after training nor did it disturb storage or retrieval of older memories. Shorter fragments of the amyloid beta protein consisting of residues 12-28, 18-28, and 12-20 also were amnestic when given intracerebroventricularly, residues 12-20 being least effective. The hippocampus, a brain structure importantly involved in learning and memory, consistently shows severe pathological changes and deposition of amyloid in patients with Alzheimer disease. Immediate post-training bilateral intrahippocampal injection of [Gln11]beta-(1-28) produced amnesia at much lower doses than did [Gln11]beta-(1-28) injected intracerebroventricularly. Thus these experimental results suggest a possible direct role of amyloid beta protein or fragments thereof in an aspect of the spectrum of cognitive deficit in Alzheimer disease.

A study was initiated to determine the effects of psychological stress on the immune response in BALB/c mice recovering from exposure to a low dose of ionizing radiation. Mice were first subjected to conditioning training for 12 days, then exposed to 200 R, subjected to psychological stress for 14 days, and assessed for peak anti-sheep RBC response. The seven treatment groups included two unirradiated groups and five irradiated groups. Mice exposed to 200 R and then subjected to conditioned psychological stress responded less vigorously to antigenic stimulation than those of the other irradiated groups. The psychological stress imposed upon these mice did not influence the antibody-forming capacity of unirradiated mice. These results indicate that a psychological stress which did not affect the immunological activity of unirradiated mice can curtail the immunological recovery of mice exposed to low doses of ionizing radiation.

Mice were trained in a passive (foot shock)avoidance task. When administered after training, the stimulants caffeine or nicotine blocked amnesia for the task that had been produced by injections of the protein synthesis inhibitor anisomycin given prior to training. With foot shock at a higher intensity, anisomycin did not produce amnesia by itself, but the administration of the depressants chloral hydrate or sodium phenobarbital after training did cause amnesia. Stimulants and depressants did not have an appreciable influence on the overall degree of protein synthesis inhibition produced by anisomycin. The results support the hypothesis that arousal after training is an important factor in the conversion of short-term to long-term memory.

Allowing mice access to food immediately after an aversive training session enhances memory retention. Cholecystokinin-octapeptide (CCK-8), which is a gastrointestinal hormone released during feeding, also enhances memory retention when administered intraperitoneally. This memory-enhancing effect of CCK-8 is blocked when the vagus nerve is cut, indicating that CCK-8 may produce its effect on memory retention by activating ascending fibers in the vagus nerve. Thus, CCK-8, a peripherally acting peptide, may mediate the memory-enhancing effects of feeding.