Paternal calorie restriction prior to conception alters anxiety-like behavior of the adult rat progeny.

The maternal environment influences a broad range of phenotypic outcomes for offspring, with anxiety-like behavior being particularly susceptible to maternal environmental perturbations. Much less is known regarding paternal environmental influences. To investigate this, adult male rats were exposed to 25% calorie restriction (CR) or glucocorticoid elevation (CORT; 200 µg/ml of corticosterone in drinking water) for ∼ 6 weeks prior to breeding. Elevated plus maze (EPM), open field (OF), predator odor (cat urine), and acoustic startle/pre-pulse inhibition (AS/PPI) were characterised in the adult male offspring. Plasma concentrations of corticotrophin-releasing hormone (CRF), adrenocorticotropin hormone (ACTH), and serum leptin were characterised in both sires and offspring. Maternal care received by litters was additionally observed. Expectedly, CR and CORT treatment attenuated weight gain, whilst only CR induced anxiolytic behavior in the EPM. The adult offspring sired by CR males also demonstrated a reduction in weight gain, food intake and serum leptin levels when compared to controls. Moreover, CR offspring demonstrated an anxiolytic-like profile in the EPM and OF, enhanced habituation to the AS pulse, reduced PPI, but no alteration to predator odor induced defensiveness compared to control. CORT offspring failed to demonstrate any behavioral differences from controls, however, exhibited a trend towards reduced ACTH and leptin concentration. Collectively, the results indicate that a reduction in calories in males prior to conception can affect the behavior of adult offspring. The phenotypic transmission of CR experiences from fathers to the progeny could potentially be mediated epigenetically. The role of glucocorticoid elevation and maternal care are also discussed.

Calorie restriction at increasing levels leads to augmented concentrations of corticosterone and decreasing concentrations of testosterone in rats.

The influence of calorie restriction (CR) on increasing life span, enhancing immunocompetence, and reducing the incidence of age-related diseases is well established. Evidence points to the involvement of neuroendocrine alterations in these beneficial effects. Accordingly, we hypothesized that CR will result in significant alterations to the hormones investigated. Little attention has been directed toward ascertaining the doses of CR required to obtain such alterations and, indeed, whether a dose-response exists. Adult rats were subjected to 1 of 5 dietary regimens: control, CR12.5%, CR25%, CR37.5%, or CR50%. Rats were decapitated 3 weeks following the onset of restriction; and trunk blood was collected and assayed for concentrations of serum adrenocorticotropic hormone, corticosterone, and testosterone, as well as plasma concentrations of noradrenalin and adrenalin. No effect was found as a result of dietary manipulation for serum concentrations of adrenocorticotropic hormone. However, all doses of CR resulted in increased serum corticosterone in a dose-response trend. A dose-response was also observed for serum testosterone, with higher doses of CR associated with lower testosterone. Concentrations of noradrenalin were not found to be altered by any CR dose, although a trend toward a down-regulation at CR50% was observed. Plasma adrenalin displayed a biphasic distribution with reductions observed at CR25% and CR50%, although the down-regulations only attained statistical significance relative to the CR37.5% and not the control group. As well as reporting the effect of CR on multiple hormones within individual animals, these results go some way in determining the optimal levels of CR needed to induce neuroendocrinologic alterations.

The effects of calorie restriction olfactory cues on conspecific anxiety-like behaviour.

Olfactory stimuli and calorie restriction (CR) have both been found to reduce anxiety-like behaviour and alter anxiety-related neurochemical mechanisms in rats. The aim of this study was to determine if exposure to olfactory cues from 25% CR male rats leads to anxiolytic-like behaviour in male rats fed ad libitum. Animals were divided into four groups: control (fed ad libitum and given new bedding every 5 days), control olfactory group (fed ad libitum and given the bedding from the control group every 5 days), CR (fed a 25% CR regime and given new bedding every 5 days), and CR olfaction (fed ad libitum and given the bedding from the CR group every 5 days). All animals were assessed on two measures of anxiety-like behaviour: the open field and the elevated plus maze. The CR group demonstrated anxiolytic-like behavioural responses in the open field test, characterised by more time spent in the aversive central zone and a higher frequency of central and middle zone entries compared to all other groups. Intriguingly, the CR olfaction group demonstrated anxiolytic-like behaviour in the elevated plus maze test, characterised by more time spent on the open arms, and a higher ratio of open compared to total arm entries relative to the control and control olfaction groups. After the completion of behavioural testing, serum corticosterone assays were conducted on trunk blood. However, only the CR group demonstrated an increase in corticosterone. Olfactory cues from conspecifics on a CR regime significantly reduced anxiety-like behaviour in rats fed ad libitum, similar to the reduction in anxiety-like behaviour following CR. This may have implications for the development of more efficacious novel treatments for anxiety disorders.

Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.

BACKGROUND: Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta). OBJECTIVE: To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties. METHODS: A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. RESULTS: Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Abeta42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated. CONCLUSION: Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein-attenuating compound.