No abstract

We used three inbred rat strains known for significant differences in the activity and reactivity of their hypothalamic-pituitary-adrenal (HPA) axis to stress [Fischer 344 (F344), Brown Norway (BN) and Lewis (Lew) rats] to search for a strain difference in the paradoxical increase in running activity induced by food restriction and to explore the role of the HPA axis in this behaviour. Rats were randomly assigned to either an ad lib sedentary group (AL), a control wheel activity group (ACT), a food restriction-induced hyperactivity group (FR-ACT) group (1.5 h/day ad lib food, 22.5 h/day ad lib wheel access) or a pair-fed group (FR). The BN and Lew rats reached the 25% body weight-loss criterion of FR-ACT (strain effect: F(2,132) = 45.58, P < 10-6) faster than the F344 strain due to higher food restriction-induced running activity (strain effect: F(2,65) = 17.43, P = 0.00001). FR and FR-ACT decreased thymus weight (marker of integrated HPA axis activation) in all strains. In Lew and BN strains, FR-ACT induced a further decrement on thymus weight compared to their FR group. Prefeeding corticosterone levels (15.00 h) increased during the study in BN and Lew FR-ACT rats, but not in F344. Total wheel turns were correlated to both final adipose weight (r = -0.49, P = 0.002) and thymus weight decrement (r = 0.59, P = 0.0001), emphasizing the relationship between fat mass and HPA axis activation in excessive running activity. Increased running in conditions of food restriction and HPA axis activation may be linked at the level of the central nervous system. However, the involvement of corticotrophin-releasing hormone, agouti-related peptide or cocaine- and amphetamine-regulated transcript in behavioural disturbances of FR-ACT rats was excluded (in situ hybridization). We propose that corticosterone may be the link between initial low levels of fat mass and/or rate of fat mass loss (peripheral energy stores) and increased wheel activity, favouring fueling through lipolysis and proteolysis and reinforcing the self starvation via reward mechanisms, thus establishing a deleterious vicious cycle.

Background Current therapies in Alzheimer's disease (AD), including Memantine, have proven to be only symptomatic but not curative nor disease-modifying. Fluoroethylnormemantine (FENM) is a structural analogue of Memantine, functionalized with a fluorine group that allowed its use as a positron emission tomography tracer. We here analyzed FENM neuroprotective potential in a pharmacological model of AD, in comparison to Memantine. Methods Swiss mice were treated intracerebroventricularly with aggregated Aβ25-35 peptide and examined after one week in a battery of memory tests (spontaneous alternation; passive avoidance; object recognition; place learning in the water-maze; topographic memory in the Hamlet). Toxicity induced in the mouse hippocampus or cortex was analyzed biochemically or morphologically. Results Both Memantine and FENM showed symptomatic anti-amnesic effects in Aβ25-35-treated mice. Interestingly, FENM was not amnesic when tested alone at 10 mg/kg, contrarily to Memantine. Drugs injected once-a-day prevented Aβ25-35-induced memory deficits, oxidative stress (lipid peroxidation, cytochrome c release), inflammation (IL-6, TNFα increases; glial fibrillary acidic protein (GFAP) and Iba1 immunoreactivity in the hippocampus and cortex), and apoptosis and cell loss (Bax/Bcl-2 ratio; cell loss in the hippocampus CA1 area). However, FENM effects were more robust than observed with Memantine, with significant attenuations vs. the Aβ25-35-treated group. Conclusions FENM therefore appeared as a potent neuroprotective drug in an AD model, with a superior efficacy as compared with Memantine, and an absence of direct amnesic effect at higher doses. These results open the possibility to use the compound at more relevant dosages than the ones actually proposed in Memantine treatment for AD.