In the current investigation, hypothalamic-pituitary-adrenal (HPA) axis function was examined in young and aged male Long-Evans rats that were initially assessed on a version of the Morris water maze sensitive to cognitive impairment during ageing. In behaviourally characterized rats, a 1-h restraint stress paradigm revealed that plasma corticosterone concentrations in aged cognitively impaired rats took significantly longer to return to baseline following the stressor than did those in young or aged cognitively unimpaired rats. No differences in basal or peak plasma corticosterone concentrations, however, were observed between young or aged rats, irrespective of cognitive status. Using ribonuclease protection assays and in situ hybridization, we evaluated mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA abundance in young and aged rats characterized on the spatial task. Abundance of MR mRNA was decreased as a function of age in stratum granulosum but not hippocampus proper, and the decrease in MR mRNA was largely unrelated to cognitive status. However, GR mRNA was significantly reduced in several hippocampal subfields (i.e. stratum granulosum and temporal hippocampus proper) and other related cortical structures (medial prefrontal and olfactory regions) of aged cognitively impaired rats compared to either young or aged cognitively unimpaired cohorts, and was significantly correlated with spatial learning ability among the aged rats in each of these brain regions. In agreement with previous stereological data from this ageing model, no changes were detected in neuron density in the hippocampus of the rats used in the in situ hybridization analysis. These data are the first to describe a coordinated decrease in GR mRNA in a functional brain system including hippocampus and related cortical areas that occurs in tandem with impairments of the HPA response to stress and cognitive decline in ageing.

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Previous studies suggest a role for basal forebrain cholinergic neurons in enhancing the inhibitory influence of the hippocampus and medial prefrontal cortex (mPFC) on glucocorticoid stress responses mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis. An inhibitory action of the basal forebrain cholinergic (BFC) system may occur through facilitation of stress-related information processing and maintenance of glucocorticoid receptor (GR) expression and negative feedback signaling in these target regions. The current study investigated the possibility that BFC input to the hippocampus contributes to habituation of the glucocorticoid response following repeated exposure to a stressor. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of restraint stress. Blood samples taken before, during and after acute stress revealed a significant increase in peak activation and protracted elevation of corticosterone in cholinergic lesioned rats. After 5 days of repeated stress, however, both groups habituated to the stressor, as indicated by similarly low corticosterone profiles throughout both the response and recovery period. Against that habituated background, rats were administered a dexamethasone challenge on day 6, so that feedback status could be examined. Dexamethasone-induced suppression of endogenous corticosterone before, during, and after stress was significantly attenuated in lesioned rats. The profile of dysfunction in glucocorticoid regulation after selective cholinergic lesions in young animals may be relevant to the adrenocortical hyperactivity and negative feedback deficits seen in conditions such as normal aging and Alzheimer's dementia, in which integrity of the basal forebrain cholinergic system is compromised.

† Recent court decisions on the invalidity or noninfringement of pharmaceutical patents reflect the vulnerabilities of these patents in protecting later stage or second generation drug products that provide improvements over earlier formulations. † Parties seeking to bring generic pharmaceutical products to market are becoming increasingly aggressive at commencing suit against pharmaceutical companies on second generation patents. Patent litigators and prosecutors must be aware of the evolving case law on issues of novelty/ anticipation, obviousness/inventive step, and the obstacles to proving infringement. † This article reviews the strategic options available for pharmaceutical companies to globally manage the life cycle of their patentable assets in view of the evolving case law.

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