Alzheimer's disease (AD) is accompanied by memory loss due to neuronal cell death caused by toxic amyloid β-peptide (Aβ) aggregates. In the healthy brain, a group of amyloid-degrading enzymes including neprilysin (NEP) maintain Aβ levels at physiologically low concentrations but, with age and under some pathological conditions, expression and activity of these enzymes decline predisposing to late-onset AD. Hence, up-regulation of NEP might be a viable strategy for prevention of Aβ accumulation and development of the disease. As we have recently shown, inhibitors of histone deacetylases, in particular, valproic acid (VA), were capable of up-regulating NEP expression and activity in human neuroblastoma SH-SY5Y cell lines characterised by very low levels of NEP. In the present study, analysing the effect of i.p. injections of VA to rats, we have observed up-regulation of expression and activity of NEP in rat brain structures, in particular, in the hippocampus. This effect was brain region- and age-specific. Administration of VA has also restored NEP activity and memory deficit in adult rats caused by prenatal hypoxia. This suggests that VA and more specific HDAC inhibitors can be considered as potential pharmaceutical agents for up-regulation of NEP activity and improvement of cognitive functions of ageing brain.

Cerebral ischemia is known to be a major cause of death and the later development of Alzheimer's disease and vascular dementia. However, ischemia induced cellular damage that initiates these diseases remain poorly understood. This is primarily due to lack of clinically relevant models that are highly reproducible. Here, we have optimised a murine model of global cerebral ischaemia with multiple markers to determine brain pathology, neurochemistry and correlated memory deficits in these animals. Cerebral ischaemia in mice was induced by bilateral common carotid artery occlusion. Following reperfusion, the mice were either fixed with 4% paraformaldehyde or decapitated under anaesthesia. Brains were processed for Western blotting or immunohistochemistry for glial (GLT1) and vesicular (VGLUT1, VGLUT2) glutamate transporters and paired helical filament (PHF1) tau. The PHF1 tau is the main component of neurofibrillary tangle, which is the pathological hallmark of Alzheimer's disease and vascular dementia. The novel object recognition behavioural assay was used to investigate the functional cognitive consequences in these mice. The results show consistent and selective neuronal and glial cell changes in the hippocampus and the cortex together with significant reductions in GLT1 (***P < 0.001), VGLUT1 (**P < 0.01) and VGLUT2 (***P < 0.001) expressions in the hippocampus in occluded mice as compared to sham-operated animals. These changes are associated with increased PHF1 (***P < 0.0001) protein and a significant impairment of performance (*p < 0.0006, N = 6/group) in the novel object recognition test. This model represents a useful tool for investigating cellular, biochemical and molecular mechanisms of global cerebral ischaemia and may be an ideal preclinical model for vascular dementia.

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Current antidepressants are crude compared with the ideal and patents on most have expired. There are therefore strong clinical and commercial pressures for new drugs to replace them. The prospects for this are, however, now markedly reduced as several major pharmaceutical companies have abandoned work in this area whilst many others have sharply decreased their research investment. These changes and the lack of progress over such a long period are indicative of a catastrophic systems failure which, it is argued, has been caused in large part by a logical flaw at the animal modelling stage. This tautology has served to lock the current antidepressant drug discovery process into an iterative loop capable only of producing further variations of that which has gone before. Drugs produced by this approach have proved to be only poorly effective in the context of the clinically depressed population as a whole. Hence, the inevitable failure of the current antidepressant drug discovery process has left little behind that can be salvaged. Therefore, it is suggested that this be urgently reformulated on more rational grounds using more appropriate species in new animal models based upon a thorough understanding of the behavioural expressions of depression in the clinic.

S_ry 1The pattern of expression of the c-erbB-2 oncoprotein was investigatdd in whole mount preparations of 11 human fetuses by immunocytochemistry using two polyclonal antibodies, 20N and 21N. c-erbB-2 was widely expressed within all three germ layers. Expression remained relatively constant in epitheliaL mesodermal and extraembryonic tissues, but varied over time during the development of the fetal skeleton. Western blotting failed to detect c-erbB-2 in normal fetal tissues but did confirm expression in a microvillous membrane preparation of placenta. c-erbB-2 expression is widespread in the human fetus and occurs at an earlier stage than epidermal growth factor receptor.The c-erbB-2 proto-oncogene encodes a 4.6 kb mRNA which specifies a 190,000 molecular weight glycoprotein with tyrosine kinase activity. This 1,255 amino acid protein reveals extensive sequence homology with the epidermal growth factor receptor (EGF-R), but unlike EGF-R, no ligand has yet been identified (for a review see Gullick & Venter, 1989). Amplification of the c-erbB-2 proto-oncogene has been demonstrated in a wide range of adenocarcinomas including those of the breast (Slamon et al., 1987;Venter et al., 1987;Van de Vijver et al., 1987, 1988, stomach (Yokota et al., 1986(Yokota et al., , 1988, salivary gland (Semba et al., 1985), kidney (Yokota et al., 1986) and lung (Cline & Battifora, 1987) and appears to be related to prognosis in breast cancer (Slamon et al., 1987;Zhou et al., 1987). The presence of amplification in colonic adenocarcinoma has been reported (Tal et al., 1988), but it is unclear if this is a frequent event as it has not been detected by other workers (Yokota et al., 1986).The physiological action of the c-erbB-2 receptor protein is unknown and its distribution in human fetal and normal tissue has yet to be fully characterised. c-erbB-2 mRNA was widely expressed in organ digests from a single human fetus (Coussens et al., 1985) but its site within these tissues has not been identified. Expression of the neu oncogene, the rat equivalent of c-erbB-2, with which it has 88% homology, has been described in fetal rats (Kokai et al., 1987) al., 1985, 1986 Bernards et al., 1987) or anti-oncogene therapy.We have investigated the presence and distribution of the c-erbB-2 protein by immunocytochemistry and Western blotting in a series of human fetuses and placentae using two previously described polyclonal antibodies . Materials and methodsFifteen whole human fetuses from spontaneous abortions were collected over several years and stored in 10% formalin. After processing and embedding four were discarded owing to the presence of mild to severe autolysis, leaving 11 well preserved fetuses for study. Estimated gestational ages were determined by a combination of foot length, crown rump length and histological assessment of tissue maturity and ranged from 6 to 12 weeks. Fetuses larger than 12 weeks could not be sectioned whole and were therefore not included in this study. Tissue from first trimester, second trimester and term p...