Biomedical subjects

A Leake

Publications and source records attributed to A Leake.

41 records · Page 3Linked to original sources

PubMed1981

Agonist and antagonist activity of en-clomiphene upon oestrogen-mediated events in the uterus, pituitary gland and brain of the rat.

The oestrogen agonist and antagonist activity of a single dose of en-clomiphene (0.5--50 mg/kg) was studied in peripheral and brain tissue in the 3 week ovariectomized rat. 17 beta-Oestradiol benzoate (100 microgram/kg) or vehicle was injected 24 h after en-clomiphene administration and data collected at 72 h. En-clomiphene produced a dose-related (agonist) fall in body weight and food intake. Agonist action was not observed upon sexual receptivity and prolactin secretion; oestrogen antagonism of these parameters was only seen at the higher doses. The effects of en-clomiphene upon serum LH and FSH were complex, both agonist and antagonist activity being demonstrated in the absence and presence of oestrogen. En-clomiphene was uterotrophic at all doses tested; however, oestrogen antagonism was only seen at the higher doses. Inhibition of the accumulation of uterine luminal fluid at the higher doses of en-clomiphene was a sensitive index of oestrogen antagonism. The results are discussed in relation to previous studies of the effects of en-clomiphene on oestrogen receptors. With the exception of the antagonism of oestrogen-induced sexual receptivity no correlation could be made between biological activity and the status of oestrogen receptors in tissue.

Animals↗

PubMed1981

Time-related effects of en-clomiphene upon central and peripheral oestrogen target tissues and cytoplasmic receptors.

The temporal effects of the oestrogen antagonist en-clomiphene were studied in the 3 week ovariectomized rat for up to 24 days after a single dose of 0.5 or 50 mg/kg. Cytosol binding of [3H]oestradiol was measured in central and peripheral target tissues. One day after treatment both doses of en-clomiphene decreased binding of [3H]oestradiol to similar levels within tissues. In brain cytosols binding of [3H]oestradiol returned to expected control values by 16 days with the exception of the hypothalamic cytosol after treatment with 50 mg/kg which, paradoxically, achieved control levels by 8 days. However, a single-point saturation assay was inadequate for the measurement of high-affinity oestrogen receptors in brain tissue. Uterine binding of [3H]oestradiol returned to control levels by 2 and 16 days after treatment with 0.5 and 50 mg/kg respectively. Replenishment of [3H]oestradiol binding was slower in pituitary cytosol and was achieved by 8 and 24 days after treatment with 0.5 and 50 mg/kg respectively. En-clomiphene was uterotrophic; the maximal increase was at 4 days and 1 day after 0.5 and 50 mg/kg and was sustained, albeit at a lower level, for 4 and 8 days respectively. En-clomiphene at 50 mg/kg increased total uterine DNA 2 days after treatment. Small dose-related sustained increases in weight of uterine luminal fluid were also observed. En-clomiphene had no effect upon serum FSH. Serum LH was decreased only on day 8 after treatment. Serum prolactin was increased to a similar level by both doses of en-clomiphene; however, the maximum was achieved 2 and 16 days after treatment with 0.5 and 50 mg/kg respectively. Rats were tested for sexual receptivity after 50 mg/kg en-clomiphene and increases were detected between 7 and 9 days of treatment. Progesterone facilitated this effect only on days 8 and 9. En-clomiphene produced dose-related falls in food intake and body weight, the latter remaining below the weights of control rats throughout the period studied. It is apparent that the temporal effects of en-clomiphene upon cytoplasmic [3H]oestradiol binding are diverse, replenishment of binding being dependent upon the dose and the tissue examined. In addition, the changes in biological activity as measured by uterine and neuroendocrine effects also appear temporally unrelated to each other and to the binding of [3H]oestradiol. Thus further studies are necessary to elucidate possible differences in tissue oestrogen receptor mechanisms and the mode of action of the oestrogen antagonists.

Animals↗

PubMedDate not supplied

Plasma N-POMC, ACTH and cortisol following hCRH administration in major depression and dysthymia.

The concentrations of plasma N-terminal pro-opiomelanocortin, adrenocorticotropic hormone and cortisol in response to a 14:30 h human corticotrophin releasing hormone (hCRH) stimulation test (1 microgram/kg) were measured in control, major depression and dysthymic subjects. The increases in all three hormones were similar in the depressed groups when compared to the control values. The elevation in cortisol after hCRH was significantly greater in major depression when compared to the dysthymic subjects. The significance of these findings is discussed.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Neuritogenic-neurotoxic effects of membrane-associated forms of amyloid precursor protein.

The membrane-bound glycoprotein, amyloid precursor protein (APP), plays a central role in Alzheimer's disease (AD). The present paper investigates the neuritogenic-neurotoxic properties of this protein and relates them to possible aetiopathological mechanisms in AD. Marked differences in neuritic differentiation were detected when comparing untransfected tetraploid mouse neuroblastoma cells (or vector only cells) with transfected cells overexpressing APP(751). Transfected cells developed neurites quicker, and whereas all transfected cells differentiated, the degree of differentiation of untransfected cells was more variable. Fully differentiated transfected and untransfected cells had marked differences in neuritic morphology. Transfected cells had more neurites per cell, these being shorter and more branched than neurites on untransfected cells. The precocious differentiation of transfected cells was not maintained with neuritic process disintegration and cell death occurring from the seventh day onwards. Untransfected cells continued to extend their neuritic processes for up to five weeks. Membrane-associated forms of APP were responsible for these effects, rather than secreted APP or the beta/A4-peptide. Combined data from Western blot and immunocytochemical procedures showed a prominent accumulation of APP-C-terminal fragments in the perinuclear region, neuritic varicosities and growth cones of transfected cells, suggesting their involvement in the neuritogenic-neurotoxic process. Similar neuritogenic-neurotoxic mechanisms occurring in vivo, in association with compensatory synaptoplastic responses in the aged brain, may be part of the pathological process in AD.

Alzheimer Disease↗

PubMedDate not supplied

Alterations in neuropeptides in aging and disease. Pathophysiology and potential for clinical intervention.

Marked specific and selective changes in the levels of some neuropeptides in age-related diseases, such as senile dementia of the Alzheimer (SDAT) or Lewy body (SDLT) types, Parkinson's disease, Huntington's disease and major depressive disorder, versus normal aging have been noted. However, the levels of most neuropeptides are normal. The only 2 peptides consistently altered in SDAT are somatostatin and corticotrophin-releasing hormone both of which are reduced. In Huntington's disease, the level of substance P in the basal ganglia is reduced suggesting a preferential vulnerability of spiny neurones in this disease. In Parkinson's disease, substance P is attenuated in the basal ganglia while somatostatin is reduced in the neocortex. These and other results suggest that substance P deficits are related to movement disorders while somatostatin deficits are related to cognitive impairment. SDLT is a type of dementia with features common to both SDAT and Parkinson's disease, although the changes in neuropeptides suggest that neurochemically the disease is more closely related to SDAT. In major depressive disorder, the level of corticotrophin-releasing hormone is reduced while there is a reciprocal increase in corticotrophin-releasing hormone receptors suggesting that the neurones remain functional. Potential clinical intervention has been limited by problems such as poor penetration of agents into the brain and the short half-lives of neuropeptide agonists and antagonists. However, some currently available agents may act, at least in part, through modulation of neuropeptide pathways, e.g. carbamazepine and alprazolam both modulate the corticotrophin-releasing hormone system in animals, and both have clinically proven antidepressant activity.

Aged↗