Showing papers by "Richard Lathe published in 2001"

Hormones and the hippocampus

Abstract: Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure Evidence is presented that its role in memory may be ancillary to physiological regulation Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception') Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (eg long-term potentiation) could facilitate throughput inhibition This may have implications for the role of the hippocampus and long-term potentiation in memory

Loss of hippocampal serine protease BSP1/neuropsin predisposes to global seizure activity.

Abstract: Serine proteases in the adult CNS contribute both to activity-dependent structural changes accompanying learning and to the regulation of excitotoxic cell death. Brain serine protease 1 (BSP1)/neuropsin is a trypsin-like serine protease exclusively expressed, within the CNS, in the hippocampus and associated limbic structures. To explore the role of this enzyme, we have used gene targeting to disrupt this gene in mice. Mutant mice were viable and overtly normal; they displayed normal hippocampal long-term synaptic potentiation (LTP) and exhibited no deficits in spatial navigation (water maze). Nevertheless, electrophysiological studies revealed that the hippocampus of mice lacking this specifically expressed protease possessed an increased susceptibility for hyperexcitability (polyspiking) in response to repetitive afferent stimulation. Furthermore, seizure activity on kainic acid administration was markedly increased in mutant mice and was accompanied by heightened immediate early gene (c-fos) expression throughout the brain. In view of the regional selectivity of BSP1/neuropsin brain expression, the observed phenotype may selectively reflect limbic function, further implicating the hippocampus and amygdala in controlling cortical activation. Within the hippocampus, our data suggest that BSP1/neuropsin, unlike other serine proteases, has little effect on physiological synaptic remodeling and instead plays a role in limiting neuronal hyperexcitability induced by epileptogenic insult.

Influence of Dehydroepiandrosterone on Rabbit Intraocular Pressure

Abstract: Purpose: The systemic concentration of dehydroepiandrosterone decreases with age in primates while in humans intraocular pressure (IOP) increases with aging. This study was designed

Vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation*

Abstract: The major adrenal steroid dehydroepiandrosterone (DHEA) enhances memory and immune function but has no known dedicated receptor; local metabolism may govern its activity. We described a cytochrome P450 expressed in brain and other tissues, CYP7B, that catalyzes the 7a-hydroxylation of oxysterols and 3b-hydroxysteroids including DHEA. We report here that CYP7B mRNA and 7a-hydroxylation activity are widespread in rat tissues. However, steroids related to DHEA are reported to be modified at positions other than 7a, exemplified by prominent 6a-hydroxylation of 5a-androstane-3b,17b-diol (A/anediol) in some rodent tissues including brain. To determine whether CYP7B is responsible for these and other activities we disrupted the mouse Cyp7b gene by targeted insertion of an IRES-lacZ reporter cassette, placing reporter enzyme activity (bgalactosidase) under Cyp7b promoter control. In heterozygous mouse brain, chromogenic detection of reporter activity was strikingly restricted to the dentate gyrus. Staining did not exactly reproduce the in situ hybridization expression pattern; post-transcriptional control is inferred. Lower level staining was detected in cerebellum, liver, and kidney, and which largely paralleled mRNA distribution. Liver and kidney expression was sexually dimorphic. Mice homozygous for the insertion are viable and superficially normal, but ex vivo metabolism of DHEA to 7a-hydroxy-DHEA was abolished in brain, spleen, thymus, heart, lung, prostate, uterus, and mammary gland; lower abundance metabolites were also eliminated. 7a-Hydroxylation of 25-hydroxycholesterol and related substrates was also abolished, as was presumed 6a-hydroxylation of A/anediol. These different enzyme activities therefore derive from the Cyp7b gene. CYP7B is thus a major extrahepatic steroid and oxysterol hydroxylase and provides the predominant route for local metabolism of DHEA and related molecules in brain and other tissues. Brain function is subject to hormonal control, notably by steroids synthesized from the adrenal glands and gonads. Accumulating evidence also points to local steroid synthesis and metabolism in brain; a growing field of investigation focuses on

Use of 7alpha-hydroxy-estradiol, 7alpha-hydroxy-dehydroepiandrosterone and 7alpha-hydroxy-pregnenolone derivatives for treating acute cellular degeneration

Abstract: A method is provided for treating a patient in need of therapy for acute neuronal degeneration due to metabolic compromise of central or peripheral nervous system cells comprising administering to that patient a therapeutically effective amount of a 7α-hydroxy substituted steroid selected from 7α-hydroxy-derivatives of estradiols, dehydroepiandrosterones and pregnenolones, and metabolic precursors thereof. Use of such compounds for manufacture of medicaments and neuroprotective compositions are also provided.

Cytoprotective steroids (ii)

Abstract: A method is provided for treating a patient in need of therapy for acute neuronal degeneration due to metabolic compromise of central or peripheral nervous system cells comprising administering to that patient a therapeutically effective amount of a 7α-hydroxy substituted steroid selected from 7α-hydroxy-derivatives of estradiols, dehydroepiandrosterones and pregnenolones, and metabolic precursors thereof. Use of such compounds for manufacture of medicaments and neuroprotective compositions are also provided.

Steroides cytoprotecteurs (ii)

Abstract: L'invention concerne un procede pour traiter un patient necessitant un traitement suite a une degenerescence neuronale aigue provoquee par une compromission metabolique de cellules des systemes nerveux central ou peripherique. Le procede consiste a administrer au patient une quantite therapeutiquement efficace de steroide 7α-hydroxy substitue selectionne parmi les derives 7α-hydroxy d'estradiols, les dehydroepiandrosterones et les pregnenolones ainsi que leurs precurseurs metaboliques. L'invention concerne aussi l'utilisation de ces composes dans la fabrication d'une composition a effet medicinal et neuroprotecteur.