Search PubMed⌕ Search

Biomedical subjects

James N Reynolds

Publications and source records attributed to James N Reynolds.

16 recordsLinked to original sources

Spatial learning deficits induced by chronic prenatal ethanol exposure can be overcome by non-spatial pre-training.

UNLABELLED: This study tested the hypothesis that behavioural intervention, in the form of non-spatial pre-training, mitigates the deficits in spatial learning tasks induced in guinea pig offspring by chronic prenatal ethanol exposure (CPEE). Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding, or water throughout gestation. Offspring received non-spatial pre-training, in which animals were exposed to the procedural requirements of the water maze in the absence of distal spatial cues, and then were tested in both stationary-platform and moving-platform tasks with spatial cues. Saliva cortisol was quantified in non-trained and pre-trained animals before and after exposure to the water maze. RESULTS: CPEE offspring exhibited performance deficits in the stationary-platform task, and non-spatial pre-training improved performance of CPEE offspring to control levels. In contrast, non-spatial pre-training had no effect on the impaired performance of CPEE offspring in the moving-platform task. Non-trained CPEE offspring had elevated saliva cortisol concentration after water-maze exposure compared to control offspring. Moreover, pre-trained control animals exhibited a sensitization of the cortisol response after repeated exposure to the water maze, and this was not evident in pre-trained CPEE offspring. CONCLUSIONS: These data demonstrate that CPEE produced deficits in spatial learning and memory processes that were partially overcome by non-spatial pre-training; however, more difficult tasks continued to reveal cognitive deficits. For repeated exposure to the water maze, CPEE offspring achieved a level of performance that was not different from control offspring, suggesting that it is the initial rate of acquisition of new learning, rather than the overall ability to learn, that is most adversely affected by CPEE.

Animals↗

Cognitive deficits in rats after forebrain cholinergic depletion are reversed by a novel NO mimetic nitrate ester.

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons.

Acetylcholine↗

Chronic prenatal ethanol exposure and increased concentration of fatty acid ethyl esters in meconium of term fetal Guinea pig.

In humans, the occurrence of prenatal exposure to ethanol is difficult to validate objectively. Increased concentration of fatty acid ethyl esters (FAEE) in the meconium of the newborn may be a biomarker of prenatal ethanol exposure. The validity of this proposed biomarker was tested in pregnant guinea pigs that received chronic oral administration of 4 g ethanol/kg maternal body weight/day (n=8), isocaloric-sucrose/pair-feeding (n=8) or water (n=2) throughout gestation. At gestational day 65 (term, gestational day 66 to 69), each dam and her offspring were euthanized, and meconium was collected from the term fetal large intestine. Eight individual FAEE (lauric, myristic, palmitic, palmitoleic, stearic, oleic, linolenic and arachidonic AEE) were measured by gas chromatography--flame ionization detection and confirmed by gas chromatography--mass spectrometry. The chronic maternal ethanol regimen decreased fetal body weight and brain weight. There was virtually no measurable FAEE in the meconium for the water group (n=3 fetuses). For meconium of the ethanol offspring (n=25 fetuses) compared with the sucrose offspring (n=23 fetuses), the total FAEE concentration was 8-fold higher; and lauric, palmitic, stearic and oleic AEE concentrations were at least 5-fold higher for the ethanol group. The data indicate that fetal meconium FAEE constitute a biomarker of prenatal ethanol exposure for a maternal ethanol regimen that restricts fetal development, with an inverse relationship between meconium total FAEE concentration and both body weight and brain weight.

Animals↗

NO chimeras as therapeutic agents in Alzheimer's disease.

NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.

Alzheimer Disease↗

A Guinea pig model for the identification of in utero alcohol exposure using fatty acid ethyl esters in neonatal hair.

Measuring levels of fatty acid ethyl esters (FAEE) in hair has been a useful way to discriminate between adult heavy and nondrinkers. Extending the use of FAEE into neonatal hair to objectively identify children exposed to alcohol in utero may revolutionize current methods used to diagnose fetal alcohol spectrum disorder (FASD). Here we confirm for the first time that chronic exposure to alcohol during pregnancy in guinea pigs leads to increased levels of FAEE in both maternal and neonatal hair. The mean cumulative FAEE concentration in exposed maternal samples taken at GD57 was 0.431+/-0.140 pmol/mg (mean+/-SEM); levels observed in corresponding sucrose and water controls were 10-fold lower. Similarly, FAEE concentrations in exposed offspring samples taken at postnatal d 1 (mean cumulative FAEE=0.491+/-0.177 pmol/mg) were more than 15-fold higher than control counterparts. Sixty percent of all alcohol-exposed animal samples contained two or more quantifiable FAEE, whereas close to 90% of either water or sucrose control samples did not have more than one quantifiable level of a single FAEE. Results of this study suggest that FAEE in neonatal hair may be useful biomarkers in identifying in utero alcohol exposure and may facilitate the early diagnosis and treatment of FASD.

Animals↗

Nitric oxide mimetic molecules as therapeutic agents in Alzheimer's disease.

Nitric oxide is multifunctional messenger molecule in the brain, playing important roles including in learning and memory and in regulating the expression of trophic factors that may be reduced with aging. Small molecules that mimic the biological activity of NO, NO mimetics, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia in Alzheimer's disease. Activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of effective neuroprotective pathways mediated by NO. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia. GT 1061 is an NO mimetic compound currently in clinical trials for Alzheimer's. A survey of current research indicates that NO mimetics will provide a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.

Alzheimer Disease↗

Organic nitrites and NO: inhibition of lipid peroxidation and radical reactions.

Organic nitrites, such as i-amyl nitrite (IAN), are nitrovasodilator drugs used both clinically and recreationally. Nitrites are also chemically reasonable biological products of NO metabolism, in particular in both inhibition of lipid peroxidation by NO and induction of lipid peroxidation by peroxynitrite and NO2. Nitrites are also potential products of biomolecule nitrosation and intermediates in biotransformation of nitrate vasodilators. Although mechanisms can be drawn for both prooxidant and antioxidant activity, IAN has been observed to inhibit lipid peroxidation in a variety of systems. To test if the antioxidant activity of nitrites results from NO release alone, inhibition of lipid peroxidation was studied for four organic nitrites and four NO donor NONOates. Iron-induced lipid peroxidation in synaptosomal tissue homogenates and azo compound-initiated lipid peroxidation in liposomes and linoleic acid SDS comicelles were examined. Lipid peroxidation was quantified by TBARS and oxygen uptake analysis. A good correlation of rate of NO release with IC50 for inhibition of lipid peroxidation was observed for the NONOates, compatible with lipid radical chain termination by NO, for which a chain termination stoichiometry of 0.4-0.5 mol of lipid peroxyl radicals per mole of NO was determined. In neutral aqueous solution, nitrites also spontaneously released NO as measured by chemiluminescence; however, no correlation was observed between the rate constants of NO release for the nitrites and their inhibitor potency toward lipid peroxidation. Long chain nitrites were seen to be relatively good inhibitors of lipid peroxidation by mechanisms that must involve factors in addition to simple homolysis to release NO. Evidence for direct alpha-hydrogen atom abstraction from the nitrite by peroxyl radicals was obtained by analysis of aldehyde products and supported by MO calculations. The data suggest that lipid nitrites formed as NO chain termination products have the capacity to further inhibit lipid peroxidation and to release NO.

Animals↗

Novel nitrates as NO mimetics directed at Alzheimer's disease.

GT 1061 is a novel therapeutic agent that is in Phase 1 clinical studies for Alzheimer's disease. GT 1061 is one of a family of novel nitrates that have demonstrated neuroprotective properties and cognition- and memory-enhancing properties in animal models. The prototype of this family, GT 715, has been reported effectively to dissociate the neuromodulatory and the systemic hypotensive effects of nitrates, the latter seriously limiting the therapeutic use of classical nitrates. Further data on the novel nitrates, GT 715 and GT 061, are presented in (a) the malonate-lesion rat model of excitotoxic neurodegeneration, and (b) the reversal of a scopolamine-induced cognition deficit in the Morris water task which tests spatial memory. These data exemplify and reinforce the combined neuroprotective and cognition enhancing properties observed in this family of NO mimetic therapeutic agents. NO mimetics, that mimic the biological activity of NO, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia. NO mimetic activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of an effective neuroprotective strategy. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia, providing a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.

Alzheimer Disease↗

Temporal profile of tissue plasminogen activator (tPA) and inhibitor expression after transient focal cerebral ischemia.

Altered tPA expression may influence the fate of neurons after cerebral ischemia. We determined the changes in tPA and plasminogen activator inhibitor (PAI-1) expression in adult rat brain after transient middle cerebral artery (MCA) occlusion. Immunohistology revealed tPA staining in ipsilateral but not contralateral cortex and striatum 6 h after occlusion. This pattern was maintained at 24 h. Staining data was supported by Western blot data which showed no tPA protein in contralateral cortex at 3 h but abundant protein in ipsilateral cortex which increased further at 6 h and 24 h. In contrast there was prominent PAI-1 immunostaining and protein expression in control tissue after MCA occlusion but it diminished progressively at 3, 6 and 24 h in the lesioned cortex.

Animals↗

Effects of chronic prenatal ethanol exposure on NMDA receptor number and affinity for [3H]MK-801 in the cerebral cortex of the young postnatal and adult guinea-pig.

The objective of this study was to test the hypothesis that chronic prenatal ethanol exposure (CPEE) produces changes in the number and/or affinity of N-methyl-D-aspartate (NMDA) receptors in the cerebral cortex that are developmental-age-dependent. Timed, pregnant Dunkin-Hartley-strain guinea-pigs received oral intubation of one of the following regimens, given daily as two equally divided doses 2 h apart, from gestational day (GD) 2 to GD 67 (term, ~GD 68): (i) 4 g ethanol kg(-1) maternal bodyweight; (ii) isocaloric sucrose with pair feeding; or (iii) water. Maternal blood ethanol concentration was measured on GD 57 or 58 at 1 h after the daily dose, and was 51.1 +/- 8.5 mM (235 +/- 39 mg dL(-1); n = 8). At postnatal day (PD) 11 (pre-weaning) and PD 61 (adulthood), body, brain and cerebral cortical weights of the offspring were measured. The number of NMDA receptors and their affinity for [(3)H]MK-801 were measured in a crude cerebral cortical membrane preparation using saturation isotherm analysis to determine the B(max) and K(D). Chronic prenatal ethanol exposure decreased offspring brain and cerebral cortical weights at PD 11 and PD 61. At PD 11, there was no CPEE-induced change of [(3)H]MK-801 binding characteristics in the cerebral cortex. At PD 61, both B(max) and K(D) for [(3)H]MK-801 binding to cerebral cortical NMDA receptors were decreased by CPEE compared with the isocaloric sucrose/pair-fed and water treatment groups. Loss of cerebral cortical NMDA receptors and increased affinity of the remaining receptors for [(3)H]MK-801 in the adult guinea-pig, compared with no change in the number or affinity of these receptors in the young postnatal offspring, demonstrated that the effects of CPEE on these ionotropic glutamate receptors are developmental-age-dependent.

Animals↗

Chronic prenatal ethanol exposure alters ionotropic glutamate receptor subunit protein levels in the adult guinea pig cerebral cortex.

BACKGROUND: The superfamily of glutamate-gated ion channels mediates fast excitatory synaptic transmission in the central nervous system and is composed of the NMDA, AMPA, and kainate receptors. Binding studies have shown that chronic prenatal and/or neonatal ethanol exposure produces persistent effects on the numbers of some of these channels. However, whether or not this chronic ethanol exposure produces long-lasting effects on the expression of specific ionotropic receptor subunits remains an open question. METHODS: Timed pregnant Dunkin-Hartley strain guinea pigs received oral administration of one of the following regimens between gestational days 2 and 67: (1) 4 g of ethanol per kilogram of maternal body weight per day with ad libitum access to pellet food and water (ethanol group), (2) isocaloric sucrose- and pair-feeding with ad libitum access to water (sucrose group), or (3) isovolumetric water with ad libitum access to food and water (water group). The maternal blood ethanol concentration produced by the ethanol regimen was 71 +/- 12 mM. Adult offspring were killed on postnatal day 61, and cerebral cortical tissue was analyzed for ionotropic glutamate receptor subunit expression by Western immunoblotting. RESULTS: There was a statistically significant decrease in NR2B subunit protein expression and an increase in GluR2/3 subunit protein expression in the ethanol group. Expression of NR1, NR2A, NR2C, GluR1, GluR6/7, and KA2 subunit proteins was not affected. CONCLUSIONS: These results demonstrate that chronic prenatal ethanol exposure produces long-lasting effects on the subunit composition of NMDA and AMPA receptors in the cerebral cortex of the adult guinea pig.

Animals↗

Chronic prenatal ethanol exposure-induced decrease of guinea pig hippocampal CA1 pyramidal cell and cerebellar Purkinje cell density.

The brain is a key target of ethanol teratogenicity, in which ethanol can produce neurodegeneration in selected areas, including the hippocampus and cerebellum. The research objective was to test the hypothesis that chronic prenatal ethanol exposure, via maternal ethanol administration, produces differential time course of decreased linear density of hippocampal CA1 pyramidal cells and cerebellar Purkinje cells. Timed pregnant guinea pigs received chronic oral administration of ethanol, isocaloric-sucrose/pair-feeding, or water throughout gestation (term, about gestational day (GD) 68), and the offspring were studied at GD 62 (near-term fetus), postnatal day (PD) 1 (neonate), PD 5, and PD 12 (early postnatal life). Ethanol treatment, compared with isocaloric-sucrose/pair-feeding and water treatments, decreased brain, hippocampal, and cerebellar weights at GD 62, PD 1, PD 5, and PD 12. Hippocampal CA1 pyramidal cell linear density and cerebellar Purkinje cell linear density were unaffected at GD 62. Ethanol treatment produced 25, 30, and 30% decreases in linear density of hippocampal CA1 pyramidal cells at PD 1, PD 5, and PD 12, respectively, and a 30% decrease in linear density of cerebellar Purkinje cells at PD 12 only. At PD 5, Purkinje cell profile linear density remained unaffected; however, ethanol treatment appeared to increase linear density of apoptotic Purkinje cell nuclei, as determined by a modified TUNEL method. The data demonstrate that chronic prenatal ethanol exposure produces apparent differential time course of decreased linear density of hippocampal CA1 pyramidal cells and cerebellar Purkinje cells in the developing guinea pig.

Administration, Oral↗

Neuroprotection against ischemic brain injury conferred by a novel nitrate ester.

Nitrates exhibit a selectivity of action in different tissue types not fully recognized: in particular, the neuromodulatory and cardiovascular properties can be dissociated. A novel nitrate showed relatively weak systemic effects, but in the middle cerebral artery occlusion rat model of focal ischemia, reduced the cerebral infarct by 60-70% when administered 4 h after the onset of ischemia.

Animals↗

Inhibition of lipid peroxidation in synaptosomes and liposomes by nitrates and nitrites.

NO is produced endogenously from arginine by the action of NO synthase, and exogenously by nitrovasodilators, including organic nitrates and nitrites. NO has been proposed as a cytotoxic and cytoprotective agent. There is strong evidence that NO acts as an apparent antioxidant in inhibiting lipid peroxidation, via chain termination, and interestingly lipid nitrates and nitrites have been proposed to be products of this chain termination. Both pro- and antioxidant mechanisms may be drawn for nitrates and nitrites; therefore, their effects on lipid peroxidation were measured in two systems, using tocopherol, thiol, and an NO donor for comparison: (1) rat cerebrocortical synaptosomes with Fe(II)-induced lipid peroxidation measured by thiobarbituric acid reactive substances (TBARS), and (2) phospholipid liposomes with an azo-initiator induction system, quantified by a fluorescent probe of peroxide formation. In contrast to the classical nitrate nitroglycerin, novel nitrates which release NO on reaction with thiols and two novel nitrates which spontaneously generate NO in aqueous solution inhibited lipid peroxidation. i-Amyl nitrite inhibited lipid peroxidation, and its properties were further studied with ESR spectroscopy. The data show that classical nitrites and novel nitrates are not prooxidants, but inhibit lipid peroxidation.

Amyl Nitrite↗

Chronic prenatal ethanol exposure alters the proportion of GABAergic neurons in layers II/III of the adult guinea pig somatosensory cortex.

Chronic prenatal ethanol exposure increases the expression of gamma-aminobutyric acid type A (GABA(A)) receptors in the adult guinea pig cerebral cortex. One possible explanation for this change in receptor number is the loss of GABAergic innervation and subsequent up-regulation of GABA(A) receptors. We tested this hypothesis by determining the relative proportion of glutamic acid decarboxylase (GAD) immunopositive cells in the cerebral cortex of adult guinea pig offspring that had received chronic daily exposure to ethanol (4 g/kg maternal body weight) throughout gestation. Chronic prenatal exposure to ethanol decreased the number of neurons that were GAD-immunopositive relative to the total number of cresyl-violet-stained neurons by approximately 30% in layers II/III of the adult guinea pig somatosensory cortex. No changes were observed in other cortical layers. These data suggest that chronic prenatal exposure to ethanol results in either a selective loss of GABAergic interneurons or failure to express GAD in layers II/III of the adult guinea pig somatosensory cortex.

Animals↗

Brain growth spurt-prenatal ethanol exposure and the guinea pig hippocampal glutamate signaling system.

This study tested the hypothesis that prenatal ethanol exposure (PEE) during the brain growth spurt (BGS) in the guinea pig suppresses the glutamate-NMDA receptor-nitric oxide synthase (NOS) signaling system in the developing hippocampus. Pregnant guinea pigs [term, about gestational day (GD) 68] received daily oral administration of 2 g ethanol/kg maternal body weight/day on GD 43 and/or GD 44 and then 4 g ethanol/kg maternal body weight/day from GD 45 to GD 62, isocaloric-sucrose/pair-feeding or water. Offspring were studied at GD 63 (near-term fetus) and postnatal day (PD) 10 (young postnatal life). Maternal blood ethanol concentration during ethanol treatment, pregnancy outcome variables, no change in spontaneous locomotor activity, and decreased brain and cerebral cortical weight data were reported previously [Neurotoxicol. Teratol. 23 (2001) 355]. This BGS-PEE regimen did not affect hippocampal stimulated glutamate release in young postnatal offspring, NMDA receptors as assessed by [3H]MK-801 binding, or NOS activity in near-term fetal offspring. Furthermore, BGS-PEE did not affect the number of hippocampal CA1 and CA3 pyramidal cells and dentate gyrus granule cells in defined locations of these three regions in the hippocampal formation. These findings are in contrast to the effects of chronic prenatal exposure to this ethanol regimen throughout gestation, including suppression of the hippocampal glutamate-NMDA receptor-NOS signaling system, decreased number of hippocampal CA1 pyramidal cells, increased spontaneous locomotor activity, and impaired performance in the Morris water maze.

Animals↗