Biomedical subjects

J Steven Richardson

Publications and source records attributed to J Steven Richardson.

7 recordsLinked to original sources

PubMed2004

Protein cross-linkage induced by formaldehyde derived from semicarbazide-sensitive amine oxidase-mediated deamination of methylamine.

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the conversion of methylamine to formaldehyde. This enzyme is located on the surface of the cytoplasmic membrane and in the cytosol of vascular endothelial cells, smooth muscle cells, and adipocytes. Increased SSAO activity has been found in patients with diabetes mellitus, chronic heart failure, and multiple types of cerebral infarcts and is associated with obesity. Increased SSAO-mediated deamination may contribute to protein deposition, the formation of plaques, and inflammation, and thus may be involved in the pathophysiology of chronic vascular and neurological disorders, such as diabetic complications, atherosclerosis, and Alzheimer's disease. In the present study, we demonstrate the induction of cross-linkage of formaldehyde with the lysine moiety of peptides and proteins. Formaldehyde-protein adducts were reduced with sodium cyanoborohydride, hydrolyzed in hydrochloric acid, and the amino acids in the hydrolysates were derivatized with fluorenylmethyl chloroformate and then identified with high-performance liquid chromatography. We further demonstrate that incubation of methylamine in the presence of SSAO-rich tissues, e.g., human brain meninges, results in formaldehyde-protein cross-linkage of particulate bound proteins as well as of soluble proteins. This cross-linkage can be completely blocked by a selective inhibitor of SSAO. Our data support the hypothesis that the SSAO-induced production of formaldehyde may be involved in the alteration of protein structure, which may subsequently cause protein deposition associated with chronic pathological disorders.

Amine Oxidase (Copper-Containing)↗

PubMed2004

The response of synaptophysin and microtubule-associated protein 1 to restraint stress in rat hippocampus and its modulation by venlafaxine.

As part of our continuing study of neural plasticity in rat hippocampus, we examined two structural proteins involved in neuronal plasticity, synaptophysin (SYP) and microtubule-associated protein 1 (MAP1) for their response to repeated restraint stress and modulation of such response by the antidepressant drug venlafaxine. This drug has the pharmacological action of inhibiting the reuptake of serotonin and norepinephrine in nerve terminals. We subjected the rats to restraint stress for 4 h per day for three days, and then injected the animals intraperitoneally (i.p.) with vehicle or 5 mg/kg/day of venlafaxine for various time periods. In all, eight groups of 10 rats each were used. The expression of these two proteins in hippocampal tissue of the rats was examined by means of western blot and immunohistochemical staining techniques. We found that restraint stress decreased the expression of SYP in the rat hippocampus by 50% (p < 0.01), and increased the expression of MAP1 by 60% (p < 0.01). SYP returned to the pre-stress levels in three weeks and MAP1 in two weeks. In animals treated with venlafaxine post-stress, SYP returned to pre-stress levels after 2 weeks and MAP1 after 1 week. These findings enhance our understanding of the compromise of the hippocampus by stressful assaults, and may be relevant to the action of venlafaxine in the treatment of patients with major depression, a mental disease thought to be related to the mal-adaptation of subjects to environmental stressors.

Animals↗

PubMed2003

Atypical antipsychotics attenuate neurotoxicity of beta-amyloid(25-35) by modulating Bax and Bcl-X(l/s) expression and localization.

We have demonstrated recently that atypical antipsychotics possess neuroprotective actions in H2O2-mediated and serum-withdrawal models of cell death. In the present study, we compared the ability of atypical and typical antipsychotics to protect against an insult mediated by Abeta(25-35), an apoptogenic fragment of the Alzheimer's disease-related beta-amyloid (Abeta) peptide. Treatment of PC12 cell cultures with Abeta(25-35) did not significantly alter total cellular expression levels of Bax, a proapoptotic Bcl-2 family member, or levels of Bcl-XL, an antiapoptotic analogue. Treatment with Abeta(25-35), however, did result in mitochondrial translocation of Bax, which effectively increased the mitochondrial ratio of Bax to Bcl-X(L). This relative increase in proapoptotic molecules was reduced by pretreatment with atypical (quetiapine and olanzapine) and typical (haloperidol) antipsychotics. We also observed a selective increase in proapoptotic Bcl-XS immunodetection in haloperidol-treated cells, which was evident particularly in the mitochondrial compartment. This increase in proapoptotic molecules may account for the lower neuroprotective potential of haloperidol, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction assay. The disparate neuroprotective effects of atypical and typical antipsychotics/neuroleptics may be due to their respective abilities to regulate pro- and anti-apoptotic protein translocation and expression.

Amyloid beta-Peptides↗

PubMed2003

Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide.

Neuroanatomical studies suggest that neuronal atrophy and destruction occur over the course of many years in neurodegenerative conditions such as schizophrenia and Alzheimer's disease. In schizophrenia, early intervention with atypical neuroleptics such as olanzapine has been shown to prevent development of some of the more serious and debilitating symptoms in many patients. The mechanisms whereby olanzapine slows or prevents symptom progression in schizophrenia remain unclear. A previous study found that olanzapine increased mRNA for the copper/zinc isoform of the superoxide dismutase enzyme (SOD-1). We investigated the effects of olanzapine in PC12 cells exposed to hydrogen peroxide. We measured cell viability, observed evidence of necrosis and apoptosis, checked the SOD-1 mRNA by Northern blot analyses, and determined SOD-1 enzyme activity. We found that: (1) the decrease in cell viability induced by hydrogen peroxide was attenuated in PC12 cells pretreated with olanzapine; (2) olanzapine increased SOD enzyme activity in PC12 cells; (3) inhibiting SOD activity with diethyldithiocarbamic acid prevented the cytoprotective actions of olanzapine; and (4) the decrease in SOD-1 mRNA level induced by hydrogen peroxide was blocked by pretreatment with olanzapine. These data indicate that the neuroprotective action of olanzapine includes the upregulation of SOD.

Animals↗

PubMed2003

Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.

It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.

Amitriptyline↗

PubMed2002

Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus.

Quetiapine is a new atypical antipsychotic drug widely used in the treatment of schizophrenia and other psychotic disorders. This study examined the influence of quetiapine on the decrease of brain-derived neurotrophic factor (BDNF) expression, induced by chronic immobilization stress, in the hippocampus of the rat. Pretreatment with 10 mg/kg of quetiapine markedly attenuated the stress-induced decrease in levels of BDNF protein, as determined by Western blot analyses, and the reduction of BDNF immunoreactivity, in hippocampal pyramidal and dentate granular neurons. These results suggest that the chronic administration of quetiapine could be neuroprotective to hippocampal neurons in schizophrenia and this effect may be related to its antipsychotic effect in patients with schizophrenia.

Animals↗

PubMed2002

Evolution of beta-amyloid induced neuropathology: magnetic resonance imaging and anatomical comparisons in the rodent hippocampus.

Alzheimer's disease (AD) is characterized by the anatomical appearance of beta-amyloid (betaA) plaques and neurofibrillary tangles. These changes are also associated with cyclical inflammation, oxidative damage and, as inferred from the autopsied brains of patients, progressive injury to neurons. Here, we report the short-term effects of an intrahippocampal injection of the toxic betaA peptide fragment 25-35 in rats using quantitative magnetic resonance imaging (MRI) methods. Physiological changes within the cornu ammonis 1 (CA1) region of the hippocampus were monitored using a 1.5 T scanner at time points of 0.25, 1 and 24 h, and 7 and 14 days post injection. Spin echo T2-weighted (T2W) and diffusion weighted (DW) images were sequentially acquired. Apparent diffusion coefficients (ADC) were calculated and compared with histological alterations. A significant elevation in mean ADC values (17%) was observed in the ipsilateral CA1 at 14 days. The ADC changes were associated with disrupted pyramidal cells and nuclear lysis observed in histological sections. The contralateral CA1 exhibited a significant decrease in mean ADC of 15% at 14 days post treatment. Histological changes in the contralateral hippocampus suggested decreased neuronal density. T2W maps revealed no significant differences between the active betaA 25-35 fragment and its non-active analog, betaA 35-25. In conclusion, these results, based on changes in hippocampal ADC, demonstrate that the betaA 25-35 treatment induced pathology consistent with edema and cellular necrosis. This is the first report describing the evolution of AD-like pathology in an animal model using DW imaging.

Alzheimer Disease↗