Biomedical subjects

Peter R Mouton

Publications and source records attributed to Peter R Mouton.

10 recordsLinked to original sources

PubMed2006

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy.

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

Amino Acid Sequence↗

PubMed2005

Efficient quantification of afferent cochlear ultrastructure using design-based stereology.

The afferent synapse between the auditory nerve fiber and the inner hair cell (IHC) represents a critical junction for hearing. Elucidation of the structure at this site will help establish the substrate for normal sound encoding as well as pathologic processes associated with hearing dysfunction. Previous applications of unbiased (design-based) stereological principles have expanded our knowledge of neuro-morphological changes evident with the light microscope. Applying these principles at the level of the synapse is a promising morphometric approach for the efficient sampling of large reference spaces with electron microscopy. This study tests the accuracy of using ultra-thin sections at a fixed interval, known as disector pairs, to quantify afferent innervation density. We analyzed the total numbers of afferent terminals, synaptic thickenings, and synaptic bodies associated with each IHC in the C57BL/6J mouse cochlea, and confirmed the accuracy of the stereological approach in comparison to three-dimensional reconstructions of serial alternate sections. The higher sampling efficiency of the disector pair method rapidly increases precision while also reducing the largest source of variability, inter-animal differences. We conclude that ultrastructural quantification of afferent innervation can be accomplished in the cochlea using efficient design-based stereology.

Animals↗

PubMed2005

Folate deficiency inhibits proliferation of adult hippocampal progenitors.

Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism repressed proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affected cell cycle distribution. Our results suggest that dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis.

Animals↗

PubMed2005

Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer's disease.

Morphological alterations in microvasculature occur as a common finding in the brains of non-demented aged persons and patients with Alzheimer's disease. Quantifying the extent of this vascular pathology, however, has been complicated by systematic error (bias) associated with the applications of assumption- and model-based morphometric techniques to human and animal tissues. The current study used novel assumption- and model-free stereological approaches to quantify capillary parameters in the corpus callosum of a double amyloid precursor protein/presenilin-1 transgenic murine model of Alzheimer's disease. The results revealed significant reductions in the total number of capillary segments in white matter of transgenic mice compared to non-transgenic littermates, with no differences in total capillary length. These findings support the view that the expression of mutant human genes for beta-amyloid peptides alters the normal architecture of cerebral capillary vessels in the white matter of mouse brain, which may model microvasculature changes reported in Alzheimer's disease.

Alzheimer Disease↗

PubMed2005

Selective neuron loss in the paraventricular nucleus of hypothalamus in patients suffering from major depression and bipolar disorder.

The structural basis for depressive disorders remains unknown. Studies using neuroimaging and postmortem brain tissue indicate that anatomic substrates may contribute to major depression disorder (MDD) and bipolar disorder (BD). The present study used design-based stereology to assess neuron loss in 2 well-defined hypothalamic structures, the paraventricular nucleus (PVN) and supraoptic nucleus (SON), in clinically well-studied cases with severe depression. The left or right diencephalon was blocked from 26 brains removed at autopsy from age-matched controls (5 male/3 female) and patients with MDD (6 male/5 female) and BD (5 male/2 female). Serial sections were cut at an instrument setting of 60 microm through the entire PVN and SON from left hypothalamus and 8 to 10 sections per brain were systematic-random sampled and stained with cresyl violet. A trained operator blind to clinical diagnosis used computerized stereology to estimate total neuron numbers in PVN and SON. The results revealed a selective, robust reduction of approximately 50% in total neuron number in the PVN for major depression and bipolar cases compared with age-matched controls, with no differences in neuron numbers in the SON. This selective neuronal loss in the PVN appears to identify an important neurobiologic substrate for the behavioral manifestations of depression.

Adult↗

PubMed2004

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration.

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It is proposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putative-cleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

Adult↗

PubMed2004

Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.

Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.

Animals↗

PubMed2002

Number of Langerhans immune cells in painful and non-painful human skin after shingles.

During injury or inflammation, paracrine sensitization of peripheral sensory neurons by immune cells contributes to the sensation of pain. It is less clear whether this neural sensitization contributes to neuropathic pain after neural injury as well. Shingles (herpes zoster) is a common disease that leaves some patients with prolonged neuropathic pain known as postherpetic neuralgia (PHN). Sensitization of cutaneous neurons has been hypothesized to contribute to PHN. Langerhans cells (LC), the Ia(+) macrophages of the skin, contact epidermal neurites and, when activated, synthesize molecules with the ability to sensitize axons. For these reasons, we examined morphological evidence for activation of LC in subjects with established PHN. We also evaluated the relationship between numbers of LC and nociceptive epidermal nerve endings; these are markedly reduced in PHN. We used design-based stereology to estimate the number of CD1a(+) LC in biopsies of painful and non-painful skin from ten adults with or without PHN after shingles on the torso. There were no differences in the number of LC in previously shingles-affected and normal-control skin biopsies. The number of LC also remained at normal levels in biopsies with near-loss of innervation from shingles. LC numbers were unrelated to the presence or severity of pain. These data suggest that neuropathic pain in established PHN is not associated with increased numbers of cutaneous macrophages, and that the number of cutaneous macrophages in skin from the human torso is independent of the number of epidermal nerve endings.

Aged↗

PubMed2002

Age and gender effects on microglia and astrocyte numbers in brains of mice.

The morphological changes that occur during normal brain aging are not well understood. This study used modern stereology to assess the effects of age and gender on total numbers of astrocytes and microglia in the hippocampal formation in C57Bl/6NNIA (B6) mice. Astrocytes and microglia were visualized using immunocytochemistry for glial fibrillary acidic protein (GFAP) and complement receptor 3 (Mac-1), respectively, and numbers of each cell type in dentate gyrus (DG) and CA1 regions were estimated using the optical fractionator method. The results reveal significantly greater ( approximately 20%) numbers of microglia and astrocytes in aged females compared to young female B6 mice. We also report that on average female B6 mice have 25-40% more astrocytes and microglia in DG and CA1 regions than age-matched male C57Bl/6J mice. Since astrocytes and microglia are thought to be targets of gonadal hormones, the effects of sex hormones and reproductive aging may be responsible for these findings.

Age Factors↗