Biomedical subjects

Diane B Miller

Publications and source records attributed to Diane B Miller.

17 recordsLinked to original sources

PubMed2006

Development of an animal model to study the potential neurotoxic effects associated with welding fume inhalation.

Serious questions have been raised regarding a possible causal association between neurological effects in welders and the presence of manganese in welding fume. An experimental model is needed that could examine the potential neurotoxic effect of manganese after pulmonary exposure to welding fume. The National Institute for Occupational Safety and Health (NIOSH) has recently finished construction of a completely automated, computer controlled welding fume generation and inhalation exposure system for laboratory animals. The system is comprised of a programmable six-axis robotic welding arm and a water-cooled arc welding torch. A flexible trunk has been attached to the robotic arm of the welder and is used to collect and transport fume from the vicinity of the arc to the animal exposure chamber. Preliminary fume characterization studies have indicated that particle morphology, size, and chemical composition were comparable to welding fume generated in the workplace. Animal inhalation studies are currently underway. With the development of this novel system, an animal model has been established using controlled welding exposures to investigate the possible mechanisms by which welding fume may affect the central nervous system.

Air Pollutants, Occupational↗

PubMed2006

Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha.

Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.

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

PubMed2006

The pharmacology of wakefulness.

Being awake, alert, and able to function in our 24-7 world is a challenge in the face of the fatigue and sleepiness engendered by long work hours, unusual work schedules, sickness, and other factors. Development of effective treatments to combat fatigue and sleepiness requires an understanding of the neurobiology of wakefulness. In this brief review, we examine the neuroanatomical, neurochemical, and molecular basis of the wakeful state to provide a framework for understanding current and future pharmacologic approaches to modification of wakefulness. The spontaneously awake state can be defined as a natural state of vigilance or arousal differing from natural sleep in both behavior and neural activity. These differences have long intrigued researchers and largely have been characterized in the brain areas and neurochemical systems affecting the sleep and wake states. Many of the strategies for promoting the awake condition involve manipulation or modulation of specific neurochemical systems with the ultimate goal of enhancing wakefulness, diminishing sleepiness, or both. Wakefulness is an important cortical function that depends on the coordinated effort of multiple brain areas including the thalamus, hypothalamus, and basal forebrain to integrate and relay information from the brainstem to the cortex. Norepinephrine and serotonin-long considered arousal-enhancing transmitters as well as glutamate, acetylcholine, histamine, and the neuromodulators hypocretin-orexins and adenosine, are known to affect the signal transduction in these brain areas and initiate, promote, or enhance wakefulness. Use of molecular tools to evaluate the awake, asleep, and sleep-deprived state has revealed novel insights concerning the gene expression events associated with wakefulness. Understanding wakefulness at this level undoubtedly will contribute to the development of pharmacologic approaches to promote or enhance the wakeful state. We caution, however, that sleep may have a necessary, restorative function for the brain; therefore, prolonging wakefulness for long periods through artificial means could have unexpected and perhaps detrimental consequences on brain health.

Brain↗

PubMed2006

Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha.

Enhanced expression of tumor necrosis factor (TNF) -alpha, is associated with the neuropathological effects underlying disease-, trauma- and chemically induced neurodegeneration. Previously, we have shown that deficiency of TNF receptors protects against MPTP-induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF-alpha in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP-induced expression of microglia-derived factors, TNF-alpha, MCP-1, and IL-1alpha, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF-alpha in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor-deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade-B staining (to identify degenerating neurons) and decreased microtubule-associated protein-2 (MAP-2) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF-alpha exerts a neurotrophic/neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and/or activity of microglia and microglia-derived factors may influence the region-specific role for this cell type. Taken together, our results are indicative of a region-specific and dual role for TNF-alpha in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus.

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

PubMed2005

The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) pilot study: methods and participant characteristics.

PURPOSE: The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study is one of the first population-based studies to integrate psychological, physiological, and subclinical measures of stress, disease, and mental dysfunction. This pilot study was undertaken to establish a methodology and descriptive results for a larger police study. METHODS: A stratified sample of 100 officers was randomly selected from the Buffalo, NY Police Department. Salivary cortisol served as a stress biomarker. Flow mediated dilation (FMD) and carotid intima-media thickness (IMT) were performed with ultrasound. Dual Energy X-Ray Absorptiometry (DEXA) and anthropometric measures assessed body composition. Self-report measures of depression and posttraumatic stress disorder (PTSD) were obtained. RESULTS: Recruitment attained for the study was 100%. Seventy-five percent showed a cortisol increase upon awakening, 90% a negative diurnal slope, and 77% an increased cortisol response after a high protein lunch challenge. Dexamethasone suppression was evident. FMD showed an increase in mean brachial artery diameter of 3.2% in men and 3.9% in women, and mean IMT was lower (male=0.67 mm; female=0.62 mm) compared to populations of similar age. For males, the mean body-mass index (BMI) was 29.8 kg/m2 and total body fat 23.4%. For females, the mean BMI was 26.7 kg/m2 and total body fat 31.5%. For all officers, 16% met criteria for depression; 36% reported elevated PTSD symptoms. CONCLUSIONS: Compared to populations of similar age, police officers had slightly lower FMD, lower carotid IMT, elevated BMI, and higher reported rates of depression and PTSD. Standardized physiological and psychological data collection and descriptive results confirmed that the methodology of the study is feasible in a working police population.

Adult↗

PubMed2005

Depression, cytokines, and glial function.

It has been known for some time that cytokines made and released during systemic illness can result in a constellation of symptoms strikingly similar to those observed in depression. The overlap of the symptoms of depression and systemic illness raises the intriguing possibility that cytokines may be involved in the development and maintenance of mood disorders. Cytokines are small ubiquitous pleiotropic molecules that are made and released in response to a variety of stimuli. They have a multitude of actions throughout the body, including actions on the central and peripheral nervous systems. Alterations in the levels of circulating cytokines, especially the key proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha , have been linked to a variety of disease states including those involving central nervous system depression. In this brief review, epidemiological and clinical data on depression, as well as findings from relevant animal models, are examined for links between cytokine expression and depression. We suggest that glial cells, both as a source and target of cytokines, represent the overlooked targets involved in the etiology of depression.

Animals↗

PubMed2004

Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?

Reactive gliosis is a hallmark of disease-, trauma-, and chemical-induced damage to the central nervous system. The signaling pathways associated with this response to neural injury remain to be elucidated, but recent evidence implicates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we used the known dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to selectively damage striatal dopaminergic nerve terminals and elicit a glial response. We then analyzed changes in gene expression and protein phosphorylation, in vivo, to identify ligands and mediators of the JAK-STAT pathway that accompany glial activation. Administration of MPTP caused rapid tyrosine (Tyr-705) phosphorylation and nuclear translocation of STAT3 in striatal astrocytes, prior to the induction of glial fibrillary acidic protein mRNA and protein. Pharmacological protection of dopaminergic nerve terminals with nomifensine abolished MPTP-mediated phosphorylation and translocation of STAT3 and prevented induction of astrogliosis. Among the Janus kinase family of tyrosine kinases, only JAK2 was associated with the phosphorylation of STAT3 after MPTP and, inhibition of JAK2 by AG490, in vivo, attenuated both the phosphorylation of STAT3 and induction of GFAP. The p44/42 mitogen-activated protein kinase (MAPK; ERK1/2) also was activated by MPTP, but was not associated with activation of STAT3, because serine (Ser-727) was not phosphorylated. The mRNA for ligands of the gp130-JAK/STAT3 signaling pathway, interleukin-6, leukemia inhibitory factor, and oncostatin M were elevated prior to activation of STAT3 and induction of astrogliosis; neuroprotection with nomifensine blocked these effects of MPTP. Taken together, our results suggest that the gp130-mediated activation of JAK2/STAT3 signaling pathway may play a key role in the induction of astrogliosis.

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

PubMed2004

Brain concentrations of d-MDMA are increased after stress.

RATIONALE: In the mouse but not the rat, d-3,4-methylenedioxymethamphetamine (d-MDMA) is a dopaminergic neurotoxicant. Various stressors and hypothermia protect against d-MDMA-induced neurotoxicity through unknown mechanisms, one of which could be a reduction in the distribution of d-MDMA to the brain. OBJECTIVES: We determined striatal levels of d-MDMA in relation to body temperature in mice exposed to a neurotoxic regimen of d-MDMA in the presence or absence of various stressors. METHODS: Female C57BL6/J mice received a neurotoxic regimen of d-MDMA (15.0 mg/kg s.c. as the base every 2 hx4) alone or in combination with manipulations with a known neuroprotective status. d-MDMA levels were determined by HPLC with fluorometric detection while rectal temperature provided core temperature status. Levels of dopamine, tyrosine hydroxylase and GFAP were used to assess neurotoxicity. RESULTS: Restraint, ethanol co-treatment and cold stress were neuroprotective, caused hypothermia and increased striatal d-MDMA levels by 4- to 7-fold. Corticosterone treatment, as a stress mimic, did not alter striatal d-MDMA or temperature and was not protective. The protective glutamate receptor antagonist, MK-801, doubled striatal d-MDMA levels and caused hypothermia. CONCLUSIONS: Although stress and other protective manipulations can alter the striatal concentration of d-MDMA their hypothermia-inducing properties appear a more likely determinant of their neuroprotection against the striatal dopaminergic neurotoxicity of d-MDMA.

Animals↗

PubMed2004

Selective changes in gene expression in cortical regions sensitive to amphetamine during the neurodegenerative process.

Gene expression profiles in several brain regions of adult male rats were evaluated following a d-amphetamine (AMPH) exposure paradigm previously established to produce AMPH neurotoxicity. Escalating doses of AMPH (5-30 mg/kg) were given over the course of 16 h per day in an 18 degrees C environment for 2 days. This paradigm produces neurotoxicity but eliminates or minimizes the hyperthermia and seizure activity that might influence gene expression in a manner unrelated to the neurotoxic effects of AMPH. The expression of 1185 genes was monitored in the striatum, parietal cortex, piriform cortex and posteriolateral cortical amygdaloid nucleus (PLCo) using cDNA array technology, and potentially significant changes were verified by RT-PCR. Gene expression was determined at time points after AMPH when neurodegeneration was beginning to appear (16 h) or maximal (64 h). Expression was also determined 14 days after AMPH to find long-term changes in gene expression that might be biomarkers of a neurotoxic event. In the parietal cortex there was a two-fold increase in neuropeptide Y precursor protein mRNA whereas nerve growth factor-induced receptor protein I-A and I-B mRNA decreased 50% at 16 h after the end of AMPH exposure. Although these changes in expression were not observed in the PLCo, insulin-like growth factor binding protein 1 mRNA was increased two-fold in the PLCo at 16 and 64 h after AMPH. Changes in gene expression in the cortical regions were all between 1.2- and 1.5-fold 14 days after AMPH but some of these changes, such as annexin V increases, may be relevant to neurotoxicity. Gene expression was not affected by more than 1.5-fold at the time points in the striatum, although 65% dopamine depletions occurred, but the plasma membrane-associated dopamine transporter and dopamine D2 receptor were decreased about 40% in the substantia nigra at 64 h and 14 days post-AMPH. Thus, the 2-day AMPH treatment produced a few changes in gene expression in the two-fold range at time points 16 h or more after exposure but the majority of expression changes were less than 1.5-fold of control. Nonetheless, some of these lesser fold-changes appeared to be relevant to the neurotoxic process.

Amphetamine↗

PubMed2004

Associations of cortical astrogliosis with cognitive performance and dementia status.

We examined 204 decedents of the autopsy component of the Honolulu-Asia Aging Study, a longitudinal cohort study, who had been clinically assessed for dementia. A sensitive ELISA technique was used to quantify glial fibrillary acidic protein (GFAP), a marker for astrogliosis, in four specific cortical brain regions and assess associations between GFAP and 1) a measure of cognitive function, 2) several clinical dementia conditions, and 3) neuritic plaque (NP) and neurofibrillary tangle (NFT) formation. Cognitive function was inversely associated with GFAP in the occipital, parietal and temporal lobes, but not in the frontal lobe. This relationship remained significant when the contribution of NP and NFT counts was removed. Further, compared to brain samples from non-demented individuals, significantly greater GFAP levels were found in samples from individuals diagnosed with Alzheimer's disease, mixed dementia, and vascular mediated dementia. Because elevated levels of GFAP reflect astroglial responses to even subtle forms of neural damage, our data indicate that increments in GFAP may provide independent, supporting evidence for the damage underlying dementia, even in the absence of other evidence of neuropathology such as the presence of NPs or NFTs. Our findings underscore the need to look beyond standard neuropathological measures putatively linked to specific neuropathological conditions in efforts to identify common cellular and molecular processes that contribute to dementia.

Aged↗

PubMed2003

Neuronal and astroglial responses to the serotonin and norepinephrine neurotoxin: 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine.

1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its other 2'-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2'-NH2-MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment. To explore the possibility that 5-HT modulates the astrocytic response to injury, 2'-NH2-MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP). Despite a 90% decrement in striatal DA in 2'-NH2-MPTP/2'-CH3-MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2'-CH3-MPTP alone. Thus, 2'-NH2-MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury.

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

PubMed2003

Elevated environmental temperature and methamphetamine neurotoxicity.

Amphetamines have been of considerable research interest for the last several decades. More recent work has renewed interest in the role of ambient temperature in both the toxicity and neurotoxicity of these drugs. We have determined that the striatal dopaminergic neurotoxicity observed in the mouse is linked in some fashion to both body and environmental temperature. Most studies of d-methamphetamine (d-METH) neurotoxicity are conducted at standard laboratory ambient temperatures (e.g., approximately 21-22 degrees C) and utilizing a repeated dosage regimen (e.g., three to four injections spaced 2 h apart). A lowering of the ambient temperature provides neuroprotection, while an elevation increases neurotoxicity. d-METH causes long-term depletions of striatal dopamine (DA) that are accompanied by other changes that are indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. Here we show that increasing the ambient temperature during and for some time following dosing increases the neurotoxicity of d-METH. Mice (female C57BL6/J) given a single dosage of d-METH (20mg/kg s.c.) and maintained at the usual laboratory ambient temperature show minimal striatal damage (an approximately 15% depletion of DA and an approximately 86% increase in GFAP). Substantial striatal damage (e.g., an approximately 70% depletion of DA and an approximately 200% elevation in GFAP) was induced by this regimen if mice were maintained at 27 degrees C for 24 or 72 h following dosing. An increase in neurotoxicity was also apparent in mice kept at an elevated temperature for only 5 or 9 h, but keeping animals at 27 degrees C for 24 or 72 h was the most effective in increasing the neurotoxicity of d-METH. Our data show how a relatively minor change in ambient temperature can have a major impact on the degree of neurotoxicity induced by d-METH. Single-dose regimens may aid in uncovering the as yet unknown mechanism(s) of substituted amphetamine neurotoxicity because they reduce the inherent complexity present in repeated dosage regimens.

Animals↗

PubMed2002

Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease.

The pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF-alpha in PD, we examined the effects of the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild-type (+/+) mice resulted in a time-dependent expression of TNF-alpha in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR-DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF-alpha is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF-alpha is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP-induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD.

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

PubMed2002

Chronic treatment with supraphysiological levels of corticosterone enhances D-MDMA-induced dopaminergic neurotoxicity in the C57BL/6J female mouse.

Chronic stress and extended periods of elevated circulating glucocorticoids have been reported to exacerbate excitotoxicity-induced hippocampal neuronal injury in rat. Despite continued interest in the effects of protracted exposure to stress or glucocorticoids, there has been little examination of how other types of neurotoxicity may be exacerbated or blocked, by stress. Here we examined the effects of chronic supraphysiologic levels of corticosterone on D-3,4-methylenedioxymethamphetamine (D-MDMA)-induced striatal dopaminergic neurotoxicity in the female C57BL/6J mouse. Corticosterone (5 mg, 15 mg or placebo) pellets were implanted to continuously elevate circulating glucocorticoids and create a model of the ultimate effect of chronic activation of the hypothalamic-pituitary-adrenal axis. After 7 days, a neurotoxic regimen of D-MDMA was administered (20 mg/kg s.c. every 2 hx4); thymus, spleen, striatum and hippocampus were collected 72 h later. Significant involution of thymus and spleen confirmed the bioavailability of the corticosterone at both dosages. D-MDMA increased the striatal levels of the astrocyte-localized protein glial fibrillary acidic protein (GFAP, a marker of gliosis); both dosages of corticosterone exacerbated this increase but only the 15 mg pellet exacerbated the decrease in tyrosine hydroxylase protein. Corticosterone alone or in combination with D-MDMA produced no neural injury in hippocampus, as measured by GFAP. Our work indicates corticosterone was able to increase the vulnerability of the striatum, but not the hippocampus to D-MDMA. An examination of other mouse strains and models of neurotoxic injury would be useful in determining the general validity of the glucocorticoid neuroendangerment hypothesis.

Adrenergic Uptake Inhibitors↗

PubMed2002

d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity.

The mechanism of 3,4-methylenedioxymethamphetamine (d-MDMA)-induced neurotoxicity may involve formation of toxic radical species. Endogenous defenses against toxic radical species include tissue stores of vitamin E, and thiols. We examined whether vitamin E deficiency could alter d-MDMA-induced neurotoxicity by administration of the drug to animals with diet induced vitamin E deficiency. Brain vitamin E levels in deficient mice were reduced 75% compared to sufficient animals. Animals received d-MDMA 5 or 10 mg/kg or saline (delivered every 2 hx4, s.c.). Diet slightly altered d-MDMA-induced temperature modulation. In brain, MDMA treatment reduced vitamin E, total antioxidant reserve and protein thiols 72 h after the first dose. In liver, MDMA treatment reduced glutathione and total antioxidant reserve at the same time point. The vitamin E-deficient group, treated with the low dose of d-MDMA, exhibited neurotoxic responses, including reduced striatal dopamine (47%) and elevated GFAP protein (3-fold): while the sufficient diet group was not altered. The higher d-MDMA dose caused neurotoxic responses in both diet groups. Liver toxicity was determined by histopathologic examination. d-MDMA caused hepatic necrosis that was more severe in vitamin E deficient than sufficient mice. These data indicate that (1) d-MDMA administration reduces antioxidant measures at a time coincident with d-MDMA-induced neuronal damage and (2) vitamin E deficiency increases susceptibility to d-MDMA-induced neurotoxicity and hepatic necrosis.

Adrenergic Uptake Inhibitors↗

PubMed2002

Neuroendocrine aspects of the response to stress.

Disruptions in homeostasis (ie, stress) place demands on the body that are met by the activation of 2 systems, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Stressor-induced activation of the HPA axis and the SNS results in a series of neural and endocrine adaptations known as the "stress response" or "stress cascade." The stress cascade is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge. Here we discuss the key elements of the HPA axis and the neuroendocrine response to stress. A challenge to homeostasis (a stressor) initiates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which in turn results in release of adrenocortiotropin hormone (ACTH) into general circulation. ACTH then acts on the adrenal cortex resulting in release of a species-specific glucocorticoid into blood. Glucocorticoids act in a negative feedback fashion to terminate the release of CRH. The body strives to maintain glucocorticoid levels within certain boundaries and interference at any level of the axis will influence the other components via feedback loops. Over- or underproduction of cortisol can result in the devastating diseases of Cushing's and Addison's, respectively, but less severe dysregulation of the HPA axis can still have adverse health consequences. These include the deposition of visceral fat as well as cardiovascular disease (eg, atherosclerosis). Thus, chronic stress with its physical and psychological ramifications remains a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. To date, treatments have been based on the existing knowledge concerning the brain areas and neurobiological substrates that subserve the stress response. Thus, the CRH blocker, antalarmin, is being investigated as a treatment for chronic stress because it prevents CRH from having its ultimate effect-a protracted release of glucocorticoids. New therapeutic strategies will depend on the discovery of novel therapeutic targets at the cellular and intracellular level. Advances in molecular biology provide the tools and new opportunities for identifying these therapeutic targets.

Animals↗

PubMedDate not supplied

Differential vulnerability of snake species to MPTP: a behavioral and biochemical comparison in ratsnakes (Elaphe) and watersnakes (Nerodia).

The synthetic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinsonian-like syndrome in humans and nonhuman primates, and also causes movement disorders in rodents, fish, amphibians and lizards. To date, the effects of MPTP have not been characterized in snakes. In this study, the behavioral and biochemical effects of MPTP were assessed in the black ratsnake Elaphe o. obsoleta and the banded watersnake Nerodia f. fasciata--species that display contrasting behavioral sensitivities to dopaminergic antagonists and to amphibian toxins. We report that MPTP induces depletion of norepinephrine and serotonin in fore, mid and hindbrain regions and depletion of dopamine in fore and midbrain regions in E.o. obsoleta. MPTP also induced a marked reduction in righting ability in E.o. obsoleta. In N.f. fasciata, norepinephrine and dopamine were depleted by MPTP in all three brain regions and serotonin was only significantly reduced in the forebrain. In contrast to E.o. obsoleta, N.f. fasciata demonstrated no behavioral disorders. This study demonstrates a behavioral and biochemical sensitivity to MPTP in E.o. obsoleta that differs from that in N.f. fasciata. The differential sensitivities to monoaminergic modulation may be related to the contrasting diets of these species.

Animals↗