Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without l-DOPA administration

Stephenson, Diane; Li, Qiu; Simmons, Carol A.; Connell, Mark A.; Meglasson, M. D.; Merchant, Kalpana; Emborg, Marina E.

doi:10.1016/j.nbd.2005.03.016

Cited by 31 publications

(21 citation statements)

References 58 publications

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“…The PCB-induced reductions in GABA content is not considered a normal in vivo response to DAergic neurotoxicants in the basal ganglia and in disease states such as PD. In vivo, reports suggest that when DA neurons are disrupted via neurotoxicant administration, an increase in GABA neuronal activity results (Stephenson et al, 2005;Diaz et al, 2003). We suggest that contaminant (e.g., PCB) induced DA dysfunction in-vivo may either not result in such marked elevations in basal ganglia oxidative stress or that higher levels of GSH may buffer changes in oxidative stress.…”

Section: Discussionmentioning

confidence: 74%

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Lyng

Seegal

2008

NeuroToxicology

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. 24 hr exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using α-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.

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Section: Discussionmentioning

confidence: 74%

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Lyng

Seegal

2008

NeuroToxicology

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“…Since GAD expression has been closely linked to GABA production and release (Segovia et al, 1990;Mason et al, 2001), we can assume that, in addition to increased DA activity in this VM/ striatal co-culture, there is increased GABA neuronal activity (Diaz et al, 2003). GAD activity is closely regulated by DA in both the adult (Lindefors et al, 1989;Stephenson et al, 2005;Diaz et al, 2003) and developing basal ganglia (Kuppers et al, 2000). While levels of GAD increase developmentally, it has been shown that the disruption of DA neurons, via neurotoxicant administration, further increases GABA activity (Stephenson et al, 2005;Diaz et al, 2003).…”

Section: Discussionmentioning

confidence: 88%

“…GAD activity is closely regulated by DA in both the adult (Lindefors et al, 1989;Stephenson et al, 2005;Diaz et al, 2003) and developing basal ganglia (Kuppers et al, 2000). While levels of GAD increase developmentally, it has been shown that the disruption of DA neurons, via neurotoxicant administration, further increases GABA activity (Stephenson et al, 2005;Diaz et al, 2003). These observations may in part explain large increases in GAD expression at 17 DIV, a time when several measures of DA neuron integrity (numbers of VM DA neurons, and levels of VM and striatal DA and TH) show decreases, likely reflecting some DA degeneration and compensatory increases in GABA function.…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures

2007

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Using organotypic co-cultures of rat embryonic day 14 (E14) ventral mesencephalon (VM and E21 striatum, we have described the developmental changes in (i) dopamine (DA) neurochemistry; (ii) numbers of DA neurons; and (iii) protein expression of tyrosine hydroxylase (TH), DA transporter (DAT), and glutamic acid decarboxylase (GAD 65/67), over 17 days in vitro (DIV). Co-cultures demonstrated changes in DA development similar to those observed in vivo. The numbers of VM DA neurons remained relatively constant, while levels of VM DA progressively increased through 10 DIV. After 3 DIV, the levels of striatal DA increased substantially, through 10 DIV. Tissue levels of DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) reflected changes in tissue DA concentrations, indicating that release and metabolism of DA are similar to these characteristics observed in vivo. Western blot analysis of TH protein expression revealed large increases in VM TH after only 3 DIV, followed by a decline in levels through 17 DIV; levels of striatal TH, in contrast, increased through this period. Additionally, DAT and GAD 65/67 expression increased, in both the VM and striatum, over 17 DIV. By 17 DIV, many measures of DA function had decreased from those assessed at 10 DIV, thus providing an approximate limit to the effective duration of use of this co-culture model. Our results provide a much-needed description of the neurochemical changes that occur during the maturation of VM and striatum in organotypic cocultures. Additionally, these results provide a foundation for future studies to assess toxic challenges of the developing nigrostriatal DA system, in vitro.

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“…L-DOPA-treated monkeys demonstrated continued improvement throughout the treatment phase (Stephenson et al, 2005). By week 3, more than half the animals had reached a PPRS rating of Յ1.5 points (normalization of PPRS) and remained at that level until the end of the study (week 8).…”

Section: Resultsmentioning

confidence: 92%

“…6). Quantitative image analysis revealed that there was a 90% reduction in TH expression and no significant change in GAD65 or GAD67 expression in basal ganglia as a function of MPTP treatment (Stephenson et al, 2005). No qualitative differences in TH expression were observed as a function of dopaminergic treatment condition.…”

Section: Antiparkinsonian Effects Of Sumanirole In Primates 1261mentioning

confidence: 87%

The Effects of a Selective Dopamine D₂ Receptor Agonist on Behavioral and Pathological Outcome in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Squirrel Monkeys

Stephenson¹,

Meglasson²,

Connell³

et al. 2005

J Pharmacol Exp Ther

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In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D 2 receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA Ͼ sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor ⌬FosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.Degeneration of the dopaminergic cells in the substantia nigra (SN) in Parkinson's disease (PD) creates a dopamine (DA) deficiency state that is repleted by administering the DA precursor L-dihydroxyphenylalanine (L-DOPA). L-DOPA is effective in ameliorating the symptoms of bradykinesia, tremors, and muscular rigidity, but it suffers from complications such as induction of motor fluctuations and dyskinesias. As an alternative to L-DOPA, dopaminergic agonists have been developed. Agonists have several potential advantages over L-DOPA: 1) they do not require metabolism to an active form; 2) they do not compete with dietary amino acids for active transport across the intestinal epithelium; 3) agonists may have better reproducibility of the dose response and time action curves; and 4) unlike L-DOPA, agonists may not generate potentially toxic free radicals and may have antioxidant properties (Schapira and Olanow, 2003).DA receptors exist as five subtypes, each of which may have different functions based on dissimilar neuroanatomical expression and pharmacological properties. D 1 and D 2 receptors are abundant in the caudate and putamen, whereas D 3 receptors are expressed at lower levels in the basal ganglia (Emilien et al., 1999). The D 2 receptor may play a key role in the pathophysiology of motor function since it is up-regulated in the striatum in response to DA denervation (Gerfen et al., 1990;Gurevich and Joyce, 1999) as well as in human PD and

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Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without l-DOPA administration

Cited by 31 publications

References 58 publications

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures

The Effects of a Selective Dopamine D₂ Receptor Agonist on Behavioral and Pathological Outcome in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Squirrel Monkeys

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Expression of GAD65 and GAD67 immunoreactivity in MPTP-treated monkeys with or without l-DOPA administration

Cited by 31 publications

References 58 publications

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures

The Effects of a Selective Dopamine D2 Receptor Agonist on Behavioral and Pathological Outcome in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Squirrel Monkeys

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The Effects of a Selective Dopamine D₂ Receptor Agonist on Behavioral and Pathological Outcome in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Squirrel Monkeys