Glutamate in Huntington's disease

Reynolds, Gavin P.; Pearson, Sally J.; Bryant, DavidJ.; Weeks, RobertA.; Marcus, ClaudeD.; Sargentoni, J; Taylor-Robinson, Simon D; Brooks, David J.

doi:10.1016/s0140-6736(94)92788-x

Cited by 12 publications

(3 citation statements)

References 5 publications

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“…(2002) using R6/2 mice and wild‐type (WT) littermates have shown that the R6/2 transgenic HD mouse model was generally less responsive to the administration of cocaine and methamphetamine (METH) than WT littermates, suggesting a close relationship between the motor symptoms of HD and dopamine regulation. Neurochemical studies have also shown that dopamine neurotransmission is dysregulated in HD (Reynolds and Pearson 1994; Reynolds et al . 1999; Abercrombie and Russo 2002; Hickey et al .…”

mentioning

confidence: 99%

Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease

Johnson

Rajan²,

Miller³

et al. 2006

Journal of Neurochemistry

119

123

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Recently, alterations in dopamine signaling have been implicated in Huntington's disease. In this work, dopamine release and uptake was measured in striatal slices from the R6/2 transgenic mouse model of Huntington's disease using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Dopamine release in brain slices from 6-week-old R6/2 mice is substantially reduced (53% of wild type), while dopamine uptake is unaffected. In agreement with this, R6/2 mice injected with the dopamine uptake inhibitor cocaine exhibited a blunted motor activity response (54% of wild type). At 10 weeks of age, an even more dramatic motor activity decrease in response to cocaine injection (21% of wild type) was observed. Moreover, the pre-drug activity of 10-weekold R6/2 mice was significantly reduced (by 37%) compared with 6-week-old R6/2 mice. Striatal dopamine release decreased with age, indicating that progressive alterations in dopaminergic pathways may affect motor activity. The inhibition constants of cocaine and methamphetamine (METH) determined in brain slices differed little between genotype or age group, suggesting that the decreased responses to cocaine and METH arise from compromised dopamine release rather than differences in uptake or drug action. Collectively, these data demonstrate (i) a reduction in the ability of dopamine terminals to release dopamine and (ii) the importance of this attenuation of release on the motor symptoms of Huntington's disease.

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mentioning

confidence: 99%

Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease

Johnson

Rajan²,

Miller³

et al. 2006

Journal of Neurochemistry

119

123

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“…One issue is whether the biological process used as a screen is relevant to the intended disease. For example, in HD there is much evidence that glutamate-mediated excitotoxicity is involved in the pathogenesis of the disease, [35][36][37][38] so drugs have been screened in vitro and in animal models to assess their ability to block this effect. Drugs that are effective in the screening process (i.e., block glutamatemediated excitotoxicity) have failed in clinical trials, suggesting that the screening model may not be relevant to the disease.…”

Section: Preclinical Drug Discoverymentioning

confidence: 99%

Evidence from biomarkers and surrogate endpoints

Feigin

2004

Neurotherapeutics

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Summary:The use of physiological, anatomical, and other biological tests is commonplace in the practice of medicine. In neurology, objectively measured tests termed biomarkers (BMs) are playing an increasing role in diagnosis and management of disease, both in clinical practice and in experimental therapeutics. This article will discuss the various applications of BMs to the assessment of therapies for neurological diseases and will use examples from neurological diseases to elucidate the strengths and potential weaknesses of BMs. As the understanding of the pathophysiology of many neurological diseases has improved, new BMs have been developed, and efforts have been made to use these as proxies for clinical endpoints. A BM used in this manner is referred to as a surrogate endpoint (SE). There are many potential advantages and disadvantages of using SEs in the evaluation of new therapies, and these will be reviewed as well. Furthermore, the evidence required for the development of an SE and the nature of the evidence that can be derived from the use of BMs and SEs will be discussed.

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“…Appel, 1993;Martin et al, 2000) and Huntington disease (e.g. Taylor-Robinson et al, 1994;Reynolds and Pearson, 1994). Glutamate neurotoxicity is also involved in the neuronal damage found in cerebral ischemia and it has been proposed to be involved in the origin of Alzheimer's (e.g.…”

Section: Introductionmentioning

confidence: 99%

Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death

et al. 2001

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Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as "scavengers" of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity. The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.

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Glutamate in Huntington's disease

Cited by 12 publications

References 5 publications

Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease

Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease

Evidence from biomarkers and surrogate endpoints

Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death

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