Therapeutic interventions for symptomatic treatment in Huntington's disease

Mestre, Tiago; Ferreira, Joaquim J.; Coelho, Miguel; Rosa, Mário Miguel; Sampaio, Cristina

doi:10.1002/14651858.cd006456.pub2

Cited by 108 publications

(85 citation statements)

References 90 publications

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“…The increase in DA tone at the early stage maximally activates D1 DA receptors on direct pathway MSNs. These findings are in line with observations that DA receptor antagonists and other agents that decrease DA reduce chorea and motor symptoms in patients and in animal models while dopaminergic stimulation can exacerbate symptoms [65, 66]. To speculate further, the lack of effect of the D1 agonist might have been caused by decreased expression of D1 receptors at the plasma membrane as reported in other hyperdopaminergic conditions [60].…”

Section: Differential Properties Of Direct and Indirect Output Pathwasupporting

confidence: 88%

Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Galvan

André

Wang

et al. 2012

Journal of Huntington's Disease

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There is morphological evidence for differential alterations in striatal medium-sized spiny neurons (MSNs) giving rise to the direct and indirect output pathways in Huntington's disease (HD). MSNs of the indirect pathway appear to be particularly vulnerable and markers for these neurons are lost early in postmortem brains and in genetic mouse models. In contrast, MSNs of the direct pathway appear to be relatively spared in the early stages. Because of the great morphological and electrophysiological similarities between MSNs of these pathways, until recently it was difficult to tease apart their functional alterations in HD models. The recent use of the enhanced green fluorescent protein gene as a reporter to identify dopamine D1 (direct pathway) and D2 (indirect pathway) receptor-expressing MSNs has made it possible to examine synaptic function in each pathway. The outcomes of such studies demonstrate significant time-dependent changes in the balance of excitatory and inhibitory inputs to both direct and indirect pathway MSNs in HD and emphasize early increases in both excitatory and inhibitory inputs to direct pathway MSNs. There also is a strong influence of alterations in dopamine modulation that possibly cause some of the changes in excitatory and inhibitory synaptic transmission in the HD models. These changes will markedly alter the output structures, the GPi and the SNr. In the future, the use of combined optogenetics with identified neurons in each pathway will help unravel the next set of questions about how the output nuclei are affected in HD.

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Section: Differential Properties Of Direct and Indirect Output Pathwasupporting

confidence: 88%

Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Galvan

André

Wang

et al. 2012

Journal of Huntington's Disease

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“…Huntington’s disease (HD) is a progressive neurodegenerative disorder for which there is currently no cure and few treatments are available (Bonelli and Hofmann, 2007; Fasano et al, 2008; Brusa et al, 2009; Mestre et al, 2009). Patients suffer from chorea (involuntary dance-like movements) in early stages, akinesia in later stages, as well as cognitive and psychiatric disturbances (Harper and Jones, 2002; Bonelli and Hofmann, 2007).…”

Section: Introductionmentioning

confidence: 99%

Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease

Parievsky

Moore

Kamdjou

et al. 2017

Neurobiology of Disease

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Huntington’s disease (HD) is a fatal genetic disorder characterized by cell death of medium-sized spiny neurons (MSNs) in the striatum, traditionally attributed to excessive glutamate inputs and/or receptor sensitivity. While changes in corticostriatal projections have typically been studied in mouse models of HD, morphological and functional alterations in thalamostriatal projections have received less attention. In this study, an adeno-associated virus expressing channelrhodopsin-2 under the calcium/calmodulin-dependent protein kinase IIα promoter was injected into the sensorimotor cortex or the thalamic centromedian-parafascicular nuclear complex in the R6/2 mouse model of HD, to permit selective activation of corticostriatal or thalamostriatal projections, respectively. In symptomatic R6/2 mice, peak amplitudes and areas of corticostriatal glutamate AMPA and NMDA receptor-mediated responses were reduced. In contrast, although peak amplitudes of AMPA and NMDA receptor-mediated thalamostriatal responses also were reduced, the areas remained unchanged due to an increase in response decay times. Blockade of glutamate reuptake further increased response areas and slowed rise and decay times of NMDA responses. These effects appeared more pronounced at thalamostriatal synapses of R6/2 mice, suggesting increased activation of extrasynaptic NMDA receptors. In addition, the probability of glutamate release was higher at thalamostriatal than corticostriatal synapses, particularly in R6/2 mice. Morphological studies indicated that the density of all excitatory synaptic contacts onto MSNs was reduced, which matches the basic electrophysiological findings of reduced amplitudes. There was a consistent reduction in the area of spines but little change in presynaptic terminal size, indicating that the postsynaptic spine may be more significantly affected than presynaptic terminals. These results highlight the significant and differential contribution of the thalamostriatal projection to glutamate excitotoxicity in HD.

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“…Clinical experience supports the use of these agents to control chorea, however, only the monoaminedepleting agent tetrabenazine has been clearly shown to reduce chorea in an appropriately powered double-blind placebo controlled study. 134,135 Adverse effects from neuroleptics and tetrabenazine can limit their use. Depression is the most concerning side effect of tetrabenazine, and the presence of depression is generally thought of as a relative contraindication to its use.…”

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confidence: 99%

The Clinical and Genetic Features of Huntington Disease

Sturrock

Leavitt

2010

J Geriatr Psychiatry Neurol

123

111

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Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that usually presents in adulthood with characteristic motor and cognitive features and with variable and diverse psychiatric disturbances. Following the discovery of the causative defect in the HTT gene in 1993, great advances in understanding the pathogenesis of HD have been made, yet no effective disease-modifying therapy has been identified. In this new era of HD research, we have seen the emergence of a number of large clinical trials, the systematic search for novel biomarkers and the recent initiation of the first pre-manifest HD clinical studies. In this review, we seek to provide an overview of the clinical and genetic features of HD together with a summary of clinical research at this time.

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Therapeutic interventions for symptomatic treatment in Huntington's disease

Abstract: No intervention proved to have a consistent symptomatic control in HD. Tetrabenazine is the anti-choreic drug with the best quality data available. Other symptomatic areas should be explored by well-designed randomised placebo-controlled studies.

Cited by 108 publications

References 90 publications

Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease

The Clinical and Genetic Features of Huntington Disease

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