Increased numbers of motor activity peaks during light cycle are associated with reductions in adrenergic α2-receptor levels in a transgenic Huntington's disease rat model

Bode, Felix J; Stephan, Michael; Wiehager, Sara; Nguyen, Huu Phuc; Björkqvist, Maria; Hörsten, Stephan von; Bauer, Andreas; Petersén, Åsa

doi:10.1016/j.bbr.2009.06.031

Cited by 36 publications

(25 citation statements)

References 53 publications

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“…In a rat model, male animals display increased daytime activity at an earlier stage of phenotype than female rats [36]. In the N171-82Q model, male mice show poorer performance on the rotarod than female mice [37].…”

Section: Discussionmentioning

confidence: 99%

Responses to Environmental Enrichment Differ with Sex and Genotype in a Transgenic Mouse Model of Huntington's Disease

et al. 2010

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BackgroundEnvironmental enrichment (EE) in laboratory animals improves neurological function and motor/cognitive performance, and is proposed as a strategy for treating neurodegenerative diseases. EE has been investigated in the R6/2 mouse model of Huntington's disease (HD), where increased social interaction, sensory stimulation, exploration, and physical activity improved survival. We have also shown previously that HD patients and R6/2 mice have disrupted circadian rhythms, treatment of which may improve cognition, general health, and survival.Methodology/Principal FindingsWe examined the effects of EE on the behavioral phenotype and circadian activity of R6/2 mice. Our mice are typically housed in an “enriched” environment, so the EE that the mice received was in addition to these enhanced housing conditions. Mice were either kept in their home cages or exposed daily to the EE (a large playground box containing running wheels and other toys). The “home cage” and “playground” groups were subdivided into “handling” (stimulated throughout the experimental period) and “no-handling” groups. All mice were assessed for survival, body weight, and cognitive performance in the Morris water maze (MWM). Mice in the playground groups were more active throughout the enrichment period than home cage mice. Furthermore, R6/2 mice in the EE/no-handling groups had better survival than those in the home cage/no-handling groups. Sex differences were seen in response to EE. Handling was detrimental to R6/2 female mice, but EE increased the body weight of male R6/2 and WT mice in the handling group. EE combined with handling significantly improved MWM performance in female, but not male, R6/2 mice.Conclusions/SignificanceWe show that even when mice are living in an enriched home cage, further EE had beneficial effects. However, the improvements in cognition and survival vary with sex and genotype. These results indicate that EE may improve the quality of life of HD patients, but we suggest that EE as a therapy should be tailored to individuals.

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Section: Discussionmentioning

confidence: 99%

Responses to Environmental Enrichment Differ with Sex and Genotype in a Transgenic Mouse Model of Huntington's Disease

et al. 2010

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“…delivery [50], and may target α-2 adrenergic receptors and PPARγ receptors in the brain [19,21]. It has been shown that the expression of α-2 adrenergic receptors is increased in the hypothalamus of transgenic rats for HD [51], but antagonism rather than agonism is involved α-2 adrenergic receptor-mediated neuroprotection [52], and therefore it is unlikely that CBG alleviates HD symptoms and disease markers by targeting this receptor. On the contrary, PPARγ agonists such as thioglitazones have been shown to have a neuroprotective effect in in vitro and in vivo models of HD [53][54][55].…”

mentioning

confidence: 99%

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Navarrete²,

et al. 2015

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Different plant-derived and synthetic cannabinoids have shown to be neuroprotective in experimental models of Huntington's disease (HD) through cannabinoid receptordependent and/or independent mechanisms. Herein, we studied the effects of cannabigerol (CBG), a nonpsychotropic phytocannabinoid, in 2 different in vivo models of HD. CBG was extremely active as neuroprotectant in mice intoxicated with 3-nitropropionate (3NP), improving motor deficits and preserving striatal neurons against 3NP toxicity. In addition, CBG attenuated the reactive microgliosis and the upregulation of proinflammatory markers induced by 3NP, and improved the levels of antioxidant defenses that were also significantly reduced by 3NP. We also investigated the neuroprotective properties of CBG in R6/2 mice. Treatment with this phytocannabinoid produced a much lower, but significant, recovery in the deteriorated rotarod performance typical of R6/2 mice. Using HD array analysis, we were able to identify a series of genes linked to this disease (e.g., symplekin, Sin3a, Rcor1, histone deacetylase 2, huntingtin-associated protein 1, δ subunit of the gamma-aminobutyric acid-A receptor (GABA-A), and hippocalcin), whose expression was altered in R6/2 mice but partially normalized by CBG treatment. We also observed a modest improvement in the gene expression for brain-derived neurotrophic factor (BDNF), insulinlike growth factor-1 (IGF-1), and peroxisome proliferatoractivated receptor-γ (PPARγ), which is altered in these mice, as well as a small, but significant, reduction in the aggregation of mutant huntingtin in the striatal parenchyma in CBGtreated animals. In conclusion, our results open new research avenues for the use of CBG, alone or in combination with other phytocannabinoids or therapies, for the treatment of neurodegenerative diseases such as HD.

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“…In most studies, the circadian disruption is associated with progressive impairment of sleep architecture and sleep EEG 153,154,156,157 suggesting an interaction between disruption of circadian behaviour and fragmented sleep architecture, but with no exact indication on any causal relationship between the two. Restoration of circadian rhythmicity and sleep has been shown to alleviate the disease course in HD: reconsolidation of circadian entrainment by pharmacological agents or other interventions slows down cognitive decline and normalizes circadian gene expression.…”

Section: Circadian Dysfunction In Hdmentioning

confidence: 99%

'The clocks that time us'—circadian rhythms in neurodegenerative disorders

et al. 2014

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Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep–wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep–wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep–wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep–wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases.

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Increased numbers of motor activity peaks during light cycle are associated with reductions in adrenergic α2-receptor levels in a transgenic Huntington's disease rat model

Cited by 36 publications

References 53 publications

Responses to Environmental Enrichment Differ with Sex and Genotype in a Transgenic Mouse Model of Huntington's Disease

Responses to Environmental Enrichment Differ with Sex and Genotype in a Transgenic Mouse Model of Huntington's Disease

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

'The clocks that time us'—circadian rhythms in neurodegenerative disorders

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