Testing of neuroprotective compounds in a transgenic mouse model of Huntington's disease

Zádori, Dénes

doi:10.14232/phd.644

Cited by 1 publication

(1 citation statement)

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“…Dantrolene is also clinically useful for the treatment of symptoms associated with spasticity (Chou et al, 2004), and rhabdomyolysis induced by exercise (Edwards et al, 2003). Furthermore, dantrolene has been shown to have neuroprotective effects in multiple models of neurodegenerative disorders like Huntington's disease (Chen et al, 2011) and Alzheimer's disease (Wang et al, 2017;Liang and Wei, 2015). The muscle relaxant properties of dantrolene have been linked with its ability reduce [Ca 2+ ] r in humans (Lopez et al, 1992), swine (Lopez et al, 1987a) and mice (Yang et al, 2006;Cherednichenko et al, 2008;Eltit et al, 2013) although the exact mechanisms by which dantrolene exerts its therapeutic effects both in muscle and neurons are not fully understood.…”

Section: Dantrolene Neuroprotection and Agingmentioning

confidence: 99%

Memory and Learning Deficits Are Associated With Ca2+ Dyshomeostasis in Normal Aging

Uryash

Flores

Adams

et al. 2020

Front. Aging Neurosci.

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Neuronal intracellular Ca 2+ homeostasis is critical to the normal physiological functions of neurons and neuronal Ca 2+ dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca 2+ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca 2+ homeostasis in cortical (in vivo) and hippocampal (in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca 2+ ] r) in cortical (in vivo) and hippocampal (in vitro) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro, removal of extracellular Ca 2+ or treatment with SAR7334 or dantrolene reduced [Ca 2+ ] r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo, both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca 2+ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.

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