Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease due to an expansion of a trinucleotide repeats in IT15 gene encoding for the protein huntingtin. Motor dysfunction, cognitive decline, and psychiatric disorder are typical clinical signs of HD. In HD, mutated huntingtin causes a major loss of brain derived neurotrophic factor (BDNF), causing striatal atrophy. Moreover, a key involvement of BDNF was observed in the synaptic plasticity that controls the acquisition and/or consolidation of certain forms of memory. We studied changes in hippocampal BDNF and in CREB in the R6/2 mouse model of HD. Moreover, we investigated if the beneficial effects of systemically administered recombinant BDNF observed in the striatum and cortex had an effect also on the hippocampus. Osmotic minipumps that chronically released recombinant BDNF or saline solution from 4 weeks of age until euthanasia were implanted into R6/2 and wild type mice. Our data show that BDNF is severely decreased in the hippocampus of R6/2 mice, while BDNF treatment restored its physiological levels. Moreover, the chronic administration of recombinant BDNF promoted the increment of phosphorylated CREB protein. Our study demonstrates the involvement of hippocampus in the pathology of R6/2 model of HD and correlates the beneficial effects of BDNF administration with increased hippocampal levels of BDNF and pCREB.

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Neuroprotective Effects of Doxycycline in the R6/2 Mouse Model of Huntington’s Disease

Molecular Neurobiology ◽

10.1007/s12035-019-01847-8 ◽

2019 ◽

Vol 57 (4) ◽

pp. 1889-1903 ◽

Cited By ~ 6

Author(s):

Emanuela Paldino ◽

Claudia Balducci ◽

Pietro La Vitola ◽

Luisa Artioli ◽

Vincenza D’Angelo ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neuroprotective Effect ◽

Neurological Dysfunction ◽

Striatal Neurons ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Doxycycline Treatment ◽

Immunohistochemical Studies

AbstractMechanisms of tissue damage in Huntington’s disease involve excitotoxicity, mitochondrial damage, and inflammation, including microglia activation. Immunomodulatory and anti-protein aggregation properties of tetracyclines were demonstrated in several disease models. In the present study, the neuroprotective and anti-inflammatory effects of the tetracycline doxycycline were investigated in the mouse model of HD disease R6/2. Transgenic mice were daily treated with doxycycline 20 mg/kg, starting from 4 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that doxycycline-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the saline-treated ones. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and the negative modulation of microglial reaction revealed a neuroprotective effect of the compound. Doxycycline provided a significantly increase of activated CREB and BDNF in the striatal neurons, along with a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings show that doxycycline treatment could be considered as a valid therapeutic approach for HD.

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Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease

Scientific Reports ◽

10.1038/s41598-019-52391-3 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Elaine E. Irvine ◽

Loukia Katsouri ◽

Florian Plattner ◽

Hind Al-Qassab ◽

Rand Al-Nackkash ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Mammalian Target Of Rapamycin ◽

Protein Aggregate ◽

Beneficial Effects ◽

Age Related ◽

Signalling Molecule ◽

Mutant Huntingtin Protein

Abstract Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.

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