Mechanisms 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.

Neuroprotective Effects of Doxycycline in the R6/2 Mouse Model of Huntington’s Disease / E. Paldino, C. Balducci, P. La Vitola, L. Artioli, V. D'Angelo, C. Giampa, V. Artuso, G. Forloni, F.R. Fusco. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - 57:4(2020 Apr 01), pp. 1889-1903. [10.1007/s12035-019-01847-8]

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

L. Artioli;
2020-04-01

Abstract

Mechanisms 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.
BDNF; Doxycycline; Huntington’s disease; Inflammation; Microglia; Neurodegeneration; pCREB; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Corpus Striatum; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Disks Large Homolog 4 Protein; Doxycycline; Female; Huntington Disease; Male; Mice, Transgenic; Microglia; Motor Activity; Neurons; Neuroprotective Agents; Open Field Test; Organ Size; Survival Analysis; Weight Loss
Settore BIO/09 - Fisiologia
Settore MED/26 - Neurologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/859644
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