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.
Highlights
Neurodegeneration of striatal projection neurons is the main event in the pathology of Huntington’s disease (HD)
To produce large quantities of dangerous compounds such as prostaglandin E2 (PGE2), nitric oxide (NO), and cytokines like tumor necrosis factor-a (TNF-a), interleukin-1 b (IL-1 b), and interleukin 6 (IL-6) that participate in the pathological processes through the activation of nuclear factor-K B (NF-k B), leading to neurodegeneration [3, 4]
At 11 weeks, wild-type mice treated with saline weighed 32 ± 0.50 g and were not significantly different from wild type treated with doxycycline
Summary
Neurodegeneration of striatal projection neurons is the main event in the pathology of Huntington’s disease (HD). The role of neuroinflammation has gained momentum. Inflammation is a physiological response aimed at repairing damaged tissue in several different conditions. Inflammation is designed to initiate healing processes, and protect the organism [1, 2]. A major role in central nervous system is played by microglia. To produce large quantities of dangerous compounds such as prostaglandin E2 (PGE2), nitric oxide (NO), and cytokines like tumor necrosis factor-a (TNF-a), interleukin-1 b (IL-1 b), and interleukin 6 (IL-6) that participate in the pathological processes through the activation of nuclear factor-K B (NF-k B), leading to neurodegeneration [3, 4]
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