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

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.

Pyroptotic cell death in the R6/2 mouse model of Huntington’s disease: new insight on the inflammasome

“…Microglial reaction increased over time, concurrently with the significantly higher expression levels of NLRP3 in other cells of the striatum. However, unlike previously described 13 , we did not observe NLRP3 immunoreaction in the Iba-1 labeled microglia 14 .

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New Synthetic 3-Benzoyl-5-Hydroxy-2H-Chromen-2-One (LM-031) Inhibits Polyglutamine Aggregation and Promotes Neurite Outgrowth through Enhancement of CREB, NRF2, and Reduction of AMPKα in SCA17 Cell Models

“…This result is in consistence with previous reports that impaired CREB-dependent transcription plays an important role in the pathogenesis of polyQ diseases [7]. Several compounds or strategies activating CREB-dependent transcription have been shown to ameliorate pathology and phenotypes of cell and animal models of polyQ diseases including SCA3 and HD [11][12][13][14][15][16]63]. Valproic acid can protect against the toxicity of expanded ataxin-3 in an inducible cell model of SCA3 by upregulating CREB-dependent transcription through hyperacetylation [13].…”

“…Rolipram provides a neuroprotective effect to R6/2 HD mice via increasing the levels of activated CREB and of BDNF in the striatal spiny neurons [15]. More recently, doxycycline improves neurological deficits and reduces neuropathology in R6/2 mice by enhancing CREB activation in striatum as well as negatively modulating neuroinflammation [16]. However, the effects of CREBactivators have never been shown in SCA17 models.…”

“…Suppression of CREB-dependent transcription has been shown in a HD cell model, HD and SCA3 mice, and human HD brains [6][7][8][9][10]. Therefore, enhancement of CREB-mediated transcriptional activation is considered as a potential therapeutic strategy for polyQ diseases [11][12][13][14][15][16]. Since transcriptional dysregulation has been shown to play a role in pathogenic mechanisms of SCA17 [17], we proposed that CREB-mediated gene expression is downregulated in SCA17 and compounds augmenting CREB activation can rescue the cytotoxicity.…”

Stereological study of organelle distribution in human oocytes at metaphase I

“…The number of publications regarding the application of stereology as quantitative tool in biomedical research has largely increased in the last fifty years (Kipanyula and Sife, 2018). Recent articles have shown the use of a stereological approach in studies related to Alzheimer's disease (Furcila et al, 2019), Huntington's disease (Paldino et al, 2019) and Parkinson's disease (Kim et al, 2020), as well as to quantify the total number of white matter interstitial neurons in the human brain (Sedmak and Judas, 2019), to name only a few. Additionally, a study quantifying the distribution of organelles in oocytes at prophase-I using a stereological analysis was performed (Pires-Luis et al, 2016).…”