losartan-potassium and Huntington-Disease

Oxidative stress and mitochondrial dysfunction are among the mechanisms expected to explain the pathogenesis of Huntington's disease. Erythropoietin (EPO) and the Bacillus Calmette-Guérin (BCG) vaccine have neuroprotective effects against neurodegenerative diseases; however, the full mechanisms of their action are currently unclear. Here, for the first time, we investigated the neuroprotective effect of BCG vaccination in Huntington-like disease induced by 3-nitropropionic acid (3-NP) and its combination with EPO. Male Wistar rats were randomized into five groups: saline-treated control; 3-NP group (20 mg/kg/day, i.p.) for 7 days; EPO-treated group (5000 IU/kg/day, i.p.) for 14 days after 3-NP administration; live BCG vaccine prophylactic group (5000 cfu/g, i.p.) 10 days prior to 3-NP administration; and live BCG vaccine (5000 cfu/g, i.p.) 10 days before 3-NP administration, followed by EPO treatment (5000 IU/kg/day, i.p.) for 14 days. In a histopathological examination, striatum neurodegeneration was evidenced in the 3-NP injected rats. Administration of 3-NP elevated the levels of p-PI3K, p-Akt, p-mTOR, p-P70S6K, BAX, malondialdehyde, nitric oxide, and cytochrome oxidase while reduced the levels of BCL-2, superoxide dismutase, reduced glutathione, and the autophagy marker microtubule-associated protein light chain 3 in the striatum. EPO and BCG ameliorated the biochemical, histopathological, and behavioral derangements induced by 3-NP, with prominent neuroprotection observed in rats administered the BCG prophylactic combined with EPO treatment. These results highlight the role played by EPO and BCG in the management of 3-NP-induced Huntington-like disease by inhibiting the PI3K/Akt/mTOR/P70S6K pathway and enhancing the autophagy.

Topics: Animals; Autophagy; BCG Vaccine; Erythropoietin; Huntington Disease; Male; Neuroprotective Agents; Nitro Compounds; Phosphatidylinositol 3-Kinases; Propionates; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases; Vaccination

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a trinucleotide (CAG) repeat expansion in the huntingtin gene (HTT). The R6/2 transgenic mouse model of HD expresses exon 1 of the human HTT gene with approximately 150 CAG repeats. R6/2 mice develop progressive behavioural abnormalities, impaired neurogenesis, and atrophy of several brain regions. In recent years, erythropoietin (EPO) has been shown to confer neuroprotection and enhance neurogenesis, rendering it a promising molecule to attenuate HD symptoms. In this study, the therapeutic potential of EPO was evaluated in female R6/2 transgenic mice. A single bilateral injection of a lentivirus encoding human EPO (LV-hEPO) was performed into the lateral ventricles of R6/2 mice at disease onset (8 weeks of age). Control groups were either untreated or injected with a lentivirus encoding green fluorescent protein (LV-GFP). Thirty days after virus administration, hEPO mRNA and protein were present in injected R6/2 brains. Compared to control R6/2 mice, LV-hEPO-treated R6/2 mice exhibited reduced hippocampal atrophy, increased neuroblast branching towards the dentate granular cell layer, and improved spatial cognition. Our results suggest that LV-hEPO administration may be a promising strategy to reduce cognitive impairment in HD.

Topics: Animals; Atrophy; Cognition; Disease Models, Animal; Erythropoietin; Female; Genetic Therapy; Hippocampus; Huntington Disease; Injections, Intraventricular; Lentivirus; Mice; Mice, Transgenic; Neural Stem Cells; Organ Size; Spatial Navigation; Transfection

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene. Both excitotoxicity and oxidative stress have been proposed to play important roles in the pathogenesis of HD. Since no effective treatment is available, this study was designed to explore the therapeutic potential of erythropoietin (EPO), a cytokine that has been found to prevent excitotoxicity, and to promote neurogenesis. To avoid the side effects of a raised hematocrit, we used asialoerythropoietin (asialoEPO), a neuroprotective variant of EPO that lacks erythropoietic effects in mice. R6/2 transgenic HD mice were treated with this cytokine from five to twelve weeks of age.. We provide new evidence that cell proliferation in the dentate gyrus of the R6/2 hippocampus is reduced by 50% compared to wild-type littermate controls. However, we found that the asialoEPO treatment did not affect the progression of motor symptoms, weight loss or the neuropathological changes. Furthermore, cell proliferation was not enhanced.. We conclude that the chosen protocol of asialoEPO treatment is ineffective in the R6/2 model of HD. We suggest that reduced hippocampal cell proliferation may be an important and novel neuropathological feature in R6 HD mice that could be assessed when evaluating potential therapies.

Topics: Animals; Asialoglycoproteins; Behavior, Animal; Cell Division; Cytokines; Dentate Gyrus; Disease Models, Animal; Disease Progression; Erythropoietin; Female; Huntington Disease; Male; Mice; Mice, Transgenic; Neuroprotective Agents; Phenotype; Treatment Failure; Weight Loss