Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters.

BACKGROUND: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. METHODS: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks. RESULTS: Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. CONCLUSION: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.

Anti-Amnesic and Neuroprotective Effects of Fluoroethylnormemantine in a Pharmacological Mouse Model of Alzheimer's Disease.

BACKGROUND: Current therapies in Alzheimer's disease (AD), including Memantine, have proven to be only symptomatic but not curative or disease modifying. Fluoroethylnormemantine (FENM) is a structural analogue of Memantine, functionalized with a fluorine group that allowed its use as a positron emission tomography tracer. We here analyzed FENM neuroprotective potential in a pharmacological model of AD compared with Memantine. METHODS: Swiss mice were treated intracerebroventricularly with aggregated Aß 25-35 peptide and examined after 1 week in a battery of memory tests (spontaneous alternation, passive avoidance, object recognition, place learning in the water-maze, topographic memory in the Hamlet). Toxicity induced in the mouse hippocampus or cortex was analyzed biochemically or morphologically. RESULTS: Both Memantine and FENM showed symptomatic anti-amnesic effects in Aß 25-35-treated mice. Interestingly, FENM was not amnesic when tested alone at 10 mg/kg, contrarily to Memantine. Drugs injected once per day prevented Aß 25-35-induced memory deficits, oxidative stress (lipid peroxidation, cytochrome c release), inflammation (interleukin-6, tumor necrosis factor-α increases; glial fibrillary acidic protein and Iba1 immunoreactivity in the hippocampus and cortex), and apoptosis and cell loss (Bcl-2-associated X/B-cell lymphoma 2 ratio; cell loss in the hippocampus CA1 area). However, FENM effects were more robust than observed with Memantine, with significant attenuations vs the Aß 25-35-treated group. CONCLUSIONS: FENM therefore appeared as a potent neuroprotective drug in an AD model, with a superior efficacy compared with Memantine and an absence of direct amnesic effect at higher doses. These results open the possibility to use the compound at more relevant dosages than those actually proposed in Memantine treatment for AD.