TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester-Induced Mitochondrial Injury and Necrotic Cell Death.

Objectives: Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP).

Methods: Changes in mitochondrial membrane potential (Δψm), cytosolic Ca ([Ca]c), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy.

Olesoxime favors oligodendrocyte differentiation through a functional interplay between mitochondria and microtubules.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by episodes of immune attacks and oligodendrocyte death leading to demyelination and progressive functional deficits. New therapeutic strategies are needed to stimulate the spontaneous regenerative process observed in some patients. Spontaneous myelin repair relies on the mobilization and differentiation of endogenous oligodendrocyte progenitors at the lesion site.

Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat.

Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements.

TRO40303, a mitochondrial-targeted cytoprotective compound, provides protection in hepatitis models.

TRO40303 is cytoprotective compound that was shown to reduce infarct size in preclinical models of myocardial infarction. It targets mitochondria, delays mitochondrial permeability transition pore (mPTP) opening and reduces oxidative stress in cardiomyocytes submitted to ischemia/reperfusion in vitro. Because the involvement of the mitochondria and the mPTP has been demonstrated in chronic as well as acute hepatitis, we investigated the potential of TRO40303 to prevent hepatocyte injury.

Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP.

Objective: Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established.

Design: We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models.