Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the  in vitro effect of combined therapy with antioxidants and β‐cyclodextrin nanoparticles

AbstractNiemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes:NPC1 orNPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated thein vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitra...
Source: Metabolic Brain Disease - Category: Neurology Source Type: research