olesoxime and Demyelinating-Diseases

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Signaling; Cell Line; Charcot-Marie-Tooth Disease; Cholestenones; Demyelinating Diseases; Diabetic Neuropathies; Drug Evaluation, Preclinical; Female; Male; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Obese; Mice, SCID; Mitochondria; Myelin Sheath; Peripheral Nerves; Rats; Schwann Cells; Voltage-Dependent Anion Channel 1

Multiple sclerosis is a neurodegenerative autoimmune disease characterized by diffuse oligodendrocyte injury, axonal loss and multifocal demyelination of myelin sheaths in the central nervous system. TRO19622 is a small cholesterol-like compound, which displays remarkable neuroprotective and neuroregenerative properties in neural cell culture and rodent models of nerve trauma. Therefore, the aim of the present study is to evaluate the pharmacological action of TRO19622 on the demyelination/remyelination processes by using a rat model of cuprizone-induced demyelination.. Using Female Sprague-Dawley rats models of demyelination, we morphologically and functionally assessed the effect of TRO19622 on myelination in vivo.. In this study, we first provided in vivo proof that cuprizone intoxication contributed to spatial learning and memory ability injury and that TRO19622 restored neurological function. The structure of myelin injury and repair in cuprizone intoxication rats was then measured by T2-weighted magnetic resonance imaging. These magnetic resonance imaging-based results and trends were confirmed by histological, immunohistochemistry and electron microscopy analyses.. The results clearly showed that TRO19622 promoted myelin formation with consequent functional improvement.

Topics: Animals; Cholestenones; Demyelinating Diseases; Disease Models, Animal; Female; Rats; Rats, Sprague-Dawley

Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo.. The effect of olesoxime on oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC-neuron cocultures. Using naive animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo.. Olesoxime accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naive animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, olesoxime favored the repair process, promoting myelin formation with consequent functional improvement.. Our observations support the strategy of promoting oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide proof of concept that olesoxime could be useful for the treatment of demyelinating diseases.

Topics: Animals; Cholestenones; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Rats; Rats, Sprague-Dawley