Martinez-Palma 2018 Neurotherapeutics
|Martínez-Palma L, Miquel E, Lagos-Rodríguez V, Barbeito L, Cassina A, Cassina P (2018) Mitochondrial modulation by dichloroacetate reduces toxicity of aberrant glial cells and gliosis in the SOD1G93A rat model of amyotrophic lateral sclerosis. Neurotherapeutics [Epub ahead of print].|
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment of AbGC reduced extracellular lactate levels indicating that the main recognized DCA action, targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase complex, may underlie our findings. Our results show that AbGC metabolic phenotype is related to their toxicity to MNs and indicate that its modulation can reduce glial mediated pathology in the spinal cord. Together with previous findings, these results further support glial metabolic modulation as a valid therapeutic strategy in ALS.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Neurodegenerative
Organism: Rat Tissue;cell: Nervous system Preparation: Intact cells
Coupling state: LEAK, ET Pathway: ROX HRR: Oxygraph-2k