Contribution of cell type specific changes of monocarboxylate transporters to amyotrophic lateral sclerosis (ALS) disease and application of boron derivatives as an alternative treatment

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized by chronic degeneration of upper and lower motor neurons. Various mechanisms have been associated with degeneration of motor neurons in ALS up to date; however, unlike the classical findings, recently lactate transporters; MCT1 and MCT4 expressions were found to be decreased, suggesting energy deprivation may play a role in ALS pathogenesis. In the current study, in order to understand the contribution of MCTs to ALS pathogenesis, the changes in expression levels of MCT1, and MCT4 in the CNS of transgenic SOD1-G93A and C9ORF72 mice were examined in a cell-type-specific manner. According to the findings, a significant increase in MCT1 expressions was determined in both whole-spinal cord materials and brain-derived oligodendrocytes, while a significant decrease in MCT4 expressions was detected in brain-derived astrocytes, and no significant change was observed in MCT2 expressions in transgenic mice, suggesting a compensatory role for MCT1 and a causal role for MCT4 in ALS. In-vitro experiments using NSC-34 motor neuron-like cells revealed that lactate at appropriate doses can be used as an energy source, as an alternative to glucose, and when MCTs were chemically blocked with AR-C155858, lactate trafficking was partially interrupted, negatively affecting cell survival. Additionally, inspired by the introduction of some boron derivatives for the treatment of neurodegenerative diseases, the effect of various boron derivatives on locomotor behaviors and molecular mechanisms were tested in the SOD1-G93A mice model. It was observed that especially sodium pentaborate pentahydrate (NaB) and sodium perborate tetrahydrate (SPT) promote a considerable improvement in motor activities of transgenic mice, and moreover, according to microarray data, they positively changed the expression of genes involved in numerous metabolic pathways associated with neurodegenerative diseases. This study provided further evidence for the role of MCTs in ALS and was the first of the related studies to elicit the possible neuroprotective effect of NaB and SPT.