Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis

Asmita Gyawali,Sana Latif,Young-Sook Kang,Seung-Hye Choi,Seung Jae Hyeon,Hoon Ryu

doi:10.1186/s12929-022-00785-3

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor.MethodsTo investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay.Results[3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines.ConclusionsTogether, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no success‐ ful therapeutics are available
Knockdown of monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) decreases their protein levels in the ALS cell lines model we examined whether SMCT1 and MCT1 Small interference RNA (siRNA) transfection affected the protein expression levels in the Motor neuron-like (NSC-34) cell lines
Smct1 and Smct2 siRNA transfection significantly decreased the [3H]Valproic acid (VPA) uptake rate in the WT cell line (Fig. 7a), but only SMCT1 siRNA. These results indicate that both SMCT1 and SMCT2 are involved in VPA influx into the WT cell lines, whereas in the MT cell lines, VPA is partly taken up by only SMCT1 (Fig. 7), which is a common transporter for VPA import into both WT and MT cell lines

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no success‐ ful therapeutics are available. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motor neurons, which originate from the brain and spinal cord, respectively [1] The two types of ALS with. MCTs belong to the solute carrier (SLC) transporter superfamily and facilitate the passive transport of monocarboxylates, such as lactate, pyruvate, butyrate, ketone bodies, and many others, via proton coupling [10, 11]. Two sodium-coupled MCTs (SMCTs), SMCT1 (SLC5A8) and SMCT2 (SLC5A12), are highly expressed in neurons, the brain, retina, intestine, and kidney and transport energy substrates, such as butyrate, lactate, pyruvate, nicotinate, and salicylate, via proton and sodium coupling [10, 12, 13]. Neurons obtain monocarboxylates from the brain via MCTs, which strongly participate in energy metabolism during the fight against neurological disorders [13, 15]

Methods

Findings

Discussion

Conclusion