Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model.

Hee Ra Park,Eun Jin Yang

doi:10.3390/antiox11010173

Abstract

To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1G93A mice. Therefore, whether combined treatment with BJIGT and RZ synergistically affects liver function in hSOD1G93A mice was investigated. Two-month-old male hSOD1G93A mice were treated with BJIGT (1 mg/g) and RZ (8 μg/g) administered orally for 5 weeks. Drug metabolism and liver function tests of serum and liver homogenates were conducted. mRNA expression levels of cytochrome P450 (CYP) isozymes, inflammatory cytokines, metabolic factors, and mitochondrial oxidative phosphorylation (OXPHOS) subunits were examined using qPCR and Western blotting. Combined administration of BJIGT and RZ did not alter mRNA expression levels of drug-metabolism-related isozymes (CYP1A2 and CYP3A4) but significantly decreased the activity of liver-function-related enzymes (AST, ALT, ALP, and LDH). Increased expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) and of intracellular stress-related proteins (Bax, AMPKα, JNK, and p38) was reduced by the combined treatment in hSOD1G93A mice compared to that in control mice. Combined administration reduced the mRNA expression of metabolism-related factors and the expression of OXPHOS subunits. Elevated ATP levels and mitochondrial-fusion-associated protein were decreased after co-administration. Co-administration of BJIGT and RZ did not cause liver damage or toxicity but rather restored liver function in hSOD1G93A mice. This suggests that this combination can be considered a candidate therapeutic agent for ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by progressive motor neuron death and is classified as a neuromuscular disease owing to muscle atrophy leading to respiratory failure and death
To determine whether combined administration of BJIGT and RZ caused toxicity in the livers of hSOD1G93A mice during drug metabolism, we evaluated mRNA expression levels of CYP1A2 and CYP3A4
We found that the combination of BJIGT and RZ did not affect drug metabolism, liver function, or hepatic histological patterns in the liver of hSOD1G93A mice

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by progressive motor neuron death and is classified as a neuromuscular disease owing to muscle atrophy leading to respiratory failure and death. Neurodegenerative diseases are often characterized by multiple pathological mechanisms, and those underlying ALS include protein misfolding, inflammation, oxidative stress, and mitochondrial dysfunction [1]. Patients with ALS and transgenic mice both have metabolic abnormalities and energy imbalance, including glucose intolerance and dyslipidemia [2,3]. These abnormalities are related to disease progression and susceptibility, the relationship between metabolic defects and ALS pathogenesis is unclear [4]. Mitochondrial dysfunction occurs in hSOD1G93A mice, the animal model of ALS, including mitochondrial degeneration, vacuolization, and oxidative phosphorylation (OXPHOS) impairment in motor neurons [6,7]

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