Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4.MethodsThe present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1G93A transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1.ResultsWe found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1G93A mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation.ConclusionsIn summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1G93A mouse model of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment
SOD1G93A mice treated with anti-high-mobility group box 1 (HMGB1) antibody from this ‘pre-onset’ age had no significant extension in survival time when compared with litter-matched untreated SOD1G93A mice (p = 0.3620, n = 13; Fig. 1a)
We investigated whether inhibition of HMGB1 in SOD1G93A mice had any effect on the expression of TNFα and IL-1β and the several major receptors of the innate immune system (RAGE, complement C5a receptor 1 (C5aR1) and TLR4) in the lumbar spinal cord. mRNA expression of tumour necrosis factor (Tnf) and Il1β was measured in isotype control and anti-HMGB1 antibody-treated SOD1G93A mice at mid-symptomatic stage of disease progression by quantitative real-time PCR
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease, which is characterised by the irreversible loss of upper and lower motor neurons in the motor cortex, brainstem and spinal cord. This selective loss of neurons leads to muscle denervation, and atrophy, resulting in paralysis and eventual death via respiratory muscle failure [1]. The receptor for advanced glycation end products (RAGE), the toll-like receptor (TLR) system and the complement C5a receptor 1 (C5aR1) are major components of the innate immune system, which have been implicated in ALS pathology. Multiple studies have demonstrated that inhibition and/or genetic deletion of RAGE, TLR4, or C5aR1 has beneficial effects on survival and disease progression in animal models of ALS [6,7,8,9,10,11], suggesting that these immune receptors play a pathogenic role in the disease.
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