Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Autor: Lee, John D., Liu, Ning, Levin, Samantha C., Ottosson, Lars, Andersson, Ulf, Harris, Helena E., Woodruff, Trent M.
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Zdroj: Journal of Neuroinflammation; 2/19/2019, Vol. 16 Issue 1, pN.PAG-N.PAG, 1p
Abstrakt: Background: Amyotrophic 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.Methods: The 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.Results: We 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.Conclusions: In 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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