Brain Protease Activated Receptor 1 Pathway: A Therapeutic Target in the Superoxide Dismutase 1 (SOD1) Mouse Model of Amyotrophic Lateral Sclerosis

International Journal of Molecular Sciences

Yoel Kloog¹  Roni Sharon²  Doron Bushi²  Efrat Shavit-Stein²  Amir Dori²  Lea Pollak²  Orna Gera²  Ihab Abu Rahal²  Nicola Maggio²  ShanyG. Gofrit²  Joab Chapman²  Kate Mindel³ 

[1]Department of Neurobiochemistry, Weiss Faculty of Life Sciences, Tel Aviv University, Tel Aviv6997801, Israel

[2]Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel

[3]Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel

关键词: amyotrophic lateral sclerosis (ALS);    superoxide dismutase 1 (SOD1);    brain;    thrombin;    protease activated receptor 1 (PAR1);   

DOI  :  10.3390/ijms21103419

来源: DOAJ

【 摘 要 】

Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.

【 授权许可】

Unknown