A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via
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RESEARCH PAPER
A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-κB Inhibition Sofía Ibarburu 1 & Mariángeles Kovacs 1 & Valentina Varela 1 & Jorge Rodríguez-Duarte 2 & Mariana Ingold 2,3 & Paulina Invernizzi 2 & Williams Porcal 2,3 & Ana Paula Arévalo 4 & Karen Perelmuter 5 & Mariela Bollati-Fogolín 5 & Carlos Escande 6 & Gloria V. López 2,3 & Peter King 7,8 & Ying Si 7,8 & Yuri Kwon 7 & Carlos Batthyány 2 & Luis Barbeito 1 & Emiliano Trias 1 Accepted: 12 October 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (E)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1G93A rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1G93A rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1G93A rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition. Key Words ALS . NF-κB-p65 . microglia . BANA.
Introduction There is no current treatment to stop disease progression in amyotrophic lateral sclerosis (ALS), a paralytic disease
characterized by progressive degeneration of motor neurons that control skeletal muscles. Survival after diagnosis average 3 to 5 years, and is largely determined by the rate of spread of motor neuron pathology along the neuroaxis [1]. ALS
* Luis Barbeito [email protected]
4
Transgenic and Experimental Animal Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay
* Emiliano Trias [email protected]
5
Cell Biology Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay
6
Laboratory of Metabolic Diseases and Aging, INDICyO
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