A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-κB Inhibition

Autor: Gloria V. López, Paulina Invernizzi, Mariana Ingold, Emiliano Trias, Mariela Bollati-Fogolín, Carlos Batthyány, Mariángeles Kovacs, Peter H. King, Williams Porcal, Carlos Escande, Ying Si, Valentina Varela, Jorge Rodriguez-Duarte, Luis Barbeito, Sofía Ibarburu, Ana Paula Arévalo, Yuri Kwon, Karen Perelmuter
Rok vydání: 2020
Předmět:
Zdroj: Neurotherapeutics
ISSN: 1878-7479
1933-7213
DOI: 10.1007/s13311-020-00953-z
Popis: 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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00953-z.
Databáze: OpenAIRE
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