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

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 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.

Evaluation of the Oral Bacterial Genome and Metabolites in Patients with Wolfram Syndrome

“…Interestingly, the role of lactic acid derivatives as signaling molecules in the brain with possible neuroprotective effects is increasingly being pointed out [ 33 ], as is the possibility of using lactic acid bacteria in an animal model of Alzheimer’s disease [ 34 ]. Furthermore, the neuroprotective properties of benzoic and acetic acid derivatives have also prompted preclinical trials of their therapeutic use in various neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) [ 35 , 36 ], and even applications in DM-induced and Parkinson’s disease (PD)-related neurodegeneration [ 37 ]. It should be noted that the results of metabolic studies can be applied not only in the search for markers of observed disorders, but also as therapeutic strategies.…”

A review for the pharmacological effects of paeoniflorin in the nervous system

“…However, it should also be noted that once paeoniflorin enters into the body, it can be converted into another molecule that crosses the blood-brain barrier, benzoic acid ( Yu et al, 2019b ). Benzoic acid supplementation can improve cognitive function in patients with schizophrenia ( Lane et al, 2013 ), dementia ( Lin et al, 2019 ; Lin et al, 2021 ), and early-phase Alzheimer’s disease ( Lin et al, 2014 ), and benzoic acid derivatives have been reported to exert numerous pharmacological effects in the nervous system, such as suppression of glaucoma-associated neurodegeneration ( Luo et al, 2020 ), inhibition of microglial activation and pathological processes of amyotrophic lateral sclerosis ( Ibarburu et al, 2021 ), and inhibition of proliferation of human glioma cells ( Yue et al, 2016 ), researchers should clarify whether the pharmacological effects of paeoniflorin in the central nervous system are mediated by benzoic acid.…”

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

“…Compounds providing protection against apoptosis and motor neurone degeneration: sphingosine-1-phosphate [24], metformin [31], thymoquinone [44], citicoline [45], nitrovinyl benzoic acid (4-[(1E)-2-nitrovinyl] benzoic acid) [46], ambroxol [47], isofagomine [47], fingolimod [47], fasudil [48], Y-27632 [48], acerogenin [49]. Xanomeline [16], telmisartan [37], orientin [50], geniposide [51], licochalcone A [52], taraxasterol [53], acetylcarnitine [54], atorvastatin [55], riluzole [56] and sulforaphane [57] protect neurons against oxygen-glucose deprivation/reperfusion.…”