Fosgonimeton, a novel, small molecule positive modulator of the HGF/MET system is neuroprotective in primary neuron culture

Abstract

AbstractBackgroundPositive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Activation of the HGF/MET system induces neuroprotective effects that counteract neurotoxicity, neuroinflammation, and oxidative stress‐induced damage, all pathological hallmarks of neurodegeneration. Herein, we investigated the in vitro neuroprotective potential of fosgonimeton (ATH‐1017), a novel, small molecule positive modulator of the HGF/MET system that has demonstrated neurotrophic and pro‐cognitive effects in vitro and in vivo. In addition, we assayed several novel compounds with related activity to fosgonimeton to establish the neuroprotective effects of a series of HGF/MET positive modulators.MethodMature rat cortical neurons were treated with the active metabolite of fosgonimeton or related HGF/MET positive modulators and subjected to a variety of neurotoxic insults including 1‐methyl‐4‐phenylpryidinium (MPP+), glutamate, lipopolysaccharide (LPS), or hydrogen peroxide (H2O2). Neuronal cell viability was determined using CellTiter Glo luminescence assay to assess relative levels of ATP. Furthermore, the effect of fosgonimeton and other test compounds on mitochondrial membrane potential (MMP) was assessed utilizing a fluorescent MMP dye.ResultCortical neurons treated with our HGF/MET positive modulators exhibited significant improvement in cell viability against MPP+ neurotoxicity, glutamate excitotoxicity, LPS‐induced cytotoxicity, and H2O2‐induced oxidative stress. For example, treatment with 1 µM fosgonimeton rescued cell viability against neurological insults with the following percent recoveries: 85% vs. MPP+, 61% vs. glutamate, 93% vs. LPS, and 144% vs. H2O2. Significant improvement in cell viability was also observed at 100 nM, 10 nM, and 1 nM fosgonimeton against all insults, highlighting its potent neuroprotective actions. Furthermore, fosgonimeton treatment led to an increase in mitochondrial membrane potential, suggesting that it may mitigate mitochondrial dysfunction associated with neurodegeneration.ConclusionOur data demonstrate the ability of fosgonimeton and related HGF/MET positive modulators to offer protection against several neurological insults that are central to neurodegeneration. The neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects, highlight its therapeutic potential to restore neuronal health and slow or reverse neurodegeneration. Fosgonimeton is currently in clinical trials for Alzheimer’s disease, Parkinson’s disease dementia, and Dementia with Lewy bodies.