![]() Emerging research has also demonstrated that brain health and cognitive function may be related to the dynamic changes in the gut microbiota. Berries may be useful in improving age-related memory deficits in humans, as well as in mice receiving high-fat diets. High-fat diets are associated with neuronal and memory dysfunction. ![]() Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer’s disease and other types of dementia. The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)–induced neuroinflammatory mouse model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. ![]() Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. All types of dementia, including Alzheimer’s disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. ![]()
0 Comments
Leave a Reply. |