Cellular Mechanisms Implicated in the Action of Neuroprotective Nutraceuticals

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My research program aims to elucidate the cellular mechanisms and pathways implicated in the action of neuroprotective nutraceuticals, specifically plant-derived molecules (phytochemicals). Nutraceuticals are products that range from isolated nutrients, dietary supplements and herbal molecules possessing beneficial physiological properties. An abundant amount of literature is currently proposing a positive effect for these natural molecules in human and animal health. However, in most cases, their alleged pleiotropic beneficial effects have not yet been accurately documented. In this context, my laboratory analyses the role of several phytochemicals in opposing neurodegeneration and neuroinflammation induced by neurotoxins or high glucose administration, in established cellular paradigms and animal models. We are specifically interested in defining the specific cellular mechanisms and pathways used by neuroprotective and anti-inflammatory phytochemicals. Recently, we demonstrated that plant derived molecules such as quercetin, cucurbitacins and sesamin possess multiple cellular properties that go beyond their anti-oxidation action generally known, but also extend to the reduction of both apoptosis and neuroinflammation. Based on our knowledge of natural compounds, for the next five years, I propose to elucidate the cellular mechanisms and pathways implicated in the action of neuroprotective phytochemicals. For this we will focus on three specific aims: 1. To define the cellular neuroprotective mechanisms of individual phytochemicals. 2. To define the cellular mechanisms by which mixtures of phytochemicals prevent neuroinflammation, in vitro. 3. To define the effects of phytochemical mixtures on neuroinflammation, in vivo. Our focus will shift from considering phytochemicals simply as antioxidants to describing them as potentially multi-targeting molecules with particular interest to their anti-inflammatory effects in a neuronal environment. In addition, we will investigate how mixtures of phytochemicals modulate multiple cellular pathways at different levels. Indeed, preliminary results in our laboratory show the use of combinations of phytochemicals to have a synergistic effect on parameters of neuroprotection. Thus my research program will test whether natural compounds, alone or in combination, reduce neurodegeneration and neuroinflammation thus promoting neuroprotection. We will use glia-neuron co-cultures, a reliable system which maintains two cell populations in separate compartments but at very close proximity, and an in vivo model of neuroinflammation, rodents fed with a high-fat diet. This novel research program is expected to yield long-awaited data describing the cellular impact of key phytochemicals in cell nerve homeostasis.