Role of microgliosis, oxidative stress and associated neuroinflammation in the pathogenesis of Parkinson's disease: The therapeutic role of Nrf2 activators

Abstract

Microglial cells are the resident immune cells of the central nervous system. They are essential for normal functioning, maintenance of tissue integrity, clearance of dying neurons, elimination of pathogens, development and maintenance of homeostasis of the CNS. Many studies have consistently reported that oxidative stress and associated neuroinflammation mediated by microglial cells have a degenerating effect on dopaminergic neurons. In Parkinson's disease, the microglial cells by a process called microgliosis undergo rapid proliferation, accumulate at the site of tissue injury and undergo phenotypic and functional changes that result in the release of massive amounts of free radicals causing inflammation and neurodegeneration of dopaminergic neurons. Following the discovery of the irrefutable role oxidative stress and associated neuroinflammation, several proven antioxidants were tested for possible protective and therapeutic potential in Parkinson's disease but the results so far have not been encouraging and equivocal. Consequently, it is rational to look for endogenous targets that enhance the oxidative defense mechanism against free radicals and protect dopaminergic neurons from neuroinflammation and neurodegeneration. One such target is a nuclear factor-erythroid -2-related factor 2 (Nrf2). Nrf2 is a redox-sensitive transcription factor located in the cytoplasm of the cells that helps cells adapt to oxidative stress and inflammation by upregulating the expression of almost 200 cytoprotective genes. Fractalkine exists in a transmembrane form and a soluble form and is a cytokine that links microglial cells and Nrf2. The fractalkine receptors, expressed exclusively by microglial cells, on activation by fractalkine protects dopaminergic neurons from degeneration caused by free radicals and pro-inflammatory mediators through increased expression of Nrf2 dependent genes. The current anti Parkinsonism drugs do not cure the disease and also cause several debilitating motor and non-motor adverse drug effects. So it becomes imperative to explore novel targets and discover novel therapeutic agents to treat Parkinson's disease in a better way and improve the quality of life of patients with Parkinson's disease.

Keywords: Antioxidants; Fractalkine; Fractalkine receptors; Microgliosis; Neuroinflammation; Nrf2; Parkinson's disease.