Role of microgliosis, oxidative stress and associated neuroinflammation in the pathogenesis of Parkinson's disease: The therapeutic role of Nrf2 activators
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Abstract
<p class="first" id="d3220295e67">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.
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