Oxidative Stress, Neuroinflammation, and Neuroprotection

Abstract

Oxidative stress is the condition when there is an imbalance in reactive oxygen species production and the antioxidant defense system. Oxidative stress and neuroinflammation are now widely recognized as two interrelated processes that contribute to neuronal dysfunction and degeneration in neurological disorders. A high level of poly unsaturated fatty acids (PUFAs), high metabolic rate and limited antioxidant defenses render the brain increasingly susceptible to the damaging effects of reactive oxygen and nitrogen species (ROS/RNS). Chronic oxidative stress can directly disrupt mitochondrial homeostasis, protein folding, and DNA integrity, and indirectly trigger neuroinflammation via activation of microglia and astrocytes that produce pro-inflammatory cytokines. In turn, the activated glia also produce large amounts of ROS, which further exacerbates the ongoing neurodegenerative process. This chapter reviews, at the molecular, cellular, and systems levels, the detailed mechanisms by which oxidative stress and neuroinflammation are linked, and how redox signaling cross-talks with inflammatory pathways via transcriptional regulators, mitochondrial dysfunction, and cytokine-mediated ROS production. The chapter also highlights endogenous and therapeutic neuroprotective strategies that aim to disrupt this feed-forward cycle. The emerging evidence from experimental and clinical studies is integrated in an attempt to focus on the convergent molecular targets that can be therapeutically modulated, and to point out some translational limitations.