The lack of success to date of clinical trials using ROS scavenging drugs has led to the hypothesis that inhibition of the generation, rather than the scavenging, of ROS may be a more successful avenue of therapy. Unfortunately, these therapies have generally been unsuccessful in clinical trials despite promise in animal models.
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Therapies attempting to target oxidative stress have typically focused on compounds that scavenge the free radicals to eliminate them from the system. From this body of research, it has become clear that pathological conditions such as ischemia, trauma, and neurodegenerative processes, markedly enhances generation of ROS in the brain. For instance, a keyword search on PubMed using the terms “oxidative stress and neurodegeneration” or “oxidative stress and brain injury” yielded over 8,400 citations, with approximately half of these occurring in the last five years. For the past several decades, evidence has accumulated supporting oxidative stress as an underlying common denominator of brain injury and neurodegenerative disorders. Although the clinical manifestations differ for these disorders, a common denominator in their pathology is the induction of oxidative stress. Neurodegenerative disorders such as stroke, traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) carry substantial disease burden, not only in terms of health suffering but also in economic costs. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. NADPH oxidase has the primary function to generate free radicals. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. However, therapies attempting to scavenge free radicals have shown little success. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury.
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