In recent years, research in the field of dementia has been exploring the role of Nrf2 in the body and uncovering its potential for antioxidant, anti-inflammatory, and mitochondrial functions.[i] Of particular interest is its role in the central nervous system (CNS) and on the aging brain. The following is a roundup of the most current knowledge about Nrf2 and its role in prominent degenerative conditions.
Nrf2 (nuclear factor erythroid 2 p45-related factor 2) is a transcription factor that regulates the expression of genes involved in cellular protection against damage caused by oxidants and inflammatory agents. Activation of Nrf2 leads to the upregulation of proteins involved in the synthesis of glutathione, the main intracellular small molecule antioxidant. Nrf2 plays a role in the maintenance of mitochondrial function, inhibits the transcription of genes encoding proinflammatory cytokines, and suppresses proinflammatory responses.
Recent findings suggest that Nrf2 activation mitigates various pathogenic processes involved in these disorders through stimulation of antioxidant response, stabilization of mitochondrial function, inhibition of inflammation, and maintenance of protein homeostasis. Pharmacological activators of Nrf2 have shown protective effects in numerous animal models and may provide disease-modifying therapeutic options in neurodegenerative disorders.
The Role of Nrf2 in Parkinson’s Disease
Oxidative stress, mitochondrial dysfunction, and neuroinflammation have all been implicated in the development and progression of Parkinson’s disease. In animal testing, Nrf2 activation showed neuroprotective effects. These effects were associated with a reduction of oxidative damage and neuroinflammation. Although Nrf2 has not yet been targeted in clinical interventions in Parkinson’s disease, epidemiological evidence suggests that consumption of high levels of the Nrf2-activating vitamins E and C is associated with decreased risk of Parkinson’s disease. In addition, treatment with Nrf-2 activators, like N-acetyl cysteine, omega 3 fatty acids, and vitamin E improved scores in the Unified Parkinson’s Disease Rating Scale (UPDRS) and increased the total antioxidant capacity.
The Role of Nrf2 in Alzheimer’s Disease
Observations of patients with early stages of Alzheimer’s disease included increased oxidative stress with diminished antioxidant capacity and reduced neuronal mitochondrial function associated with low nuclear expression of Nrf2. The activation of Nrf2 reduces amyloid secretion and normalizes cytokines in Alzheimer’s disease astrocytes, while also protecting against cell death in isolated neurons exposed to Ab. Although pharmacotherapies specifically targeting Nrf2 should be investigated clinically, some evidence suggests that Nrf2 activators like vitamin E, omega 3 fatty acids, and alpha lipoic acid could be beneficial. Trials with vitamin E have shown slight improvements in cognitive function and daily life activities at high doses, whereas treatment with a combination showed decline in the mini-mental state exam, as well as in daily life activities.
The Role of Nrf2 in Multiple Sclerosis
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder characterized by demyelination, axonal degeneration, and astrocytosis. The activation of microglia and macrophages is a major contributor to the increased reactive oxygen species (ROS) seen in MS. These elevated ROS levels, along with the enhanced inflammatory response, are associated with mitochondrial injury, oxidative stress, and altered metabolism, leading to the formation of plaques and neurodegeneration, which are prominent features of disease. Loss of Nrf2 has been shown to result in more rapid disease onset and a more severe clinical course, whereas a large quantity of Nrf2-activating compounds (dimethyl fumarate/Tecfidera, Vitamin D, omega 3 fatty acids, and lipoic acid) showed decreased inflammatory response, increased antioxidant capacity, improvements on the expanded disability status scale, and overall beneficial effects in MS patients.
The Role of Nrf2 in Other Disorders
Potential therapeutic effects of Nrf2 activators have been observed in the treatment of Huntington’s disease, Friedreich’s ataxia, and ischemic stroke.
How Worldwide Is Contributing to Dementia Research
During Worldwide’s more than 40 years designing and executing central nervous system clinical trials, we’ve seen numerous groundbreaking developments, including repurposing treatments from one area of CNS clinical research to another. This is why we’re continuously improving how we approach CNS clinical research. Talk to one of our CNS experts about starting your CNS clinical development program.