Nrf2 pathway in psychiatric disorders
Pathophysiological role and Potential Targeting
Introduction: All psychiatric disorders exhibit excitotoxicity, mitochondrial dysfunction, inflammation, oxidative stress, and neural damage as their common characteristic. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is implicated in the defense mechanism against oxidative stress and has a significant role in psychiatric disorders.
Areas covered: We explore the role of Nrf2 pathway and its modulators in psychiatric disorders. The literature was searched utilizing various databases such as Embase, Medline, Web of Science, Pub-Med, and Google Scholar from 2010 to 2020. The search included research articles, clinical reports, systematic reviews, and meta-analyses.
Expert opinion: Environmental factors and genetic predisposition can be a trigger for the development of psychiatric disorders. Nrf2 downregulates certain inflammatory pathways and upregulates various antioxidant enzymes to maintain a balance. However, its intricate balance with NF-Kβ (Nuclear factor kappa light chain enhancer of activated B cells) and its crosstalk with the transcription factor Nrf2 is critical in severe oxidative stress. Several Nrf2 modulators are now in clinical trials and can help reduce oxidative stress and neuroinflammation. There are immense potential opportunities for these modulators to become a novel therapeutic option.
- Oxidative stress followed by neuroinflammation has been implicated as a critical driver of various obnoxious events in the pathophysiology of psychiatric disorders.
- Nrf2 has a wider role to play, it acts as a protective mechanism against oxidative stress by increasing the production of various antioxidant enzymes like HQ-1, glutathione, NQO1, and NADPH.
- Diseases such as depression, anxiety, schizophrenia, autism, obsessive-compulsive disorder show an increase in oxidative stress as part of their pathophysiology. Upregulation of oxidative stress leads to impairment in the Nrf2 pathway leading to poor homeostatic antioxidant control.Nrf2/Keap1 and NFḳβ pathways crosstalk to maintain control of the oxidative stress and inflammation under basal conditions. With increased oxidative stress, the Nrf2 pathway becomes saturated and the activity of the NFḳβ pathway is increased leading to an increased production of pro-inflammatory cytokines.
- Various natural and synthetic Nrf2 modulators have shown strong potential to upregulate Nrf2 and thus control the oxidative stress condition observed during oxidative stress.
- The Nrf2-Keap1 pathway can be explored as a viable therapeutic target in neurological conditions. Its activation is responsible for attenuating various processes including mitochondrial dysfunction, oxidative stress, and neuroinflammation which are involved in neuropsychiatric and neurodegenerative disorders.
- Nrf2 compounds have already been US-FDA approved for use in multiple sclerosis. Such activators could be warranted in many other neurodegenerative conditions.
Autism
Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes expression of a large number of antioxidant genes and multiple studies have described oxidative stress and impaired methylation in autism spectrum disorder (ASD), including decreased brain levels of methylcobalamin(III) (MeCbl). Here we report decreased expression of the Nrf2 gene (NFE2L2) in frontal cortex of ASD subjects, as well as differences in other genes involved in redox homeostasis.
Diabetes
Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities
Alzheimer's
Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD).
Neuropsychiatric Disorders
Depression, anxiety, schizophrenia, autism, obsessive-compulsive,
(Nrf2) signaling pathway is implicated in the defense mechanism against oxidative stress and has a significant role in psychiatric disorders.
Stroke
Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus and induces the transcription of enzymes involved in counteracting oxidative stress, endobiotic and xenobiotic metabolism, regulators of inflammation, and others.
Corona: Progressive Maladaptation
A systematic review of neurological symptoms and brain abnormalities in SARS-CoV-2 infections
SARS-CoV-2 can infect multiple brain areas, sometimes with asymptomatic conditions. As a result, Wang et al. [6] reported the following symptoms in general: (1) headache, languidness, unstable walking, and malaise; (2) cerebral hemorrhage; (3) cerebral infarction; (4) other neurological diseases. Although previous reviews on neurological symptoms and the type and location of brain abnormalities associated with COVID-19 exist [7], the rapid spread of the virus and the continued increase in cases have escalated the number of publications reporting brain damage in patients affected by COVID-19. In this way, the knowledge about brain alterations and neurological symptoms that seem to be associated with COVID-19 has expanded exponentially in the last few months.
Microbleeds & Strokes Associated with Covid-19
Many people have reported microbleeds and strokes after infection. Schifitto says that the virus often infects endothelial cells anywhere in the body, including those in the brain vessels. He explains, “The virus affects the endothelial cells. Small strokes, large strokes, or dysregulation of the blood-brain barrier, which then could predispose to additional inflammation coming from the bloodstream into the brain.”
GrExploring Therapeutic Approaches for Long COVID Neuropsychiatric
Despite the significant toll long COVID takes on individuals, there is limited literature on potential therapeutic agents for this condition. In this report, we discuss several possible therapeutic psychopharmacologic agents and explore how they may be beneficial in the treatment of long COVID.
1 in 3 Covid-19 patients are diagnosed with a neuropsychiatric condition in the next six months
Six months after being diagnosed with Covid-19, 1 in 3 patients also had experienced a psychiatric or neurological illness, mostly mood disorders but also strokes or dementia, a large new study shows.
About 1 in 8 of the patients (12.8%) were diagnosed for the first time with such an illness, most commonly anxiety or depression. Compared to control groups of people who had the flu or other non-Covid respiratory infections, first-ever neuropsychiatric diagnoses were almost twice as high.
C- Reactive Neurocognitive Symptoms
Insomnia, psychosis, cognitive impairment, and mood disorders during the acute stage of COVID-19 infection have been described in numerous reports.
ICUs in France described agitation in 40 (69%) confusion in 26 (65%) Confusion Assessment Method for the ICU. At discharge, 15 (33%) of 45 patients who were assessed had a dysexecutive syndrome with symptoms such as inattention, disorientation, or poorly organized movements in response to command. COVID-19 patients in Turkey showed that 34.9% of participants had significant levels of anxiety and 42.0% had depression at or above threshold . A study comparing the mental status and inflammatory markers patients infected demonstrated higher levels of depression, anxiety, and post-traumatic stress symptoms as assessed in online surveys. Levels of C-reactive protein correlated positively with the patients who presented symptoms of depression, suggesting a potential inflammatory pathway underlying these symptoms.
The “Show Me the Value” Health Care Revolution
It is a situation that cries out for sophisticated management, for managers comfortable with MDs and MBAs, behavioral economics and Big Data, operational change and human obstinancy. Health care is entering an era of detailed scrutiny of both processes of care and outcomes, and this new era will bring with it new rules.
Government-controlled systems excel at the first two options. They set global budgets, prescribe prices and proscribe pricy new technologies until there’s tangible proof of need. The decisions about each individual’s care may ultimately lie with clinicians, but government or government-funded intermediaries can place a heavy thumb on the scale. In this country, Medicare and Medicaid offer less-comprehensive versions of price and utilization controls through a kind of single-payer “light.”