Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder

Elhaik, Eran; Zandi, Peter P.

doi:10.1016/j.jpsychires.2015.08.009

Cited by 35 publications

(29 citation statements)

References 144 publications

(170 reference statements)

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“…We speculate that SIDS is caused by prolonged and repetitive iatrogenic stressful, painful, or traumatic experiences during critical development stages that constitute allostatic overload (156). Over the past years, allostatic load models were proposed to explain several leading medical conditions, including mental health disorders (157, 158), preterm birth (159), and chronic stress (160). …”

Section: Introductionmentioning

confidence: 99%

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Elhaik

2016

Front. Neurol.

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Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures.

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Section: Introductionmentioning

confidence: 99%

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Elhaik

2016

Front. Neurol.

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“…In the earlier stages of the disorder, interleukins and TNF-α are up-regulated while in later stages IL-6 and TNF-α levels expression are maintained (Rege and Hodgkinson, 2013). An up-regulation of all these pro-inflammatory cytokines could be related to overexpression of NF-κB; as the expression subunit of NF-κB, NF-κB2, has been found to be overexpressed in frontal cortex of BD patients (Elhaik and Zandi, 2015). The alteration in NF-κB might account for brain atrophy and apoptosis observed in BD.…”

Section: Molecular Basis Of Bipolar Disorder Progressionmentioning

confidence: 98%

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

Naaldijk¹,

Bittencourt²,

Sack

et al. 2016

Biological Chemistry

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Bipolar disorder (BD) is a severe psychiatric disorder that affects up to 15% of the worldwide population. Characterized by switches in mood between mania and depression, its etiology is still unknown and efforts have been made to elucidate the mechanisms involved in first episode, development and progression of the disorder. Microglia activation, abnormal activity of GSK-3β and reduction in neurotrophic factor expression related to neuroinflammatory processes have been indicated to be part of the disorder's pathophysiology. Lithium, the main mood stabilizer used for the treatment and prevention of relapses, acts as an anti-inflammatory agent. Based on that, here we suggest a neuroinflammatory pathway for would be BD progression, in which microglia activation states modulated via constitutive induction of kinin-B1 receptor and reduction of kinin-B2 receptor expression and activity.

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“…The growth of the blastocyst into the uterus is similar to a bacterial infection and has to be considered as a stressful event for the mother [58]. During pregnancy a reduction of the steroidal hormone androstenediol takes place in the first trimester, which is a key steroidal hormone to facilitate innate immunity protection [59] and can be related to the gene expression of p53 gene, a hallmark gene for cell differentiation and apoptosis in mammals [60]. In mice, androstenediol plays a key role in parturition, as it modifies immunity [60].…”

Section: Dna Repair As Part Of Innate Immunity Response In Human Pregmentioning

confidence: 99%

“…During pregnancy a reduction of the steroidal hormone androstenediol takes place in the first trimester, which is a key steroidal hormone to facilitate innate immunity protection [59] and can be related to the gene expression of p53 gene, a hallmark gene for cell differentiation and apoptosis in mammals [60]. In mice, androstenediol plays a key role in parturition, as it modifies immunity [60]. Androstenediol stimulates innate immune cell function in nerve system cells and in healthy cells reduces DNA damage and induces genes that modulate genes related to the innate immunity in nerve cells [61].…”

Section: Dna Repair As Part Of Innate Immunity Response In Human Pregmentioning

confidence: 99%

The evolution of genomic stability to a mechanism in reproduction and psychiatry

Regidor

Volko

Schindler³

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.

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Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder

Cited by 35 publications

References 144 publications

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

The evolution of genomic stability to a mechanism in reproduction and psychiatry

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