Can Melatonin Prevent and Ameliorate Bipolar Disease in at Risk and Affected?

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder

This article is supplementary to the adolescent monocyte macrophage inflammatory findings in progeny of a bipolar parent in advance of expressed disease.  Complex 1 is one of 5 complexes in the mitochondrial electron transport chain that produces ATP or cellular energy.

To wit, in this article older bipolar patients are inflamed and specifically show dysfunction in Complex 1, the downstream target of inflammatory damage to mitochondrial energy production.

Ubiquinol the reduced form of CoQ10, specifically is involved in complex 1 and is an antioxidant  in the cytosol that reduces reactive oxygen species that trigger the inflamasome.  Melatonin is a cytosol AND mitochondrial ( a transcellular) antioxidant that might prevent the activation of adolescent immune macrophage cells that are at risk of neuroinflammatory changes.

Conjecture:  Macrophage cells in the brain otherwise named microglial cells become inflamed and activate the systemic and innate immune system of neurons and their energy producing mitochondria.

Conjecture:  Manifest bipolar disease treatment should target Complex 1 with Ubiquinol in addition to Melatonin supplementation to reduce neuroinflammation.

Conjecture:  Adolescents with a bipolar parent should reduce monocyte macrophage and microglial inflammation by nightly Melatonin supplementation.  They should also follow a Mediterranean diet which is inherently higher with dietary sources of Melatonin.

Melatonin is a safe and harmless supplement which may or may not prevent the "downstream targets of complex 1 dysfunction in bipolar disorder."  

https://tspace.library.utoronto.ca/handle/1807/69325

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder

Neurogenesis and BDNF and VEGF

Dad,

The TED talk on the factors that improved neurogenesis (production of new nerve in adult brains) resulting in improved memory and improved mood was informative.  It is perfectly consistent with what I have previously pointed out in my DrLiverman.blogspot.com.  It begs the question and evidentiary exegesis below.

How does intermittent fasting, Exercise, Reservatrol, antidepressants and  brain training increases neurogenesis in the hippocampus (the memory learning center of the brain) thereby improving memory and improving mood?  And the corollary question, how does alcohol, opiates and other depressant drugs, high fat diet, chemotherapy, sedentary lifestyle and non-stimulating non-learning environment decrease neurogenesis in the hippocampus thereby degrading memory and degrading mood?

Herein is an article comparing studies in rodents and humans verifying exercise and virtual or real environmental enrichment via 1. BDNF (and its pathway) and 2. VEGF (blood vessel growth factor) were fundamental to spatial neurons (bookmarks), neurogenesis, learning, positive mood and neuron survival.

I want to draw your attention to the relation between memory and navigation of actual(or virtual space.)  Prodigious memory feats use memory palaces or a well known location tag for ordered memory objects.  This is akin to a database written on new cells and dendrites (physical connections with other nerves like a clasped handshake) on flash memory in the hippocampus.  Consolidation is the process of transferring those flash memories to cerebral (thinking part of the brain) and  subcortical ( primitive reptile brain) neurons under stress and over time.  This is best accomplished with quality sleep both REM (rapid eye movement dreaming sleep ) and NonREM sleep.

The metabolic health and energy efficiency of those brain cells preserve memory and make them available for use in making new memories or understanding the present in relation to the past and perhaps predicting a possible or likely future.  With exercise, diet and thinking able to increase neurogenesis/ via BDNF, a bio marker of a metabolic turbocharger, and in conjunction with adequate blood flow for energy support from VEGF, it is clear that the exercise, diet and cognitive activity improves and preserves the entire body of cells.

Consider disabled ALS astrophysicist Stephen Hawkins, his body survives decade from a short term terminal disease disconnected from direct brain wiring but enriched from brain activity in a theoretic and virtual realm of physics by the production and sharing of brain produced BDNF.  The BDNF produced is released to peripheral blood and can become a metabolic turbocharger of any cell type.  This is repeatedly demonstrated when exogenous BDNF is injected into organisms and cell cultures.

Lifestyles that promote BDNF improve cellular structure and function and thereby improves life, central executive function (frontal lobe where non-impulsive judgement takes place), mood, social function and the real and virtual environments in which one lives.

One can choose BDNF increasing lifestyle or BDNF decreasing lifestyle with opposite results.

Most do not choose but live a blended lifestyle.  These choices are more impactful at the beginning and end of life before 25 and after 40.

http://www.sciencedirect.com/science/article/pii/S235215461500039X

Environmental enrichment and neurogenesis: from mice to humans

The brain is a dynamic structure that constantly undergoes cellular and molecular changes in response to the environment. Ultimately, these experience-dependent changes modify and shape behavior. One example of this neuroplasticity is the robust and continuous generation of new neurons that occurs in the dentate gyrus (DG) of the hippocampus. These new neurons are thought to play a fundamental role in hippocampus-dependent behavior and are modulated by experience and changes in the environment. In this review, we will focus on the cognitive and molecular relationship between environmental enrichment and adult neurogenesis. In addition, we discuss some of the similarities between the human and animal literature in regards to neurogenesis, hippocampus-dependent behavior, and environmental enrichment.

Current Opinion in Behavioral Sciences 2015, 4:56–62

This review comes from a themed issue on Cognitive enhancement

Edited by Barbara J Sahakian and Arthur F Kramer

For a complete overview see the Issue and the Editorial

Available online 2nd March 2015

http://dx.doi.org/10.1016/j.cobeha.2015.02.005

2352-1546/© 2015 Elsevier Ltd. All rights reserved.

Overview on Importance of Metabolic Cellular Health

Overview of Metabolic Cellular Health

Machines require energy.  Biological entities require energy. Cells require energy.

Organisms degrade because organs degrade because cells degrade because their metabolic energy and substrate needs are not met because their mitochondria are degraded by inflamaging or injury.

Can this be avoided or reversed?  Consider "immortal" cell cultures of human cells and the variable length of life of various mammals as evidence that cellular life and organism life can be enhanced.

All energy comes from the sun and its energy dividends for the "circle of life" on earth.

Spiritual wisdom summarizes the known why, how and what of life  in human thought.  By this I mean to use common frames of Christian scripture to reframe the above biology!

Consider the following scriptures:

Jesus stated in John 10:10, " My purpose is to give them a rich and satisfying life...I came that they may have life, and may have it abundantly."

Proverbs 10:16 states "the wages of the righteous is life..."

Paul states that the "wages of sin is death..."

Consider the following equalities:

Wealth + Wages - Expenses

This formula for secondary property that is important but also can be taken away like silver and gold.

Health + BDNF (brain derived neurotrophic factor) -  Inflamaging (activated cellular innate immune activity)

This formula for primary property is more essential for life and cannot be taken away for the gain of others.

Here I see the energy and health of the cell as essential for a rich, satisfying and lengthy life for you.  More BDNF and less Inflamaging.  In the word of Mr. Miyagi, "wax on, wax off" meaning more life is the balance of more wax/life building action.

Perform activities that promote BDNF levels.
Avoid activities and substances that reduce BDNF or that yield more inflamaging than BDNF, more wax off than wax on.

Consider as adjuncts to more BDNF, anti-inflamaging strategies to avoid activation of the cellular inflamasome and its components NLRP3, Pro-interleukin 1beta and Caspase which together lead to apoptosis or programmed cell death.

Agents that inhibit the inflamasome components include Melatonin, DHA and Beta hydroxybutyrate (coconut oil or MCT oil derivative), red near infrared light.  See prior blogs for details.  Also know that medications including centrally acting ACE and ARB drugs inhibit the inflammasome and prolong life in heart failure, renal failure and cognitive decline secondary to neurodegenerative diseases.

Melatonin plus exercise yields neuroregeneration

Here using a middle cerebral rodent infarct model the following conclusions can be drawn:

1.  Melatonin protects injured but recoverable stunned brain cells. (Antioxidant effect)

2.  Exercise increases connectivity of neurons that survive. (BDNF effect)

3.  Both together protect via Melatonin inhibiting Reactive oxygen species directly, inhibiting inflammasome indirectly; and, Exercise increasing BDNF directly and thereby increasing nerve connectivity via dendrites, synaptic message amplification, cellular energy metabolism, hippocampal neurogenesis allowing reintegration of the command and control of these cells for future recovery and conscious use.

The brain of the brain is the hippocampus.  It learns, predicts and motivates the rest of the brain.

Adult neurogenesis is what makes BDNF the memory chemical.

Adult neurogenesis is what makes BDNF the positive mood chemical.

BDNF promotes distal command and control systems primarily as a hormone effect with neuron  connections as target organ.

BDNF promotes cellular energy efficiency as a paracrine effect with energy sensing and promotion as targets.

http://www.fasebj.org/content/29/1_Supplement/LB723.short

Pivotal role of melatonin plus exercise as a neuroregenerator following focal cerebral ischemic injury

1. Sookyoung Park1,2, 
2. Seunghoon Lee2,3 and 
3. Yonggeun Hong2,3,4

+ Author Affiliations

Among the numerous studies related to therapeutic mechanism following stroke, neurogenesis plays a critical role. Therefore, we hypothesized that combination therapy with melatonin and exercise might exert on the neurogenesis after focal cerebral ischemia. Sprague-Dawley rats were randomly divided into control (Con) and middle cerebral artery occlusion (MCAo) groups treated vehicle (Veh), melatonin (MT), exercise (EX), and melatonin with treadmill exercise (MT+Ex). MCAo-induced neurological deficits were improved by melatonin with and without exercise. Furthermore, we confirmed the expression of NeuN and Doublecortin were significantly reduced in MCAo+Veh, while melatonin with without exercise attenuated these alterations. The expression of BDNF, in particular mature-BDNF was increased, but not pro-BDNF after MCAo. These changes were reduced at chronic phase of MCAo. GFAP expression was increased in lesion area of MCAo+Veh, then melatonin with and without exercise decreased these changes. By histological examination, MCAo-induced infarction volumes were reduced by melatonin with and without exercise. We found that neurite length from perikaryon was markedly diminished than control rat. However, melatonin plus exercise promotes neurite outgrowth from penumbra to infarct core lesion. Thus, these results demonstrate that melatonin plus exercise could contribute to neuroregeneration and support the potential use for stroke. Funding: 2014R1A1A3051724, 2013 Post-Doctoral Research Program of Inje University, 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512

Adolescents with bipolar lineage have decreased BDNF and increased inflammasome activity.

Adolescents with bipolar lineage have decreased BDNF and increased inflammasome activity.  

Can one prevent and or improve bipolar onset or symptoms in susceptible or diagnosed individuals?  

BDNF is normal in bipolar individuals without symptoms but decreased in both depressed and manic states.

Bipolar has 1% lifetime prevalence.  Depression has 6% prevalence.

How to treat follows:

DHA and Melatonin reduces brain Inflammasome activity.  Slow paced breathing reduces brain TNF alpha and cortisol.

1.  DHA. 1000 mgs daily.

2.  Melatonin 3 mgs at evening.

3.  Shoulders level throughout belly breathing 5 seconds in 5 seconds out for 2 minutes twice daily.

Intermittent fasting, high intensity interval exercise, slow paced breathing and brain.hq.com increases neuroprotective BDNF.

1.  See beginning of blog.

I believe from this evidence below that Bipolar and other mood disorders can be prevented or countered by the same treatments for prevention of Alzheimer's and Parkinson's; 1. increasing BDNF and 2. inhibiting the inflammasome especially of glial and macrophage cells which are the bridge between cellular innate immunity and the systemic immune system.

This bipolar disease prevention strategy is analogous to diabetes prevention strategy via exercise and diet.  

The link below has abstract and full text.

http://onlinelibrary.wiley.com/doi/10.1111/bdi.12231/full

Joseph Thomas (Tony) Liverman, Jr.

BDNF Levels and Addiction are Inversely Proportional

Corticostriatal BDNF and alcohol addiction — ScienceDirect

Alcohol, like opiates, reduce BDNF gene expression which moderates substance use.

Low BDNF = high substance use...uncontrolled substance use.

My DrLiverman.blogspot.com is based on lifestyle that promotes higher BDNF, improved metabolic health and reduced inflamaging.

Intermittent fasting, low glycemic diet, 4 minutes of high intensity interval exercise daily, weekly resistance training, 2 minutes of slow paced diaphragmatic breathing and brain speed training all increase brain and peripheral BDNF.

Addicts and alcoholics could apply this science in their recovery plans.

This includes gambling from prior studies.

Brain speed training alone reduced relapse of gambling or opiate use from 68% to 44% in separate published studies.

If combined lifestyle changes raises BDNF gene expression and levels, one could reasonably expect increased reduction of relapse.

In another study comparing high intensity interval training with and without brain speed training combined allowed men to pedal 115% farther in an exercise to exhaustion test compared to 42% without a second proved BDNF elevator.

Corticostriatal BDNF and alcohol addiction

http://www.sciencedirect.com/science/article/pii/S0006899315002218.

Joseph Thomas (Tony) Liverman, Jr. MD

Melatonin as Antioxidant Blocks Inflamasome Caused Fibrosis

This article was sent to me stating that melatonin prevented or cured an animal model of pulmonary artery hypertension.

Melatonin as preventative and curative therapy in pulmonary hypertension.

http://onlinelibrary.wiley.com/doi/10.1111/jpi.12263/full

This is a provocative abstract.  I had also previously reviewed other various animal models of inducing pulmonary artery hypertension and cardiomyopathy. (Resulting in thickened, fibrosed blood vessels, heart and lung interstiums with decreased compliance or elasticity.). Incidentally this also describes changes occurring with skin aging.

To wit.  The fibrosis, inflammation and pulmonary artery hypertension is due to pressure and degenerative changes via the inflamasome mechanism.  Melatonin blocks the increase in oxygen radicals that activate the inflamasome cascade of caspase and Il-1B.

Melatonin can be given ahead or at the time of ischemia-reperfusion and acts via blocking the inflamasome.

This same inflamasome causes pyroptosis or cellular degradation leading to disruption of cellular calcium potassium channels and mitochondrial integrity with further activation of the inflamasome.  Without energy or capital, cells degrade, fibrose or die.

This is the fate of pancreatic beta cells and alpha cells.  Inflamasome activation and mitochondrial pyroptosis leading to energy poor cells and little or no production of glucagon or insulin.

Broadly speaking, there are studies supporting four methods to block the inflamasome.

1. DHA 1000 mgs daily.

2. Melatonin 3-6 mgs in evening.

3.  MCT oil or coconut oil 30 mls daily blended in food or liquid.

4.  Red Near Infrared light absorbed by cytochrome c in mitochondria yielding additional infusion of ATP for cell energy and cell capital.  More on this in my next blog post.

The core defect of metabolic syndrome is decreased fatty acid oxidation leading to greater reliance on glucose metabolism and net loss of peak cellular energy.  A cell or business bleeding energy, cash or capital will become weak.

BDNF is a bio marker for efficient fatty acid oxidation and metabolic health.

When BDNF is elevated by lifestyle, diet and brain fitness, cells have abundant energy with strong reserves in stored body fat for the body and glucose and ketones for the brain.

Experiment:  treat metabolic syndrome patients with Mediterranean diet, intermittent weekly fasting, HIIE 4 minutes daily, Weekly resistance training, Brain speed training to restore BDNF levels and fatty acid oxidation.  With and without the 4 blocking the inflamasome measures above.  Return to normal? Reversed metabolic syndrome?

An inverse study variation of the above would be to inversely treat metabolic healthy persons and give a high carb diet, little or no exercise, no computer access no socialization.  

Prisoners? Trauma victims? Open heart surgery patients? Stroke patients?  BDNF should go down, energy down, apathy up, cognitive slowing ( all symptoms of depression) and increased inflammatory markers up as the inflamasome is not inhibited.  Expect increase numbers of Metabolic syndrome markers with inflammation markers up.

Joseph Thomas (Tony) Liverman, Jr. MD