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Bipolar Disorder. The effects of nutrition on the process of demyelination By Elise Handley University of Colorado EPOB 4800. Symptoms of bipolar disorder. Roller Coaster of Mood Swings Definitive changes in energy or activity level Changes in thinking and perception Suicidal thoughts

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bipolar disorder

Bipolar Disorder

The effects of nutrition on the process of demyelination

By Elise Handley

University of Colorado

EPOB 4800

symptoms of bipolar disorder
Symptoms of bipolar disorder
  • Roller Coaster of Mood Swings
  • Definitive changes in energy or activity level
  • Changes in thinking and perception
  • Suicidal thoughts
  • Destructive/Impulsive behavior
  • Sleep Problems
bpdi vs bpdii
BPDI is defined as at least 1 episode of manic or mixed disorder and at least one episode of major depressive disorder

BPDII is defined as at least 1 hypomanic disorder and one major depressive episode

  • Current treatments include use of many different drugs such as antidepressants, anti-psychotics, mood stabilizers etc.
  • The problem with the current approach is that it ignores the possibility of larger underlying neurological problems.
  • Many studies have implicated that demyelination may be the root cause of BPD
brain basics1
Brain Basics
  • Before we talk about demyelination, let’s talk about the structure of the brain.
  • White matter consists of bundles of myelinated fibers, which are supported by the neuroglia.
  • The neuroglia are comprised of astrocytes, oligodendrocytes, and microglia.
  • Oligodendrocytes support myelin formation and are key to this whole process
  • Astrocytes are primarily responsible for neuron maintainance
brambilla et al
Brambilla et al.
  • Anatomical abnormalities have been found in the corpus callosum of BPD patients
  • The decreased size may indicate degeneration or improper aging of white matter tracts as well as decreased connectivity between the two hemispheres
sassi et al 2003
Sassi et al. (2003)
  • White matter hyperintensities were noted in the brain structure of BPD patients, however they were not significant (contrary to many previous papers)
  • It is commonly believed that these white matter regions are areas of increased water density, possibly due to cerebrovascular damage
  • Moore et al. noted that only patients that failed to respond to treatments had increased amounts of hyperintensities
kieseppa et al 2003
Kieseppa et al. (2003)
  • This twin study indicated that identical twins (where one had BPD and the other did not) both had more hyperintensities than the healthy control twins. However, only the BPD twin had a significant increase.
  • This study failed to report an increased ventricular size, perhaps due to the sample population
possible conclusions to kieseppa et al 2003
Possible Conclusions to Kieseppa et al (2003)
  • The hyperintensities may be due to a genetic pre-disposition
  • They may be case-specific, not a marker of this disease
  • They may be a marker of mental-illness in general, as they are often noted in schizophrenia
friedman et al 1999
When compared on seven measures, there were no significant differences between BPD patients and schizophrenic patients

They differed from control in intracranial volume, adjusted ventricular volume, frontal fluid percent, and temporal fluid percent

There was also a trend in decreased head circumference11

Friedman et al. (1999)
  • Micrencephaly is a sign of mental disorder in general, not of BPD or schizophrenia.
  • To further this claim, Friedman et al. believes that the increased ventricular size and sulcal prominence are also indicative of mental disorder, not BPD
uranova et al 2001
Uranova et al. (2001)
  • Uranova focused on abnormalities in the physical make-up of the brain
  • It was found that BPD brains had several symptoms indicative of myelin breakdown
normal brains vs bpd brains
Round Nucleus

Electron dense heterochromatin

Granular ER in the cytoplasm

Free ribosomes, mitochondria etc.

Swelling of cytoplasm and organelles

Clumping of heterochromatin

Decreased nuclear size

All signs were consistent with programmed cell death in oligodendrocytes

Myelinated fibers had various changes

Normal Brains vs. BPD Brains
uranova et al 20011
Uranova et al. (2001)
  • In 31% of cases, oligodendrocyte density was decreased significantly
  • This pathology is remarkably similar to the pathology of multiple sclerosis where there is a loss of oligodendroglial cells and focal demyelination!
  • In Schizophrenia, antibrain and myelin antibodies are produced, indicating an immune response.
so what is going on in bpd
So what is going on in BPD?
  • More studies are required to determine to what extent demyelination occurs.
  • Demyelination can occur in several ways. Thus, before appropriate therapies can be developed, the mechanism must be discovered.
demyelination the rat model
Demyelination: The Rat Model
  • Arvanitogiannis and Shizgal (1999) induced severe demyelination with NMDA
  • Because demyelination occurred in 24 hrs, it was not a result of immune response
how did demyelination occur
It is believed that the elevation of glutamate levels at the lesion site caused subsequent activation of AMPA receptors

This resulted in the selective killing of oligodendrocytes

The elevation in glutamate may be due to a thinning in the astrocyte population.

Another possibility is that NO (which is a ROS) levels increased

NO is known to damage oligodendrocytes

How did demyelination occur?
rats again
Rats again…
  • NMDA was again used to cause demyelination in rats brains
  • Myelinated fibers near the lesion took on a braided appearance
the after effects
The after-effects
  • Within 14 days, the myelinated strands at the edge of the lesion were less abnormal
  • After 4 weeks, myelin dots could be seen at the center of the lesion
  • After 2 months, strands of myelin passed through the lesion
  • Myelin growth predominantly occurred near blood vessels
  • HOWEVER, this myelin was not entirely normal
the blood brain barrier
The Blood Brain Barrier
  • The astrocyte population was thinned, allowing normally separate cells (including immune cells) to penetrate the BBB
  • However, after 12 days, the BBB was functionally normal.
  • This supports the theory that immune response plays a role in demyelination
  • This is the primary model that is currently used for MS, where the T-cells fail to recognize the myelin basic proteins
reactive oxygen species
Reactive Oxygen Species
  • Oligodendrocytes require a large portion of energy to form myelin.
  • This means that oligodendrocytes form a lot of reactive oxygen species as a result of mitochondrial respiration
  • Flavonoids are most commonly found in fruits and vegetables
  • They have antioxidant properties, which allow them to scavenge oxidants like superoxide, hydrogen peroxide, nitric oxide, and hydroxyl radicals
oxidation in the brain
Oxidation in the Brain
  • Flavonoids have been reported to inhibit the transcription factor NF-kappaB, thus suppressing the production of pro-inflammatory cytokines and nitric oxide
  • Macrophages, which are essential in immune-mediated response (as may occur with demyelination) is one possible source for inflammatory mediators like cytokines and prostaglandins
  • When tested, all flavonoids, with the exception of epicatechin inhibited myelin phagocytosis
  • flavonoids may “mediate their effect by influencing signal transduction pathways, enzyme systems, modify cytoskeletal elements, and reduce complement activation” (Hendriks et al. 2003)
did flavonoids help
At higher concentrations, morin and apigenin were cytotoxic and decreased cell viability, while quercetin increased cell viability.

Luteolin was the “most potent” flavonoid tested, but quercetin, fisetin, and apigenin did inhibit myelin phagocytosis at higher concentrations

Did flavonoids help?
other antioxidants
Other antioxidants
  • Two antioxidants, Q10 and alpha-lipoic acid ultimately increased cell viability by scavenging for hydroxyl radicals, hydrogen peroxide, singlet oxygen, nitric oxide, and peroxynitrite as well as enabling removal of oxidized proteins
  • Alpha-lipoic acid also had inhibitory effects on NF-kappaB
antioxidant regeneration
Antioxidant regeneration
  • Alpha-lipoic acid was also able to regenerate many other anti-oxidants, including glutathione disulfide, dehydroascorbate, or Q10
  • Q10 was able to to regenerate the antioxidant -alpha-tocopherol (Vitamin E), which ultimately increases the antioxidant activity within the cell
polyunsaturated fatty acids
The focus was on arachidonic acid (AA; 20:4 n-6) and eicosapentaenoic acid (EPA; 20:5 n-3), metabolites of linoleic (18:2 n-6), and linolenic acid (18:3 n-3), respectively.

EPA affected the expression of proteolipid proteins (PLP) by means of accelerating the developmental expression, while AA caused no significant changes

Polyunsaturated Fatty Acids
epa and apoptosis
EPA and apoptosis
  • “… EPA treatment reversed several changes, indicative of apoptotic cell death, in the brain of aged rats with restoration of long-term potentiation” (Salvati et al. 2004)
  • Oral administration of retinoids to the EAE rat model (a model of MS) lead to stabilization of the disease
  • This implies that retinoids are “(1) immunosuppressive, (2) capable of inducing immune-deviation in potentially encephalitogenic T cells, and (3) capable of influencing the differentiation of multipotential T cells to a Th2-like phenotype (Racke and Racke 2002).”
the th 2 switch
There are Th2-mediated illnesses (such as asthma) that may involve inflammation

This means that use a switch to a Th2 pathway may aggravate these illnesses

There is decreased incidence of allergic disease in patients with MS

The Th-2 switch
the next step
The next step:
  • The next logical step is to ask whether BPD patients experience a decreased incidence in allergic diseases as well?
the results
If they experience this decreased incidence in allergic disease… then it may be immune mediated like MS

More research is needed in this field

Both vitamin A and D have been shown to suppress EAE, and vitamin D3 has been shown to enhance the Th2 cell development (Racke and Racke 2002).

Thus, these treatments may be effective in the fight against BPD

The results