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Vitamin D and Neurological Disorders

Vitamin D and Neurological Disorders

Vitamin D
Vitamin D is a steroid hormone that is mainly found in the body in two forms: vitamin D3 and vitamin D2. Vitamin D3, or cholecalciferol, is formed in the skin after exposure to sunlight or ultra violet radiation. Vitamin D3, or ergocalciferol, is obtained from various food sources including milk and fish

Physiology
With the two forms of vitamin D, the body uses it in a few ways :


 * Calcium absorption, which is necessary for bone health.
 * Phosphate absorption

Hypovitaminosis D
Hypovitaminosis D is described as any deficiency of Vitamin D. In the past, hypovitaminosis D has been defined as blood concentrations lower than 30ng/ mL. However, this standard has changed and is not permanent. Subnormal levels of vitamin D are usually caused by poor nutrition or lack of sun exposure. Risk factors for hypovitaminosis D include premature birth, darker skin pigmentation, sun exposure/living at higher altitudes, obesity, malabsoprtion and old age.

Location in the Central Nervous System
The brain requires the use of many "neurosteroids" to develop and function properly. These molecules are often identified as one of many common substances including thyroid hormones, glucocorticoids, and androgens. However in recent studies, vitamin D has begun to surface as one of these neurosteroids located throughout the brain and spinal fluid. Several vitamin D metabolites are found in cerebral spinal fluid and have the ability to cross the blood brain barrier. This is similar to many of the previously known neurosteroids. These Vitamin D metabolites include 25OHD3, 1,25OH2D3, and 24,25OH2D3. Derivatives of these metabolites are highly expressed in the substantia nigra and the hypothalamus. These two brain structures are responsible for motor functions and linking the nervous system to the endocrine system, respectively. The expression of these metabolite derivatives in these areas indicates that these structures have the ability to synthesize these products.
 * Metabolites:

In addition to vitamin D metabolites, vitamin D receptors (VDR) proteins are also found in the brain; more specifically, they are found in the cerebellum, thalamus, hypothalamus, basal ganglia, and hippocampus. Highest density of vitamin D receptors is located in substantia nigra, one of the primary areas of dopamine production. Another significant portion of the receptors is located in the hypothalamus (supra optic and paraventricular nuclei) and external granule cell layer of the prefrontal. Vitamin D receptors are also found in the hippocampus (CA1 and CA2) areas, but not at such a high density. Explain what role vitamin d receptors play and why this piece is important
 * Receptors:

Function in the Central Nervous System
Now that the presence of vitamin D has been established in the brain, it has led to the question of what role the Vitamin D plays in the brain. Vitamin D has exhibited functionality as a modulator in brain development and as a neuroprotectant. In recent studies, Vitamin D has exhibited an association with the regulation of nerve growth factor (NGF) synthesis. NGF is responsible for growth and survival of neurons. This relationship has also been studied in embryonic and neonatal rats. Developmental vitamin D deficient (DVD) rats have decreased levels of neurotrophic factors, increased mitosis, and decreased apoptosis.

Vitamin D and Neurological Disorders
Hypovitaminosis D is associated with several neuropsychiatric disorders including dementia, Parkinson's Disease, multiple sclerosis, epilepsy, and schizophrenia. There are several proposed mechanisms by which hypovitaminosis D may impact these disorders. One of these mechanisms is through neuronal apoptosis. Neuronal apoptosis is the programmed death of the neurons. Hypovitaminosis D causes this specific apoptosis through decreasing the expression of cytochrome C and decreasing the cell cycle of neurons. Cytochrome C is a protein that promotes the activation of pro-apoptotic factors. A second mechanism is through neurotrophic factors like NGF, BDNF, GDNF.

Dementia: Alzheimer's
Dementia is a branch of disorders characterized by a loss of executive functioning like sequencing and problem solving. Within this umbrella, there is Alzheimer's Disease. This condition specifically includes a loss of cortical functions like language and motor skills. From a mechanistic view, Alzheimer's Disease is associated with a decrease in vitamin D receptors in the Cornu Ammonius areas (CA 1& 2) of the hippocampus. The hippocampus is a portion of the limbic system responsible for memory and spatial navigation. Additionally, Alzheimer's Disease is associated with an increase in vitamin D receptor polymorphism. Vitamin D receptor polymorphism is a genetic variation that appears in more than 1% of the genetic population.

Parkinson's
Parkinson's disease is characterized by the deterioration in movement and coordination capabilities. In many patients with Parkinson's Disease, there is a loss of dopaminergic (DA) neurons in the substantia nigra. The substantia nigra functions in reward, addiction, and movement. Low vitamin D levels have also been shown to play a role in this disorder and in many cases, vitamin D supplements have been known to lessen the effects of Parkinson's Disease. This association was presented in a study with vitamin D receptor knockout mice. The mice without any vitamin D receptors exhibited motor impairments similar to that of Parkinson's Disease. The proposed mechanism linking vitamin D to this disorder involves the Nurr 1 gene. A vitamin D deficiency causes the decreased expression of the Nurr1 gene. The Nurr1 gene is responsible for development of DA neurons and therefore a lack of Nurr1 expression causes a failure to form DA neurons. Rat subjects lacking Nurr1 experienced hypoactivity followed by death shortly after birth.

Multiple Sclerosis
Multiple sclerosis is an autoimmune disease causing the demyelination within the central nervous system. In the central nervous system, there are many cells encased in a fatty coating called the myelin sheath. This sheath allows for a signal to be transmitted at a greater speed down through the cell. In multiple sclerosis, this sheath deterioration causes a slower transmission of nerve signals. This ultimately results in severe motor deficits. There is a well-established correlation between multiple sclerosis and latitude; there is a higher multiple sclerosis prevalence in northeastern regions than in the south and western regions. At the same time, on average higher vitamin D levels are found in the south and western regions than in the northeast. Based on this correlation and other studies, the higher intake of vitamin D is associated with a lower risk for MS. The mechanism for this association is not fully established, however, a proposed mechanism involves inflammatory cytokines. Hypovitaminosis D causes an increase in pro-inflammatory cytokines and decrease in ant-inflammatory cytokines. The increase in these specific cytokines is associated with the degradation of the myelin sheath.

Epilepsy and Seizures
Seizures are disturbances in brain activities where neurons fire abnormally. Epilepsy is a condition in which a person experiences repeated seizures. In clinical studies, vitamin D supplementation has resulted in decreased seizures. Vitamin D is associated with proconvulsant and anticonvulsant factors. More specifically, Vitamin D is involved in the down regulation of cytokine IL-6, which is a proconvulsant. Additionally, vitamin D is associated with the up regulation of neurotrophic factors including GDNF and TN3. These neurotrophic factors are anticonvulsant. In the absence or depletion of vitamin D, the proconvulsant factors are not down regulated and the anticonvulsant factors are not up regulated. This disturbance in homeostasis promotes convulsive activity. Lastly, vitamin D has also been shown to promote the expression of calcium binding proteins that are known to possess anti-epileptic properties.

Schizophrenia
Schizophrenia is a neuropsychiatric disorder characterized by inability to perceive reality and think clearly. This condition has genetic and developmental causes. In this disorder, vitamin D is believed to be involved in the development of the brain during the gestational period. Gestational Vitamin D deficiency in rats is associated with reduced levels of neurotrophic factors NGF and GDNF. NGF is the nerve growth factor, which is involved in neurotransmission. GDNF is the glial cell lined derived neurotrophic factor, which is involved in the survival and differentiation of dopaminergic neurons.

Other hypovitaminosis D Associations
Hypovitaminosis D has also been associated with many other conditions, including both neurological and non neurological conditions. These include but are not limited to autism, diabetes, and osteoporosis.

Future research: Cause or Effect
Hypovitaminosis D has been associated with many neurological conditions. However, an actual mechanism of attack for each of the conditions has yet to be solidified. Many researchers have questioned whether the depletion of vitamin D actually causes these disorders or if vitamin D is a symptom of these disorders. Future research is needed to fully answer these questions.