Vitamin D and neurology

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Vitamin D
Drug class
Cholecalciferol-3d.png
Cholecalciferol (D3)
Class identifiers
Use Rickets, osteoporosis, vitamin D deficiency
ATC code A11CC
Biological target vitamin D receptor
Clinical data
Drugs.com MedFacts Natural Products
External links
MeSH D014807
Legal status
In Wikidata

Vitamin D is a steroid hormone that plays a vital role in calcium and phosphate absorption. Recent studies show several associations between low levels of vitamin D, or hypovitaminosis D, and neuropsychiatric disorders, [1] including Alzheimer's disease, autism, epilepsy, multiple sclerosis, Parkinson's disease, and schizophrenia. [1] [2]

Contents

Physiology

Vitamin D (the inactive version) is mainly from two forms: vitamin D3 and vitamin D2. Vitamin D3, or cholecalciferol, is formed in the skin after exposure to sunlight or ultra violet radiation or from D3 supplements or fortified food sources. Vitamin D2, or ergocalciferol, is obtained from D2 supplements or fortified food sources. [3] These two forms of vitamin D are metabolized in the liver and stored as 25-hydroxyvitamin D. [4] Before biological use, the storage form must be converted into an active form. One common active form is 1,25-dihydroxyvitamin D. [4] The term vitamin D in this article means cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, and the active forms. The role of vitamin D is best characterized as enabling calcium absorption and regulating calcium homeostasis. Vitamin D also play a role in phosphate absorption. [5]

Hypovitaminosis D

Hypovitaminosis D is any deficiency of vitamin D. A vitamin D blood-concentration standard for diagnosing hypovitaminosis D does not exist. In the past, hypovitaminosis D was defined by blood concentrations lower than 20 ng/mL. [6] However, in more recent literature many researchers have considered 30 ng/mL to be an insufficient concentration of vitamin D. [6] Subnormal levels of vitamin D are usually caused by poor nutrition or a lack of sun exposure. [5] Risk factors for hypovitaminosis D include premature birth, darker skin pigmentation, obesity, malabsorption, and older age.

Vitamin D and the central nervous system

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, throughout the brain and spinal fluid, vitamin D has begun to surface as one of these neurosteroids.

Location of brain regions related to vitamin D Basal Ganglia and Related Structures.svg
Location of brain regions related to vitamin D

Function in the central nervous system

The presence of vitamin D, its activating enzyme, and VDR in the brain leads researchers to question what role vitamin D plays in the brain. Research suggests that vitamin D may function as a modulator in brain development and as a neuroprotectant. [1] In recent studies, vitamin D has exhibited an association with the regulation of nerve growth factor (NGF) synthesis. NGF is responsible for the growth and survival of neurons. [8] 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. These findings suggest that vitamin D potentially affects the development of neurons as well as their maintenance and survival. Current research is underway investigating whether vitamin D is a factor contributing to normal brain functioning.

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 by 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. [9] A second mechanism is through the association of neurotrophic factors like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF). These neurotrophic factors are proteins that are involved in the growth and survival of developing neurons and they are involved in the maintenance of mature neurons. [10]

Dementia: Alzheimer's disease

The brain of a normal adult compared to that of a patient with Alzheimer's disease Alzheimer's disease brain comparison.jpg
The brain of a normal adult compared to that of a patient with Alzheimer's disease

"Dementia" is a term referring to neurodegenerative disorders characterized by a loss of memory and such brain functions as executive functioning. Included under this umbrella term is Alzheimer's disease. Alzheimer's disease is characterized by the loss of cortical functions like language and motor skills. [7] Patients with Alzheimer's disease exhibit an extreme shrinkage of the cerebral cortex and hippocampus with an enlargement of the ventricles. In several recent studies, higher vitamin D levels have been associated with lower risks of developing Alzheimer's disease. [11] Alzheimer's disease is associated with a decrease in vitamin D receptors in the Cornu Ammonius areas (CA 1& 2) of the hippocampus. [7] The hippocampus is a portion of the limbic system responsible for memory and spatial navigation. Additionally, certain VDR haplotypes were detected with increased frequency in patients with Alzheimer's disease while other VDR haplotypes were detected with decreased frequency, suggesting that specific haplotypes may increase or decrease risk of developing Alzheimer's. [12] [13] It is hypothesized that this lack of VDRs in the hippocampus prevents the proper functioning (ie. memory) of this structure.

Parkinson's disease

This image depicts the circuits of the basal ganglia in patients with Parkinson's disease. Pay close attention to the role of the substantia nigra and the dopaminergic neurons Basal ganglia in Parkinson's disease.png
This image depicts the circuits of the basal ganglia in patients with Parkinson's disease. Pay close attention to the role of the substantia nigra and the dopaminergic neurons

Parkinson's disease is characterized by progressive deterioration of movement and coordination. Patients with Parkinson's disease lose dopaminergic (DA) neurons in the substantia nigra, [14] a part of the brain that plays a central role in such brain functions as reward, addiction, and coordination of movement. Studies suggest that low vitamin D levels could play a role in PD, and in one case report, vitamin D supplements lessened parkinsonian symptoms. In a study of vitamin D receptor knockout mice, mice without VDR exhibited motor impairments similar to impairments seen in patients with Parkinson's disease. [7] One proposed mechanism linking vitamin D to Parkinson's disease involves the Nurr 1 gene. Vitamin D deficiency is associated with decreased expression of the Nurr1 gene, a gene responsible for development of DA neurons. It is therefore plausible that a lack of Nurr1 expression leads to impaired DA neuronal development. Failure to form DA neurons would lead to lower dopamine concentrations in the basal ganglia. Additionally, rats lacking Nurr1 exhibited hypoactivity followed by death shortly after birth. [14]

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease causing demyelination within the central nervous system. [15] In the central nervous system, there are many cells encased in a fatty coating called the myelin sheath. This sheath allows for informational signals to be transmitted at greater speeds down through the cell. In multiple sclerosis, this sheath deterioration causes a slower transmission of nerve signals. This ultimately results in severe motor deficits.

The prevalence of MS is associated with latitude. In this image, red indicates a high prevalence of MS while yellow indicates a lower prevalence Multiple sclerosis world map - DALY - WHO2004.svg
The prevalence of MS is associated with latitude. In this image, red indicates a high prevalence of MS while yellow indicates a lower prevalence

There is a well-established global 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. [15] Based on this correlation and other studies, the higher intake of vitamin D is associated with a lower risk for MS. Research has also shown that in relation to geological position (latitude), patients who later developed MS saw an earlier age of onset of symptoms in the more northern latitudes than in the southern hemisphere. [15] [16] [17] [18] The mechanism for this association is not fully established, however, a proposed mechanism involves inflammatory cytokines. Hypovitaminosis D is associated with an increase in proinflammatory cytokines and decrease in anti-inflammatory cytokines.[ medical citation needed ] The increase in these specific cytokines is associated with the degradation of the myelin sheath. [19]

The increase of vitamin D into the body has shown to increase the amount of anti-inflammatory cytokines and molecules within the body. As this research progresses, the understanding grows of how vitamin D and its complementary receptor (vitamin D receptor, VDR) are incorporated in expressing and regulating 900 genes within our bodies, as well as how this pair interacts genetically. [20] [21] For example genes can be upregulated or downregulated when the highly active form of vitamin D, 1,25-alpha dihydroxyvitamin D3 binds to the VDR on chromosomal regions of gene expression that manage the balance or ratio between differentiating immune cells into Th1 and Th2 T cell proteins. [22] The upregulation of Th2 T cell proteins, like IL-4 and TGF-β, are the main focus of some research which aims to minimize the effects seen in the model organism disease EAE (experimental autoimmune encephalomyelitis), studied for its similarities to multiple sclerosis. Though this study of gene regulation is observed within murine models, it focuses on MS orthologs to humans and research has shown that it may also help to manage: rheumatoid arthritis (RA), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), cardiovascular disease (CVD), and other chronic inflammatory diseases. [23] [24]

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 one small pilot study (Christiansen, 1974, BMJ), vitamin D supplementation, but not placebo treatment was associated with decreased seizures. Vitamin D regulates proconvulsant and anticonvulsant factors. More specifically, Vitamin D is involved in the down regulation of cytokine IL-6, which is a proconvulsant. [7] Additionally, vitamin D is associated with the up regulation of neurotrophic factors: GDNF and TN3. These neurotrophic factors are anticonvulsant. In the absence or depletion of vitamin D, research suggests that the proconvulsant factors will not be down regulated and the anticonvulsant factors will not be up regulated. It is hypothesized that this disturbance in homeostasis may lower the threshold for 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. [7]

Schizophrenia

The effects of schizophrenia on the brain Schizophrenia PET scan.jpg
The effects of schizophrenia on the brain

Schizophrenia is a neuropsychiatric disorder characterized by the inability to perceive reality and think clearly. This condition has genetic and developmental causes. [25] 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. [7] 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. [1]

Future research: cause or effect

Hypovitaminosis D has been associated with many neurological conditions. However, an actual mechanism of action 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 deficiency is a symptom of these disorders.[ medical citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Neurotrophin</span>

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

<span class="mw-page-title-main">Glial cell line-derived neurotrophic factor</span> Protein-coding gene in the species Homo sapiens

Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particularly GFRα1. It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received by RET proto-oncogene (RET) and by forming gradient with SCF it divides the spermatogonia into two cells. As the result there is retention of spermatogonia and formation of spermatocyte.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

<span class="mw-page-title-main">Vitamin D receptor</span> Transcription factor activated by vitamin D

The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer with the retinoid-X receptor. The VDR heterodimer then enters the nucleus and binds to Vitamin D responsive elements (VDRE) in genomic DNA. VDR binding results in expression or transrepression of many specific gene products. VDR is also involved in microRNA-directed post transcriptional mechanisms. In humans, the vitamin D receptor is encoded by the VDR gene located on chromosome 12q13.11.

Neurturin (NRTN) is a protein that is encoded in humans by the NRTN gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the transforming growth factor beta (TGF-beta) subfamily along with its homologs persephin, artemin, and GDNF. It shares a 42% similarity in amino acid sequence with mature GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial settings for the potential treatment of neurodegenerative diseases, specifically Parkinson's disease.

Persephin is a neurotrophic factor in the glial cell line-derived neurotrophic factor (GDNF) family. Persephin shares around a 40% similarity in amino acid sequence compared to GDNF and neurturin, two members of the GDNF family.

The GDNF family of ligands (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

Translational neuroscience is the field of study which applies neuroscience research to translate or develop into clinical applications and novel therapies for nervous system disorders. The field encompasses areas such as deep brain stimulation, brain machine interfaces, neurorehabilitation and the development of devices for the sensory nervous system such as the use of auditory implants, retinal implants, and electronic skins.

Epigenetics of depression is the study of how epigenetics contribute to depression.

<span class="mw-page-title-main">BNN-20</span> Chemical compound

BNN-20, also known as 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol, is a synthetic neurosteroid, "microneurotrophin", and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA). It acts as a selective, high-affinity, centrally active agonist of the TrkA, TrkB, and p75NTR, receptors for the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as for DHEA and DHEA sulfate (DHEA-S). The drug has been suggested as a potential novel treatment for Parkinson's disease and other conditions.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors. Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.

References

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