Nutrition Guide

Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and leads to an eventual atrophy of the hippocampus if exposure is persistent. Atrophy of the hippocampus and other limbic structures has been shown to take place in humans suffering from chronic depression.[19] In addition, rats bred to be heterozygous for BDNF, therefore reducing its expression, have been observed to exhibit similar hippocampal atrophy, suggesting that an etiological link between the development of depressive illness and regulation of BDNF exists. On the other hand, the excitatory neurotransmitter glutamate, voluntary exercise,[20] caloric restriction, intellectual stimulation, curcumin and various treatments for depression (such as antidepressants and electroconvulsive therapy) strongly increase expression of BDNF in the brain, and have been shown to protect against this atrophy.[citation needed]

Various studies have shown possible links between low levels of BDNF and conditions such as depression, schizophrenia, Obsessive-compulsive disorder, Alzheimer’s disease, Huntington’s disease, Rett syndrome, and dementia, as well as anorexia nervosa and bulimia nervosa, though it is still not known whether these levels represent a cause or a symptom.[18][citation needed]

The BDNF protein is coded by the gene that is also called BDNF. In humans this gene is located on chromosome 11.[2][3] Val66Met (rs6265) is a single nucleotide polymorphism in the gene where adenine and guanine alleles vary resulting in a variation between valine and methionine at codon 66.[14][15]

As of 2008 Val66Met is probably the most investigated SNP of the BDNF gene but besides this variant other SNPs in the gene are C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442.[citation needed]

The polymorphism Thr2Ile may be linked to congenital central hypoventilation syndrome.[16][17]

BDNF binds at least two receptors on the surface of cells which are capable of responding to this growth factor, TrkB (pronounced “Track B”) and the LNGFR (for “low affinity nerve growth factor receptor”, also known as p75).[12] It also might bind to the nAchR-?7.[13]

TrkB is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkB mediates the effects of BDNF and NT-4, TrkA binds and is activated by NGF, and TrkC binds and is activated by NT-3. NT-3 binds to TrkA and TrkB as well, but with less affinity.[12]

The other BDNF receptor, the p75, plays a somewhat less clear role. Some researchers have shown the p75NTR binds and serves as a “sink” for neurotrophins. Cells which express both the p75NTR and the Trk receptors might therefore have a greater activity - since they have a higher “microconcentration” of the neurotrophin.[citation needed] It has also been shown, however, that the p75NTR may signal a cell to die via apoptosis - so therefore cells expressing the p75NTR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.[citation needed]

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses.[4][5] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.[6] BDNF itself is important for long-term memory.[7] BDNF was the second neurotrophic factor to be characterized after nerve growth factor (NGF).

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active.[8][9][10] Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.[11]

Despite its name, BDNF is actually found in a range of tissue and cell types, not just in the brain. It is also expressed in the retina, the CNS, motor neurons, the kidneys, and the prostate.[citation needed]

Anti-VEGF therapies [2] are important in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab (Avastin), antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib (Sutent), sorafenib (Nexavar), axitinib, and pazopanib. Both antibody-based compounds are commercialized. The first two orally available compounds are commercialized, as well. The latter two are in clinical trials, the results of which were presented (June 7) at ASCO.

Bergers and Hanahan concluded in 2008 that anti-VEGF drugs can show therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. But, “the benefits are at best transitory and are followed by a restoration of tumour growth and progression.” [3]

AZ2171, a multi-targeted tyrosine kinase inhibitor has been shown to have antiedema effects by reducing the permeability and aiding in vascular normalization.

VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the “angiogenic” switch. Although VEGFxxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.

VEGFxxx is also released in rheumatoid arthritis in response to TNF-?, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).

VEGFxxx is also important in diabetic retinopathy (DR). The microcirculatory problems in the retina of people with diabetes can cause retinal ischaemia, which results in the release of VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.

VEGFxxx plays a role in the disease pathology of the wet form age-related macular degeneration (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differes between the two diseases.

VEGF-D serum levels are significantly elevated in patients with angiosarcoma (PMID 14746640)

Once released, VEGFxxx may elicit several responses. It may cause a cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of cancer. The first anti-VEGF drug, a monoclonal antibody named bevacizumab, was approved in 2004. Approximately 10-15% of patients benefit from bevacizumab therapy, although biomarkers for bevacizumab efficacy are not yet known.

Current studies show that VEGFs are not the only promoters of angiogenesis. In particular FGF2 and HGF [1] are potent angiogenic factors.

Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.

In the kidney increased expression of VEGFxxx in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.[2]

VEGFxxx production can be induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces HIF, Hypoxia Inducible Factor, a transcription factor. HIF stimulates the release of VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis.

The broad term ‘VEGF’ covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene. The two different families are referred to according to their terminal exon (exon splice site - the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb). In addition, alternate splicing of exon 6 and 7 alters their heparin binding affinity, and amino acid number (in humans: VEGF121, VEGF121b, VEGF145, VEGF165, VEGF165b, VEGF189, VEGF206; the rodent orthologs of these proteins contain one fewer amino acid). These domains have important functional consequences for the VEGF splice variants as the terminal (exon splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition inclusion or exclusion of exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors (VEGFRs).