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REVIEW ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 5  |  Page : 619-628  

Brain-derived neurotrophic factor and its clinical applications


1 26 Medical Center, Bangkok, Thailand
2 Department of Community Medicine, Dr DY Patil University, Pune, Maharashtra, India

Date of Submission13-Mar-2021
Date of Decision13-May-2021
Date of Acceptance20-Jun-2021
Date of Web Publication16-Feb-2022

Correspondence Address:
Rujittika Mungmunpuntipantip
26 Medical Center, Bangkok
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_195_21

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  Abstract 


Brain-derived neurotrophic factor (BDNF) is a protein found in human beings. This protein is a member of the neurotrophic family of growth factors that relates to the canonical nerve growth factor (NGF). Its main biological process in human is on neurons of the central nervous system and the peripheral nervous system. This protein supports the survival of neurons and promotes growth and differentiation of new neurons and neurological synapses. This protein plays a role in many clinical disorders, including Alzheimer's disease, epilepsy, and aging. In this review, the authors summarize and provide insight into the molecular characteristics and clinical association with the objective to highlight and explore the potential clinical usefulness of BDNF in clinical medicine. The alteration of BDNF is seen in many disorders, especially for neurological diseases. The change of BDNF level is associated with clinical presentation of the patients. The increases or decreases of BDNF expression occur and further play a role in phenotypic expression, the clinical presentation. BDNF might be a new useful laboratory investigation for managing of patients, especially for those with neurological problems.

Keywords: Application, brain-derived neurotrophic factor, clinical


How to cite this article:
Mungmunpuntipantip R, Wiwanitkit V. Brain-derived neurotrophic factor and its clinical applications. Med J DY Patil Vidyapeeth 2022;15:619-28

How to cite this URL:
Mungmunpuntipantip R, Wiwanitkit V. Brain-derived neurotrophic factor and its clinical applications. Med J DY Patil Vidyapeeth [serial online] 2022 [cited 2022 Dec 6];15:619-28. Available from: https://www.mjdrdypv.org/text.asp?2022/15/5/619/337803




  Introduction Top


There are many important proteins that are originated from neurological system.[1],[2],[3],[4],[5] Brain-derived neurotrophic factor (BDNF) is a protein found in human beings. BDNF is classified as a neurotrophin.[1],[2],[3],[4],[5] This neuro-derived protein is a member of the neurotrophin family of growth factors. This protein is related to the canonical NGF. Its main biological process in human is on neurons of the central nervous system (CNS) and the peripheral nervous system. It plays an important role as an important regulator in key brain circuits involved in emotional and cognitive function.

BDNF plays a role in neuronal growth and survival. BDNF acts as a neurotransmitter modulator, and participates in neuronal plasticity, which is necessary for memory and learning. Hence, BDNF has an important function for harmonizing neurological function of an individual.[1],[2],[3],[4],[5] Regarding its physiological action, BDNF binds cellular receptors that are capable of responding to this growth factor, TrkB and the LNGFR or p75. With these molecular actions, BDNF has a main role in synaptic transmission using glutamatergic signaling and GABAergic signaling.[1],[2],[3],[4],[5] According to described process, BDNF has a critical association with neurological function, neurosynapse maintenance, and memory[1],[2],[3],[4],[5] [Figure 1].
Figure 1: The pictographic presentation showing biological process of brain-derived neurotrophic factor

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The scientific evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in many psychological and neurological disorders.[4] The significant change of this protein is also observed in animal models of stress.[4]

BDNF is one of the most widely studied neurotrophin at present.[6] There are many ongoing researches on this protein in both healthy and diseased neuropathic subjects. The biological functions of BDNF include neuronal harmonization, neuronal survival, plasticity, synapse function maintenance, and neurotransmitter regulation.[6] The abnormalities of this protein are observed in patients with psychiatric and neurodegenerative disorders.[1],[2],[3],[4],[5] The decreased BDNF concentrations in their blood and brain are observed in those patients.[1],[2],[3],[4],[5] It is hypothesized that that these abnormal BDNF levels might be related to the chronic inflammatory state of the neurological organ in certain pathological disorders.[6]

BDNF plays a role in many clinical disorders, including Alzheimer's disease, epilepsy, and aging via neuroinflammation process resulted from several BDNF-related signaling pathways.[6] In this review, the authors provide insight into the molecular characteristics, highlight the important details of this new laboratory investigation, and explore the potential clinical usefulness of BDNF with special focus on neurological problems. For literature reviewing, the authors performed a literature searching using international database for recruited publications (original article, review article, and case report) until end of 2020 for further literature analysis based on standard PRISMA statement.


  Characteristics of Brain-Derived Neurotrophic Factor Molecule Top


BDNF is a protein. It is also named abrineurin. In 1982, the purification of this protein was firstly reported. This protein is detectable in human and other animals. The example of animals that have this protein are Gallus gallus, Peromyscus californicus, Breviceps ombelanonga, Pipistrellus kuhlii, Rhinolophus ferrumequinum, P. kuhlii, Tylototriton taliangensis, and B. ombelanonga. For human DNF, its UniProt code is P23560. The human BDNF (Accession: P23560.1) has 247 amino acids. The amino acid sequence of human BDNF is as the following “MTILFLTMVISYFGCMKAAPMKEANIR GQGGLAYPGVRTHGTLESVNGPKAGSRGLT SLADTFEHVIEELLDEDQKVRPNEENNKDAD LYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAAN MSMRVRRHSDPARRGELSVCDSISEWVTAADK KTAVDMSGGTVTVLEKVPVSKGQLKQYFYET KCNPMGYTKEGCRGIDKRHWNSQCRTTQS YVRALTMDSKKRIGWRFIRIDTSCVCTLTIKRGR.” This protein has a molecular weight equal to 27817.72 and basal isoelectric point equal to 9.01.[7],[8],[9] There are 5 human isoforms of this protein. The tertiary structure of this protein can be displayed in ribbons and thread form as seen in [Figure 2] (the most common isoform, isoform 1). The BDNF is a mature form of protein and sometimes called mBDNF. Its immature form is called proBDNF. The proBDNF presents a molecular weight of 32 kDa, while mBDNF is usually observed at 14 kDa, with few cases where a 28 kDa structure is reported (truncated BDNF).[7],[8],[9]
Figure 2: Tertiary structure of brain-derived neurotrophic factor

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This protein belongs to the NGF family. BDNF is detectable in blood plasma and saliva. BDNF is observed at a high level in the brain. In the brain, this protein is highly expressed in the cerebral cortex, cerebellum, hippocampus, and amygdala. The other organs that this protein can be detected are heart, lung, skeletal muscle, testis, prostate and placenta.[5] The protein also exists in a small level in eye, ovary, kidney, ovary, and skin.[5]

The biological process of this protein includes (a) activation of phospholipase C activity, (b) axon guidance and BDNF signaling pathway, (c) negative regulation of myotube differentiation, (d) collateral sprouting; negative regulation of apoptotic signaling pathway, (e) positive regulation of synapse assembly and regulation of protein localization to cell surface, (f) regulation of signaling receptor activity and synapse assembly, (g) nervous system development and neurotrophin TRK receptor signaling pathway, and (h) positive regulation of neuron projection development.[5] BDNF mediates its neurotrophic properties by signaling through the high affinity cell surface receptor gp145/trkB. BDNF is initially produced with a signal peptide (a. a. 1–18) and a propeptide (a. a. 19–128) sequence, the removal of which yields the mature BDNF.[5],[10]

BDNF is genetically encoded by the BDNF (also known as BULN2) gene (Gene ID 627) in humans. The corresponding gene for the synthesis is at chromosome 11, location 11p14.1. Focusing on the molecular biosynthesis process, this protein is synthesized in the endoplasmic reticulum and secreted from dense-core vesicles.[5],[10] A human BDNF gene has many promoters and initiation sites for BDNF expression. There are 11 exons and 9 functional promoters which are brain and tissue region specifically. The genetic polymorphism of BDNF plays a role in its function and clinical association. Many conditions where BDNF is a key factor are related to single-nucleotide polymorphisms; hence, there are many deviations from the earlier mentioned UniProt Accession.[11]

Regarding RNA expression, tissue enhancement occurs in the brain (the highest level is at cerebral cortex) and skeletal muscle. Little expression is observed in the lung, eye, liver, kidney, and endocrine tissue. Less expression is observed in blood.[5] For protein expression, medium score is observed in the brain, whereas a low score is observed in thyroid, parathyroid, adrenal gland, testes, and fallopian tube.[5] The protein expression is not detected in blood and other tissue.[5]


  Important Clinical Disorders and Brain-Derived Neurotrophic Factor Top


The abnormality of the biological process of BDNF is observable in many medical disorders, especially for those disorders of the neurological system. Alzheimer's disease and epilepsy are examples of important medical problems with abnormal BDNF. Here, the authors summarize on those important neurological disorders.

Neurological disorder and brain-derived neurotrophic factor

Since BDNF is a protein produced from neurological system. The clinical importance of BDNF is proposed in many neurological problems. The details of some important neuropsychiatric disorders and BDNF will be further presented.

Epilepsy

Epilepsy is an important neurological disorder due to the disruption of the neuroelectrophysiological system. Epilepsy is due to pathology of neuroelectric system. There is an abrupt aberration of neuroelectrophysiological system. This disease presents as an enduring predisposition to generate epileptic seizures and can cause neurobiological, cognitive, psychological, and social consequences. The patient might express periods of unusual behavior, abnormal sensations, and sometimes awareness loss.[12],[13] This CNS disorder might be due to several reasons (such as infectious disease).[14] The role of BDNF in pathogenesis of epilepsy is widely studied.[15],[16],[17],[18] The important reports on this specific issue are presented in [Table 1]. In epilepsy, increased BDNF expression is observed in many areas of the brain involved in seizures. During a seizure, there is an abnormal neuronal excitability and a reduction of TNF-α and IL-6 levels, which result in upregulation of BDNF levels.[17] Increased BDNF mRNA levels in the temporal lobe of epilepsy patients are believed to be an important pathogenesis of epilepsy.[5]
Table 1: Some important reports on brain-derived neurotrophic factor and epilepsy

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Alzheimer's disease

Alzheimer's disease is a neurological disease with the brain degeneration. It is an irreversible, progressive brain disorder. This medical disorder is an irreversible disorder. It is characterized by progressive brain disorder with slow memory impairment and thinking skills.[19],[20],[21] Alzheimer's is the most common form of dementia in the present day. A disease can progressively worsen beginning with mild memory loss possibly leading to loss of the ability totally. The role of BDNF in pathogenesis of Alzheimer's disease is widely studied.[22],[23],[24],[25],[26],[27],[28],[29],[30] The important reports on this specific issue are presented in [Table 2]. In Alzheimer's disease, there is a decreased BDNF level in both brain and blood. The amyloid-beta deposit is an important pathology in the CNS of patients with Alzheimer's disease. The amyloid beta soluble forms can interrupt tPA/PAI-1 system and disrupts conversion process from pro-BDNF to the mature BDNF.[25] This pathological process results in a downregulation of BDNF mRNA in the degenerated brain cortex. In addition, deprivation of BDNF/TrkB in Alzheimer's disease results in increased inflammatory cytokines.[26] The pro-inflammatory cytokines further play a role in reduction of peripheral BDNF production and function.[27] When there is a progression of disease, more pathological expression of BDNF occurs and it is related to the severity of clinical problem in the course of disease.[27]
Table 2: Some important reports on brain-derived neurotrophic factor and Alzheimer's disease

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Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that affects predominately dopaminergic neurons in substantia nigra. Similar to Alzheimer's disease, Parkinson's disease is a neurological abnormality due to the brain degeneration at basal ganglia. It is the second most common neurodegenerative disease after Alzheimer's disease. An alteration of the basal ganglia thalamocortical networks, primarily due to degeneration of nigrostriatal dopaminergic neurons, is identified as important pathological finding in Parkinson's disease. This medical disorder is an irreversible. It is characterized as a progressive brain disorder with significant impaired motor dysfunction. The common problems in the patients with Parkinson's disease include shaking, stiffness, imbalance, walking difficulty, and masked face.[31],[32],[33],[34],[35] The role of BDNF in pathogenesis of Parkinson's disease is widely studied. The important reports on this specific issue are presented in [Table 3].[30],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45]
Table 3: Some important reports on brain-derived neurotrophic factor and Parkinson's disease

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For Parkinson's disease, many reports show that BDNF plays an important role in the pathogenesis. Downregulation of BDNF is observed in the brain of a patient with Parkinson's disease. The patient with Parkinson's disease has decreased BDNF in the brain. The regional decrease is seen at basal ganglia. The decreased level of BDNF is related to clinical symptoms. The effect of genetic polymorphism, especially for BDNF Val66Met polymorphism, on disease presentation and progression is also reported.[43],[44] In the early stages of Parkinson's disease, the alteration of BDNF/α-synuclein (α-syn) axis is observed. In a person with mutated polymorphism, there is an upregulated miRNA-7 in the brain, which results in the dysregulation of BDNF/α-syn axis.[43],[44] The downregulation of α-syn is directly linked to the neuropathology of Parkinson's disease.

Recently, BDNF is also proposed as a new alternative drug for Parkinson's disease therapy.[38] The newly synthetic BDNF is already available for managing of the patient with Parkinson's disease at present.

Huntington's disease

Huntington's disease (HD) is a genetic progressive brain disorder. This disease is classified as an autosomal-dominant disorder. The abnormality of BDNF is also reported in Huntington's disease.[46],[47],[48],[49],[50],[51],[52],[53],[54] Huntington's disease is a progressive neurodegenerative disorder with a distinct phenotype, including incoordination, cognitive decline, chorea and dystonia, and behavioral problems.[46],[47],[48],[49],[50] The role of BDNF in pathogenesis of Huntington's disease is widely studied. The important reports on this specific issue are presented in [Table 4].[51],[52],[53],[54],[55]
Table 4: Some important reports on brain-derived neurotrophic factor and Huntington's disease

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For Huntington's disease, many reports show that BDNF plays an important role in the pathogenesis. In Huntington's disease, the mutant huntingtin, CAG repeats, is observed. Since huntingtin plays roles in regulating BDNF through the interaction with the neuron-restrictive silencer factor, the repeats mutant results in the downregulation of BDNF.[54],[55] Similar to Parkinson's disease, the decreased level of BDNF is related to clinical symptoms of Huntington's disease. According to many animal model studies, the new recombinant BDNF administration and BDNF-overexpressing neural stem cell transplantation are also proposed as a new alternative therapy for Huntington's disease.[54],[55]

Cerebrovascular stroke

Cerebrovascular stroke is a pathological condition result from hemorrhagic or thrombotic vascular problem of cerebrovascular. Cerebrovascular stroke is a common non-communicable medical disorder at present. The stroke is related to many complications such as paralysis and disability. BDNF can induce antiapoptotic mechanisms after cerebrovascular stroke. This is a natural defense in human body aiming at reducing infarct size and secondary neuronal cell death. In the recovery phase of cerebrovascular stroke, an increased modified Rankin Scale (mRS), which indicates recovery property, is related to the increased BDNF level.[56] Furthermore, the BDNF level is also related to the central post-stroke pain.[57]

As a conclusion, there are many reports regarding chance of DNF in several neurological disorders. There are two trends of chance, increasing or decreasing. Decreased BDNF is observed in degenerative disorders and strike which contain damage of neuron. Increased BDNF is observed in epilepsy, which has a stimulating neuroelectrical function [Table 5].
Table 5: Abnormality of brain-derived neurotrophic factor in different neurological diseases

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Cancer and BDNF

Similar to a neuropsychiatric disease, there is a change of BDNF in the pathology of some tumors. The change of BDNF is reported in brain tumors. For example, Japón et al. studied on glial-DNF and RET gene expression in normal human anterior pituitary cell types and in pituitary tumors and concluded that glial-DNF played a role in the regulation of somatotroph cell growth and functioning in the human anterior pituitary gland.[58] Nevertheless, Yoshimoto et al. found that GDNF gene did not play a role in the pituitary tumorigenesis.[59]

Regarding ex-nervous system cancer, there are also reports on the clinical aspects of BDNF. The changes of BDNF are reported in colorectal cancer,[60] hepatocellular carcinoma,[61] lung cancer,[62],[63] and head and neck squamous cell carcinoma.[64],[65] The role of BDNF as a biomarker and tumor marker is an interesting issue for researching in clinical oncology.

Infection and BDNF

Similar to neuropsychiatric disease and cancer, the aberration of BDNF is observable in infectious disease. The significant change of BDNF is seen in nervous system infection. There are many reports on the usefulness of BDNF determination in several infectious diseases.

Viral encephalitis

The abnormal BDNF level is observable in viral encephalitis.[66],[67],[68] Sellner et al. studied in in experimental herpes simplex virus encephalitis model and found that the neurotrophic factors play an important role in neuronal survival and recovery after acute injury to the CNS.[67]

Meningitis

The abnormal BDNF level is reported in patients with meningitis.[66],[67] Tokunaka et al. studied CSF BDNF and found that there was no clinical association with meningitis.[67] Zizawa-Ueda et al. performed another similar study and found the similar findings.[66]

Dengue and Zika virus infection

Dengue and Zika virus disease are two important arboviral infections transmitted by Aedes spp. mosquito vector. Both diseases can cause acute febrile illness and the patient might present a clinical triad consisting of hemoconcentration, thrombocytopenia, and atypical lymphocytosis. Considering Zika virus infection, the abnormal fetal with CNS problem of the Zika virus-infected mother leads to the worldwide consideration on this new arboviral infection. Costa et al. found that dengue virus 1 immunity to gestational ZIKV infection in offspring was associated with an increase in BDNF levels in the hippocampus during adolescence.[69]

COVID-19

COVID-19 is the new emerging coronavirus infection. This disease caused pandemic in 2020 and becomes the most problematic virus infection at present. COVID-19 has a wide clinical spectrum ranging from asymptomatic to fatal clinical feature. The neurological problem in COVID-19 is also observable. Kermanshahi et al. studied BDNF in COVID-19 and noted that exacerbation of Alzheimer's disease in COVID 19 was possible.[70]

HIV infection

HIV infection is still the important global public health problem. The neurological problem is possible in HIV-infected patients. The aberration of BDNF in HIV infection is possible and there are some reports on this topic. The important reports on this specific issue are presented in [Table 6].[71],[72],[73],[74],[75],[76],[77] Many reports are on the role of BDNF against neurotoxicity caused by HIV.
Table 6: Some important reports on brain-derived neurotrophic factor and HIV infection

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  Conclusion Top


BDNF is a protein generated by the human neurological system. This protein plays an important role in neurological homeostasis, promoting neuron survival, and controlling growth and differentiation of new neurons and synapses. Specific intracellular signaling and changed expression of BDNF are reported in many diseases. In brief, background genetic factors and external environmental insult play roles as triggering factors that can further result in focal abnormalities. The regional increasing or decreasing of BDNF expression might occur and further play a role in phenotypic expression, the clinical presentation. The abnormal BDNF level is seen in many neurological disorders. In degenerative disorders, such as Alzheimer's disease and Parkinson's disease, the decreasing of BDNF is observed, while there is an increasing BDNF is cases with epilepsy. The association between clinical presentation/progression of disease is associated with BDNF. Conclusively, BDNF is a new laboratory test that is useful for the management of patients with neurological problems. Furthermore, there are some new reports on application of BDNF in nonneurological diseases. Extended advantages of BDNF test in other nonneurological disorder are expected.

Highlights

  • Brain-derived neurotrophic factor (DNF) is a biomolecule that relates to the canonical nerve growth factor
  • The alteration of BDNF is seen in many disorders, especially for neurological diseases
  • The increases or decreases of BDNF expression occur and further play a role in phenotypic expression, the clinical presentation.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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