Terapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury

Mary Wurzelmann, Jennifer Romeika, Dong Sun

Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA

Terapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury

Mary Wurzelmann, Jennifer Romeika, Dong Sun*

Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA

How to cite this article:Wurzelmann M, Romeika J, Sun D (2017)erapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury. Neural Regen Res 12(1):7-12.

Open access statement:is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries oen leads to further neural tissue loss.us far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.e neurotrophin brain‐derived neurotrophic factor (BDNF) has signi fi cant e ff ect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the fl avonoid 7,8‐dihydroxy fl avone (7,8‐DHF), a small TrkB agonist that mimics BDNF function, has shown similar e ff ects as BDNF in promoting neuronal survival and regeneration following TBI. Com‐pared to BDNF, 7,8‐DHF has a longer half‐life and much smaller molecular size, capable of penetrating the blood‐brain barrier, which makes it possible for non‐invasive clinical application. In this review, we sum‐marize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8‐DHF as a therapy for TBI.

7,8-dihydroxy fl avone; brain-derived neurotrophic factor; tropomyosin related kinase B (TrkB) receptor; traumatic brain injury; neuroregeneration; neuroprotection

Accepted: 2017-01-16

Introduction

Traumatic brain injury (TBI) is a global public health issue with few treatment options available (Chauhan, 2014). With approximately 10 million people a ff ected by TBI annually, it is a major cause of death and disability worldwide, and the World Health Organization projects that it will surpass the mortality and morbidity of many diseases by the year 2020. It is di fficult to quantify the full magnitude of TBI, as multi‐ple factors in fl uence it being underreported, including mild head trauma, the most common brain injury that is oen not reported and not physically observed, but may lead to memory or cognitive deficits at a later time (Hyder et al., 2007).

TBI is the loss or alteration of brain function generated by an external force (Menon et al., 2010). TBI can be diag‐nosed with symptoms and signs that are temporally close to the external insult, including damage to blood vessels, ax‐ons, neurons, and glia, which are considered primary dam‐ages. Following primary injury, which refers to the imme‐diate death of cells on impact from the external disruption, secondary injury is the result of a series of biochemical changes in the surrounding area of the primary injury that induces further tissue damage leading to functional de fi cits (Stoica and Faden, 2010).us far, there is no e ff ective treatment for TBI. Current therapies are primarily focused on reducing the extent of secondary insult and enhancing the regeneration process. Strategies that have neuroprotective effects, salvaging the injured brain tissue in the early stages post‐injury and pro‐moting regeneration at the recovery stage, are desirable.e brain‐derived neurotrophic factor (BDNF) and its high affinity receptor tropomyosin‐receptor‐kinase B (TrkB) play a critical role in promoting neuronal survival, plastici‐ty, and memory function (Park and Poo, 2013; Leal et al., 2015).erapeutic potential of BDNF and its mimics have been reported in many neurological conditions including TBI. This review summarizes the signaling pathway of BDNF/TrkB and studies targeting this signaling pathway for treating TBI.

Neurotrophins and the Receptors

Neurotrophins are endogenous peptides secreted from neu‐ronal and glial cells, and are associated with regulating the function, survival, and development of individual cells and neuronal networks across the entire brain. More speci fi cally, neurotrophins regulate synaptic plasticity, protect neurons from oxidative stress and apoptosis, and can stimulate neu‐rogenesis (Skaper et al., 1998; Leal et al., 2015; Kuipers etal., 2016).e neurotrophin family members include nerve growth factor (NGF), BDNF, neurotrophin‐3 (NT‐3), and neurotrophin‐4/5 (NT‐4/5), which are classified together based on their structural similarity to NGF, the fi rst neuro‐trophin discovered (Skaper, 2012).

Neurotrophins are able to exert their neuroprotective effects through the transmembrane receptors they bind to and the signaling cascades they initiate.ere are two main classes of transmembrane neurotrophin receptors, which include the Trk family of tyrosine kinase receptors, TrkA, TrkB, and TrkC, and the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis‐factor family (Marco‐Salazar et al., 2014). NGF preferentially binds to TrkA, BDNF and NT‐4/5 to TrkB, and NT‐3 to TrkC, all with high a ffinity, while each of these neurotrophins binds with low affinity to p75NTRreceptors (Skaper, 2008; Mar‐co‐Salazar et al., 2014). Additionally, p75NTRcontributes to proper Trk receptor function, and promotes ligand binding of neurotrophins with their correct Trk receptor (Skaper, 2012). Once bound to their Trk receptors, neurotrophins activate a cascade of events through Ras, phosphatidyli‐nositol 3‐kinase (PI3K), phospholipase‐Cγ (PLCγ), and mitogen‐activated protein kinase (MAPK) signaling path‐ways (Skaper, 2008).

BDNF and its Downstream Pathways

Among neurotrophins, BDNF is the most widely studied due to its potent e ff ects at synapses and wide expression in the brain. Two different classes of receptors are responsi‐ble for mediating BDNF signaling: p75NTRand TrkB (Lu et al., 2008). BDNF has a Kd= 9.9 nM for the TrkB receptor and a Kd～1.0 nM for the p75NTRdemonstrating its binding selectivity and affinity for each of the receptor types (Ber‐nard‐Gauthier et al., 2013). It is through its high a ffi nity for TrkB that BDNF is able to provide neuronal survival, neuro‐nal plasticity, and neurogenesis (Lu et al., 2008).e p75NTRreceptor is more associated with apoptosis. ProBDNF binds to the p75NTRreceptor while the mature form of BDNF has a high a ffi nity to TrkB (Bollen et al., 2013). However, the ma‐ture form of BDNF can bind to p75NTRreceptor when there are high concentrations of BDNF (Boyd and Gordon, 2001). Both of the BDNF receptors can be found in the same cell, coordinating and modulating neuronal responses. Further‐more, the signals generated by each receptor can augment each other or go against each other, fluctuating between a enhancing and suppressing relationship (Kaplan and Miller, 2007).

Upon binding to the TrkB receptor, BDNF induces di‐merization and autophosphorylation of the receptor, which causes internalization of the TrkB receptor and initiates intracellular signaling cascades (Levine et al., 1996) (Figure 1). These signaling cascades include the phosphatidyli‐nositol‐3‐kinase (PI3K) pathway, the PLCγ pathway, and the MAPK pathway. The PI3K pathway activates protein kinase B (Akt), which ultimately promotes cell survival by inhibiting Bad and consequently allowing the expression of anti‐apoptotic proteins, such as Bcl2 (Yoshii and Constan‐tine‐Paton, 2010). Phosphorylation of Akt at the proper site also results in the suppression of pro‐apoptotic proteins, pro‐caspase‐9 and Forkhead (Kaplan and Miller, 2007). Upregu‐lated Bcl2 levels are correlated with positive outcomes, such as attenuated cell death and a better prognosis (Nathoo et al., 2004).e PLCγ pathway leads to the release of intracellular calcium storesviaactivation of the inositol triphosphate (IP3) receptor, and helps to increase calmodulin kinase (CamK) activity, and thus synaptic plasticityviathe transcription factor CREB (cyclicAMP response element binding protein).e MAPK pathway, also referred to as extracellular related signal kinase (ERK) pathway, aids in cell growth and di ff er‐entiation. A PLCγ mediated response is likely responsible for quick, short‐term actions, while MAPK and PI3K pathways involve long‐term transcriptional effects (Yoshii and Con‐stantine‐Paton, 2010).

Function of BDNF andrkB Pathways in the Central Nervous System

BDNF and TrkB pathway have profound e ff ects in regulat‐ing cell survival and other biological processes. BDNF is important for neurite and axonal growth (Yoshii and Con‐stantine‐Paton, 2010), and is required for the survival and development of dopaminergic, GABAergic, serotonergic, and cholinergic neurons (Pillai, 2008).

Activation of the TrkB pathways has been shown to improve cognition, and has also been correlated with an increase in synaptic density (Castello et al., 2014). BDNF and TrkB are upregulated in areas where there is neuronal plasticity occurring. Due to this relationship, BDNF is con‐sidered a molecular mediator in the function and structure of synaptic plasticity, and plays a pivotal role in memory for‐mation as well as memory consolidation (Zeng et al., 2012). Even a disruption in the pathway that transports and pro‐duces BDNF can result in the clinical symptoms of deterio‐rating memory and cognitive dysfunction (Leal et al., 2015). Clinical studies have shown a causal relationship between lower levels of BDNF and cognitive declines observed in ag‐ing, schizophrenia, and Rett syndrome (Zuccato et al., 2011; Autry and Monteggia, 2012; Soares et al., 2016).

BDNF andraumatic Brain Injury

By virtue of its role in neuronal di ff erentiation, survival, and plasticity, it is no surprise that BDNF plays an important role following TBI. In response to TBI, the mRNA expression lev‐el of BDNF is transiently and signi fi cantly increased. Studies have reported that within hours post‐injury, the expression level of BDNF mRNA is significantly upregulated in the injured cortex and in the hippocampus (Yang et al., 1996). The level of BDNF declines at 24 hours post‐injury, and is no longer signi fi cant at 36 hours post‐injury (Oyesiku et al., 1999). Following injury, the mRNA expression level of TrkB receptor is also transiently upregulated in the hippocampus and dentate gyrus (Merlio et al., 1993).is transient surge of BDNF and its receptor following TBI suggests that BDNF acts as an endogenous neuroprotective response attempting to attenuate secondary cell damage following TBI (Mattson and Sche ff, 1994).

The importance of the BDNF/TrkB signaling pathway in regulating CNS function has led to many studies exploring the therapeutic potential of BDNF/TrkB for various neurological diseases, including TBI.e therapeutic potential of BDNF is restricted due to its short half‐life (＜ 10 minutes) and inability to cross the blood‐brain barrier (BBB) because of its large size (27 kDa) (Price et al., 2007). Thus far, direct application of BDNF for TBI has not been efficacious in experimental TBI studies. However, limited studies have shown when delivered indirectly, BDNF can signi fi cantly improve functional recovery of injured animals. In a recent study, poly(lactic‐co‐glycolic acid) nanoparticles coated with surfactant poloxamer 188 was used to deliver BDNF to the injured brain by receptor‐mediat‐ed transcytosis (Khalin et al., 2016). Following intravenous in‐jection of nanoparticle‐bounded BDNF, increased BDNF levels were found in the brain, and animals had improved neurolog‐ical and cognitive functions following a weight‐drop injury in mice (Khalin et al., 2016).

Compared to BDNF, small compounds such as TrkB ago‐nists that mimic BDNF’s neurotrophic signaling without its pharmacokinetic barriers may have greater therapeutic potential. In an e ff ort to search for small molecules mim‐icking BDNF function, Jang and colleagues conducted a series of cell‐based TrkB receptor‐dependent survival assays to screen chemical libraries and resulted in the discovery of a flavone derivative, 7,8‐dihydroxyflavone (7,8‐DHF) (Jang et al., 2010). 7, 8‐DHF is a polyphenolic compound found in fruits and vegetables, which mimics BDNF functions due to its ability to bind to TrkB (Chen et al., 2011; Zeng et al., 2012). 7,8‐DHF speci fi cally binds to the receptor extracellular domain of TrkB with high affinity, and induces the receptor dimerization and auto‐phosphorylation (Jang et al., 2010), initiating activation of the downstream signaling pathways as described above in BDNF/TrkB pathway (Figure 1).

Compared to BDNF, 7, 8‐DHF‐induced TrkB receptor phosphorylation lasts much longer. Additionally, TrkB re‐ceptors activated by 7,8‐DHF are not degraded, but instead are recycled to the cell surface aer internalization, as op‐posed to BDNF activated TrkB receptors, which are tagged for ubiquitination and degraded aer internalization (Liu et al., 2014). Internalization is a vital part of initiating sig‐nal transduction for the neurotrophin‐Trk complex. 7,8‐DHF can successfully mimic BDNF‐TrkB internalization in neurons, producing endosomes with TrkB as early as 10 minutes, as BDNF does, and producing a more robust endocytic response than BDNF at 60 minutes (Liu et al., 2014).

7,8‐DHF has a longer half‐life compared to BDNF (134 minutes in plasma following 50 mg/kg oral administration versus less than 10 minutes) (Zhang et al., 2014). It is con‐siderably smaller than BDNF, with a molecular size of 254 Da compared to BDNF’s 27 kDa, which allows for greater permeability crossing the BBB (Liu et al., 2014). It is orally bioactive with an oral bioavailability of 5% (Zhang et al., 2014; Liu et al., 2016).

7,8‐DHF is a selective TrkB agonist which is able to ac‐tivate TrkB receptors without binding to p75 receptors, initiating signaling pathways that only in fl uence neuropro‐tection, plasticity, and neurogenesis without activating the apoptotic processes (Bollen et al., 2013). The binding of 7,8‐DHF to the TrkB extracellular domain activates signal cascades that induce autophosphorylation of TrkB, lead‐ing to activation of MAPK, PI3/Akt, and ERK1/2 signal pathways in a time frame that is comparable to BDNF and in a dose‐dependent manner (Liu et al., 2010; Jiang et al., 2013).

Since its discovery, 7,8‐DHF has been documented in providing neuroprotection and neuroplasticity in animal models of various neurological diseases and disorders in‐cluding TBI. In particular, the bene fi cial e ff ect of 7,8‐DHF has been observed in animal models of Parkinson’s disease (Sconce et al., 2015), Alzheimer’s disease (Castello et al., 2014; Zhang et al., 2014), amyotrophic lateral sclerosis(Korkmaz et al., 2014), Huntington’s disease (Jiang et al., 2013), stroke (Wang et al., 2014), depression and Rett syn‐drome (Liu et al., 2010), and TBI (Wu et al., 2014; Agrawal et al., 2015).

Figure 1e activation pathways of therkB receptor.

In recent years, the therapeutic potential of 7,8‐DHF for TBI has been explored in several types of TBI models, and the underlying mechanisms were explored as well. In anin vitrostretch injury model, 7,8‐DHF treatment can attenuate stretch injury induced cytotoxicity and apoptosis in cultured primary neurons (Wu et al., 2014). In a mouse focal con‐trolled cortical impact (CCI) injury model, intraperitoneal injection of 7,8‐DHF at the dose of 20 mg/kg beginning at 10 minutes following moderate CCI injury, and subsequent single daily doses for 3 days had signi fi cant bene fi cial e ff ects including reducing brain edema, cortical contusion volume, neuronal cell death and apoptosis, as well as improving motor functions of injured animals (Wu et al., 2014). The neuroprotective e ff ect of 7,8‐DHF was also observed when the initial treatment was delayedstarting at 3 hours following TBI as demonstrated by reduced cortical lesion volumes (Wu et al., 2014).

In a fl uid percussion injury (FPI) rat model, animals that received 7,8‐DHF following injury at the single daily dose of 5 mg/kg for 7 consecutive days had enhanced learning and memory functions (Agrawal et al., 2015). In both the CCI and FPI studies, enhanced phosphorylation of TrkB recep‐tor and activation of downstream signaling proteins such as Akt and CREB was observed, con fi rming that the protective e ff ect of 7,8‐DHF for TBI was through activation of TrkB re‐ceptor (Wu et al., 2014; Agrawal et al., 2015).

At the dose of 5 mg/kg giving at 1, 24, 48 and 72 hours following TBI in a mouse CCI model, 7,8‐DHF can also prevent dendritic degeneration of cortical neurons and improve motor functional deficits (Zhao et al., 2016a). Pretreatment of 7,8‐DHF before TBI in the mouse CCI model can enhance neuroprotection by reducing inju‐ry‐induced neuronal cell death of immature neurons in the dentate gyrus of the hippocampus (Chen et al., 2015). When given post‐TBI, 7,8‐DHF also protects newly gener‐ated immature neurons in the dentate gyrus of the hippo‐campus from injury‐induced cell death and promotes their dendritic development in a mouse CCI model (Zhao et al., 2016b).

Our lab has recently found that in a rat CCI model, 5‐day treatment of 7,8‐DHF at the dose of 5 mg/kg started either at 1 hour or 2 days post‐injury could provide pro‐tective e ff ect with reduced lesion volume and neuronal cell loss in the hippocampus, as well as improved motor and cognitive functions (unpublished data).

Apart from direct neuronal function, 7,8‐DHF has also demonstrated a role in modulating inflammation. In cultured murine microglial cells, 7,8‐DHF can inhibit transcription activities of nuclear factor‐κB and MAPK signaling, and thus reduce the production of iNOS (in‐ducible nitric oxide synthase), COX‐2 (cyclooxygenase‐2), tumor necrosis factor‐α and interleukin‐1β following lipopolysaccharide‐stimulation (Park et al., 2014).is an‐ti‐in fl ammation e ff ect of 7,8‐DHF likely contributes to its bene fi cial e ff ects following TBI.

Conclusion and Perspectives

In summary, 7,8‐DHF has proven a viable therapy option for TBI and multiple degenerative neurological disorders.rough its activation of the TrkB receptor and downstream signaling pathways, it promotes survival and dendritic integ‐rity of neurons, reduces injury‐induced tissue damage, and ameliorates motor and cognitive functional impairments. Its ability to cross the BBB and broad therapeutic potential in the CNS makes it a valuable compound deserving further examination for its application in TBI and other neurologi‐cal diseases in clinic.

Author contributions:MW and DS wrote the article, and JR provided some information.

Con fl icts of interest:None declared.

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Dong Sun, M.D., Ph.D., dsun@vcu.edu.

10.4103/1673-5374.198964

＊< class="emphasis_italic">Correspondence to: Dong Sun, M.D., Ph.D., dsun@vcu.edu.

orcid: 0000-0002-3837-7319 (Dong Sun)