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

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Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared 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 summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.
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NEURAL REGENERATION RESEARCH
January 2017,Volume 12,Issue 1
erapeutic potential of brain-derived neurotrophic
factor (BDNF) and a small molecular mimics of BDNF
for traumatic brain injury
Introduction
Traumatic brain injury (TBI) is a global public health issue
with few treatment options available (Chauhan, 2014). With
approximately 10 million people a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cult to quantify the full magnitude of TBI, as multi-
ple factors inuence it being underreported, including mild
head trauma, the most common brain injury that is oen
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cits
(Stoica and Faden, 2010).
us far, there is no e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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 et
Abstract
Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults,
a cascade of secondary injuries oen 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cant eect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis.
Recently, the avonoid 7,8-dihydroxyavone (7,8-DHF), a small TrkB agonist that mimics BDNF function,
has shown similar e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.
Key Words: 7,8-dihydroxyavone; brain-derived neurotrophic factor; tropomyosin related kinase B (TrkB)
receptor; traumatic brain injury; neuroregeneration; neuroprotection
INVITED REVIEW
*Correspondence to:
Dong Sun, M.D., Ph.D.,
dsun@vcu.edu.
orcid:
0000-0002-3837-7319
(Dong Sun)
doi: 10.4103/1673-5374.198964
Accepted: 2017-01-16
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.
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Wurzelmann et al. / Neural Regeneration Research. 2017;12(1):7-12.
al., 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 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nity, while each of these neurotrophins binds
with low affinity to p75NTR receptors (Skaper, 2008; Mar-
co-Salazar et al., 2014). Additionally, p75NTR contributes 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ects at synapses and wide expression in
the brain. Two different classes of receptors are responsi-
ble for mediating BDNF signaling: p75NTR and TrkB (Lu et
al., 2008). BDNF has a Kd = 9.9 nM for the TrkB receptor
and a Kd ~1.0 nM for the p75NTR demonstrating its binding
selectivity and affinity for each of the receptor types (Ber-
nard-Gauthier et al., 2013). It is through its high anity for
TrkB that BDNF is able to provide neuronal survival, neuro-
nal plasticity, and neurogenesis (Lu et al., 2008). e p75NTR
receptor is more associated with apoptosis. ProBDNF binds
to the p75NTR receptor while the mature form of BDNF has a
high anity to TrkB (Bollen et al., 2013). However, the ma-
ture form of BDNF can bind to p75NTR receptor 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 stores via activation of the inositol triphosphate (IP3)
receptor, and helps to increase calmodulin kinase (CamK)
activity, and thus synaptic plasticity via the 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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 and TrkB Pathways in the
Central Nervous System
BDNF and TrkB pathway have profound e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).
e cellular basis for learning and memory is considered
to be at the synapses within the hippocampus. BDNF is a
key molecule which controls neuronal differentiation and
survival, synaptic formation and plasticity, as well as activ-
ity-dependent changes in synaptic structure and function
(Park and Poo, 2013). Long-term potentiation (LTP) is a
specific form of plasticity that occurs in the hippocampus
and is the cellular basis of learning and memory. BDNF is a
major regulator for the induction and maintenance of LTP in
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Wurzelmann et al. / Neural Regeneration Research. 2017;12(1):7-12.
the hippocampus and other brain regions (Leal et al., 2014,
2015). Studies have established that adult neurogenesis in
the hippocampus is involved in learning and memory func-
tions (Aimone et al., 2006; Deng et al., 2009). BDNF and
TrkB signaling influences adult neurogenesis by mediating
neuronal differentiation and survival of newly generated
neurons (Scharfman et al., 2005; Chan et al., 2008; Gao and
Chen, 2009). e inuence of BNDF and TrkB signaling on
neurogenesis likely contributes to its function on learning
and memory.
BDNF and Traumatic Brain Injury
By virtue of its role in neuronal di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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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, 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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).
e Molecule 7,8-Dihydroxyavone
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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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 aer internalization, as op-
posed to BDNF activated TrkB receptors, which are tagged
for ubiquitination and degraded aer 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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).
erapeutic Potential of 7,8-DHF for TBI
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cial e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
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Wurzelmann et al. / Neural Regeneration Research. 2017;12(1):7-12.
(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).
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 an in
vitro stretch 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cant benecial e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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 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rming that the protective
e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-
Figure 1 e activation pathways of the TrkB receptor.
e binding of BDNF or 7,8-DHF leads to auto-phosphorylation of the intracellular domain of the receptor and activation of the downstream
pathways. 1) e MAPK pathway. Activation of this pathway stimulates anti-apoptotic proteins, including Bcl2 and cAMP response-element bind-
ing protein (CREB). CREB is required by neurotrophin mediated neuronal survival. Activation of the MAPK pathway also stimulates extracellular
signal related kinase (ERK), which induces phosphorylation of Synapsin I mediating the clustering and release of synaptic vesicles. 2) Activation of
the PI3K pathway, which activates Akt. Akt inhibits apopotosis by inhibiting activation of antiapoptotic proteins including Bad, Pro-caspase 9 and
Forkhead. PI3K = phosphatidylinositol 3 kinase; Akt = Protein Kinase B, PKB; Bad = Bcl2 associated death promoter. 3) e Phospholipase C-gamma
(PLCγ) pathway. PLC-γ can lead to an increase in intracellular calcium levels, which activates the calcium/calmodulin pathway leading to CREB
activation. 7,8-DHF: 7,8-Dihydroxyavone; BDNF: brain-derived neurotrophic factor; MAPK: mitogen-activated protein kinase; TrkB: tropomyo-
sin related kinase B.
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Wurzelmann et al. / Neural Regeneration Research. 2017;12(1):7-12.
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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ammation eect of 7,8-DHF likely contributes to its
benecial e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icts of interest: None declared.
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... Among the most significant enriched pathways identified by the bioinformatic analysis, the activation of BDNF/ TrkB signaling via PI3K/AKT/MAPK pathway appears as a promising neuroprotective strategy for treatment of TBI (He et al. 2018;Wang et al. 2014;Wurzelmann et al. 2017). Furthermore, the post-TBI administration of EGF improved cognitive function and showed neuroprotective effects associated with proliferation of astrocytes in hippocampus of TBI animals (Sun et al. 2010). ...
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Our previous research showed that traumatic brain injury (TBI) induced by controlled cortical impact (CCI) not only causes massive cell death, but also results in extensive dendrite degeneration in those spared neurons in the cortex. Cell death and dendrite degeneration in the cortex may contribute to persistent cognitive, sensory, and motor dysfunction. There is still no approach available to prevent cells from death and dendrites from degeneration following TBI. When we treated the animals with a small molecule, 7,8-dihydroxyflavone (DHF) that mimics the function of brain-derived neurotrophic factor (BDNF) through provoking TrkB activation reduced dendrite swellings in the cortex. DHF treatment also prevented dendritic spine loss after TBI. Functional analysis showed that DHF improved rotarod performance on the third day after surgery. These results suggest that although DHF treatment did not significantly reduced neuron death, it prevented dendrites from degenerating and protected dendritic spines against TBI insult. Consequently, DHF can partially improve the behavior outcomes after TBI.
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Currently, traumatic brain injury (TBI) is the leading cause of death or of disabilities in young individuals worldwide. The multi-complexity of its pathogenesis as well as impermeability of the blood-brain barrier (BBB) make the drug choice and delivery very challenging. The brain-derived neurotrophic factor (BDNF) regulates neuronal plasticity, neuronal cell growth, proliferation, cell survival, and long term memory. However, its short half-life and low BBB permeability are the main hurdles to be an effective therapeutic for TBI. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated by surfactant can enable the delivery of a variety of molecules across the BBB by receptor-mediated transcytosis. This study examines the ability of PLGA nanoparticles coated with poloxamer 188 (PX) to deliver BDNF into the brain and neuroprotective effects of BNDF in mice with TBI. C57bl/6 mice were subjected to weight-drop closed head injuries under anesthesia. Using enzyme-linked immunosorbent assay, we demonstrated that the intravenous (IV) injection of nanoparticle-bound BDNF JUST ACCEPTED Downloaded by [193.176.145.37] at 05:35 09 June 2016 coated by PX (NP-BDNF-PX) significantly increased BDNF levels in the brain of sham-operated mice (p<0.001) and in both ipsi- (p<0.001) and contralateral (p<0.001) parts of brain in TBI mice compared to controls. The present study also showed using the passive avoidance (PA) test, that IV injection of NP-BDNF-PX 3 hours post-injury prolonged the latent time in mice with TBI thereby reversing cognitive deficits caused by brain trauma. Finally, neurological severity score test demonstrated that our compound efficiently reduced the scores at day 7 after the injury indicating the improvement of neurological deficit in animals with TBI. This study shows that PLGA nanoparticles coated with PX effectively deliver BDNF into the brain, and improve neurological and cognitive deficits in TBI mice, thereby providing a neuroprotective effect.
Article
Objectives: Decreased levels of brain derived neurotrophic factor (BDNF) have been found in adult patients with bipolar disorder (BD) compared with a comparison group, yet there are no data specifically examining this in geriatric patients. The objective of this study was to examine whether euthymic late-life BD patients have lower BDNF levels than healthy comparators. Design: Cross-sectional study. Setting: Clinics at the University of Pittsburgh and the Centre for Addiction and Mental Health (Toronto). Participants: Older patients with BD (age ≥50 years, N = 118) and similarly aged healthy comparators (N = 76). There were both BD type I (N = 91) and type II (N = 27) patients. Measurements: Serum BDNF levels were assessed in BD patients and healthy comparators. Results: We found lower levels of BDNF in patients with BD than in healthy comparators (9.0 ± 6.2 versus 12.3 ± 8.9 pg/µg, t(192) = -3.01, p = 0.002), which remained even after controlling for age, sex, lithium use, and site (F(1,176) = 4.32, p = 0.039). This decrease was found specifically in patients with BD type I (8.0 ± 5.5 versus 12.3 ± 8.9 pg/µg, t(165) = 3.7, Bonferroni p < 0.001), but not type II (12.0 ± 7.5 versus 12.3 ± 8.9 pg/µg, t(101) = 0.14, Bonferroni p = 1.0). Conclusions: Older patients with BD have lower serum levels of BDNF compared with similarly aged comparators. These effects appear to be specific to patients with BD type I. Future studies are needed to investigate the impact of reduced BDNF levels on cognition, mood, and other aspects of BD throughout the life course.
Article
Previous studies in rodents have shown that after a moderate traumatic brain injury (TBI) with a controlled cortical impact (CCI) device, the adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus. There is no effective approach for preventing immature neuron death after TBI. We found that tyrosine-related kinase B (TrkB), a receptor of brain-derived neurotrophic factor (BDNF), is highly expressed in adult-born immature neurons. We determined that the small molecule imitating BDNF, 7, 8-dihydroxyflavone (DHF), increased phosphorylation of TrkB in immature neurons both in vitro and in vivo. Pretreatment with DHF protected immature neurons from excitotoxicity-mediated death in vitro, and systemic administration of DHF before moderate CCI injury reduced the death of adult-born immature neurons in the hippocampus 24 hours after injury. By contrast, inhibiting BDNF signaling using the TrkB antagonist ANA12 attenuated the neuroprotective effects of DHF. These data indicate that DHF may be a promising chemical compound that promotes immature neuron survival after TBI through activation of the BDNF signaling pathway.
Article
Traumatic brain injury (TBI) is followed by a state of metabolic dysfunction, affecting the ability of neurons to use energy and support brain plasticity; there is no effective therapy to counteract the TBI pathology. Brain-derived neurotrophic factor (BDNF) has an exceptional capacity to support metabolism and plasticity, which highly contrasts with its poor pharmacological profile. We evaluated the action of a flavonoid derivative 7,8-dihydroxyflavone (7,8-DHF), a BDNF receptor (TrkB) agonist with the pharmacological profile congruent for potential human therapies. Treatment with 7,8-DHF (5mg/kg, ip, daily for 7days) was effective to ameliorate the effects of TBI on plasticity markers (CREB phosphorylation, GAP-43 and syntaxin-3 levels) and memory function in Barnes maze test. Treatment with 7,8-DHF restored the decrease in protein and phenotypic expression of TrkB phosphorylation after TBI. In turn, intrahippocampal injections of K252a, a TrkB antagonist, counteracted the 7,8-DHF induced TrkB signaling activation and memory improvement in TBI, suggesting the pivotal role of TrkB signaling in cognitive performance after brain injury. A potential action of 7,8-DHF on cell energy homeostasis was corroborated by the normalization in levels of PGC-1α, TFAM, COII, AMPK and SIRT1 in animals subjected to TBI. Results suggest a potential mechanism by which 7,8-DHF counteracts TBI pathology via activation of the TrkB receptor and engaging the interplay between cell energy management and synaptic plasticity. Since metabolic dysfunction is an important risk factor for the development of neurological and psychiatric disorders, these results set a precedent for the therapeutic use of 7,8-DHF in a larger context. Copyright © 2015. Published by Elsevier B.V.
Article
Parkinson's disease (PD) is a progressive neurological disorder and current therapies help alleviate symptoms, but are not disease modifying. In the flavonoid class of compounds, 7,8-dihydroxyflavone (7,8-DHF) has been reported to elicit tyrosine kinase receptor B (TrkB) dimerization and autophosphorylation that further stimulates signaling cascades to promote cell survival/growth, differentiation, and plasticity. In this study we investigated if 7,8-DHF could prevent further loss of dopaminergic cells and terminals if introduced at the midpoint (i.e. intervention) of our progressive mouse model of PD. In our model, 1-methyl-4phenyl-1,2,3,6-tetrahyrdopyridine (MPTP) is administered with increased doses each week (8, 16, 24, 32 kg/mg) over a 4-week period. We found that despite 4 weeks of MPTP treatment, animals administered 7,8-DHF starting at the 2-week time period maintained 54% of the tyrosine hydroxylase (TH) levels within the dorsolateral striatum compared to the vehicle group, which was comparable to animals treated with MPTP for 2 weeks and was significantly greater compared to animals treated with MPTP for the full 4 weeks. Animals treated with MPTP and 7,8-DHF also demonstrated increased levels of, a sprouting associated protein, superior cervical ganglion-10 (SCG10), phosphorylated TrkB (pTrkB), and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) within the dorsolateral striatum and substantia nigra (SN) compared to the 4 week MPTP treated animals. In addition, motor deficits seen in the 2- and 4-week MPTP treated animals were restored following administration of 7,8-DHF. We are reporting here for the first time that intervention with 7,8-DHF blocks further loss of dopaminergic terminals and restores motor deficits in our progressive MPTP mouse model. Our data suggest that 7,8-DHF has the potential to be a translational therapy in PD. Published by Elsevier Ltd.