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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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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
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.,
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
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
*Correspondence to:
Dong Sun, M.D., Ph.D.,
(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,
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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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.,
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.,
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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(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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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.,
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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... These effects on astroglial genes provide a frame of reference for analysis of genes associated with the reactive astrocyte response (timp1, steap4, Figure 7A,B) or neuroprotective activity: bdnf (brain-derived neurotrophic factor; [23]), manf (Mesencephalic astrocytederived neurotrophic factor [24], clusterin (e.g., [25]), and ubiquitin carboxy-terminal hydrolase L1 (uchl-1) [26] (Figure 7C-F). Although timp1 expression was moderately elevated after 24 hrs, steap4 expression remained stable throughout the post-injury interval. ...
... Others showed a more delayed increase in expression (nestin, fabp7). These effects on astroglial genes provide a frame of reference for analysis of genes associated with the reactive astrocyte response (timp1, steap4, Figure 7A,B) or neuroprotective activity: bdnf (brain-derived neurotrophic factor; [23]), manf (Mesencephalic astrocyte-derived neurotrophic factor [24], clusterin (e.g., [25]), and ubiquitin carboxy-terminal hydrolase L1 (uchl-1) [26] (Figure 7C-F). Although timp1 expression was moderately val. ...
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Traumatic Brain Injury (TBI) is a global driver of disability, and we currently lack effective therapies to promote neural repair and recovery. TBI is characterized by an initial insult, followed by a secondary injury cascade, including inflammation, excitotoxicity, and glial cellular response. This cascade incorporates molecular mechanisms that represent potential targets of therapeutic intervention. In this study, we investigate the response to focal impact injury to the optic tectum of Xenopus laevis tadpoles. This injury disrupts the blood-brain barrier, causing edema, and produces deficits in visually-driven behaviors which are resolved within one week. Within 3 h, injured brains show a dramatic transcriptional activation of inflammatory cytokines, upregulation of genes associated with inflammation, and recruitment of microglia to the injury site and surrounding tissue. Shortly afterward, astrocytes undergo morphological alterations and accumulate near the injury site, and these changes persist for at least 48 h following injury. Genes associated with astrocyte reactivity and neuroprotective functions also show elevated levels of expression following injury. Since our results demonstrate that the response to focal impact injury in Xenopus resembles the cellular alterations observed in rodents and other mammalian models, the Xenopus tadpole offers a new, scalable vertebrate model for TBI.
... 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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History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain’s inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein–protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.
... In panel (E), the antidepressant-like actions of TLQP-62 are shown to be mediated through an unknown receptor (in gray), leading to activation of known glutamatergic signaling pathways, including NMDAR and mGluR5 (Thakker-Varia et al., 2014), the BDNF/TrkB signaling cascade (Jiang et al., 2019a), and calcium channels which activate GluR1 (Jiang et al., 2019a). Other BDNF mimetic/agonists, including LM22A-4 (Fletcher et al., 2021) and 7,8-DHF (Wurzelmann et al., 2017), have shown antidepressant efficacy via TrkB activation. Additionally, vascular endothelial growth factor (VEGF) is shown to induce antidepressant effects via PI3K/PKB/mTORC1 pathways that activate CREB. ...
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This article reviews the current progress in our understanding of the mechanisms by which growth factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and select neurotrophin-regulated gene products, such as VGF (non-acronymic) and VGF-derived neuropeptides, function in the central nervous system (CNS) to modulate neuropsychiatric and neurodegenerative disorders, with a discussion of the possible therapeutic applications of these growth factors to major depressive disorder (MDD) and Alzheimer’s disease (AD). BDNF and VEGF levels are generally decreased regionally in the brains of MDD subjects and in preclinical animal models of depression, changes that are associated with neuronal atrophy and reduced neurogenesis, and are reversed by conventional monoaminergic and novel ketamine-like antidepressants. Downstream of neurotrophins and their receptors, VGF was identified as a nerve growth factor (NGF)- and BDNF-inducible secreted protein and neuropeptide precursor that is produced and trafficked throughout the CNS, where its expression is greatly influenced by neuronal activity and exercise, and where several VGF-derived peptides modulate neuronal activity, function, proliferation, differentiation, and survival. Moreover, levels of VGF are reduced in the CSF of AD subjects, where it has been repetitively identified as a disease biomarker, and in the hippocampi of subjects with MDD, suggesting possible shared mechanisms by which reduced levels of VGF and other proteins that are similarly regulated by neurotrophin signaling pathways contribute to and potentially drive the pathogenesis and progression of co-morbid neuropsychiatric and neurodegenerative disorders, particularly MDD and AD, opening possible therapeutic windows.
... Altered expression levels of neurotrophins and Trk receptors resulted to be modified by the ingestion of flavonoids. It appears that the activation of MAP kinase plus PI3 kinase intracellular signaling pathways [16] and the incremented synthesis of NGF together with BDNF improve not only cognitive events [17,18] but also motor disorders [19]. ...
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Current evidence supports the beneficial role of phytoestrogens in metabolic diseases, but their influences on spontaneous motor and anxiety behaviors plus neuroprotective effects have still not been completely elucidated. With the present study, neuro-behavioral activities were correlated to daidzein (DZ)-dependent expression changes of a high affinity catalytic receptor for several neurotrophins, and namely tropomyosin-related kinase B receptor (TrkB) in the cerebellar cortex of high-fat diet (HFD) hamsters (Mesocricetus auratus). Indeed, these changes appear to be tightly linked to altered plasma lipid profiles as shown by reduced low-density lipoproteins plus total cholesterol levels in DZ-treated obesity hamsters accounting for increased spontaneous locomotor together with diminished anxiety activities in novel cage (NCT) and light/dark box (LDT) tests. For this latter case, the anxiolytic-like hamsters spent more time in the light compartment, which was retained the aversive area of the LDT box. As for the evaluation of the neurotrophin receptor site, significantly elevated TrkB levels were also detected, for the first time, in the cerebellum of obese hamsters treated with DZ. In this condition, such a treatment widely led to an overall improvement of HFD-induced neurodegeneration damages, above all in the Purkinje and granular layers of the cerebellum. In this context, the notably active TrkB signaling events occurring in a DZ-dependent manner may turn out to be a key neuroprotective element capable of restoring normal emotional and spontaneously linked locomotor behaviors regulated by cerebellar cortical areas especially in obesity-related conditions.
... Purple sweet potato water extract with the main content of anthocyanins has been shown to have a direct effect in suppressing oxidative stress and inflammation, thereby triggering apoptosis and causing neuroprotective effects, such as an increase in neurogenesis and improvement of spatial working memory. These results support previous research by Wurzelmann et al. 12 who demonstrated the neuroprotective role of anthocyanins on the mechanisms of oxidative stress and inflammation in dementia mice model. Based on the results of the research and discussion, an illustration scheme was made. ...
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Alzheimer's dementia (AD) is a neurodegenerative disease. The mechanism of oxidative stress in AD is due to amyloid beta (Aβ) protein that aggregates to form plaques, which further triggers chronic inflammation and neuronal apoptosis. Purple sweet potato extract with the main content of anthocyanins is a potential antioxidant with a direct target on the amyloid cascade hypothesis. Objective: The research objective was to determine the role of purple sweet potato water extract as an antioxidant and anti-inflammatory in preventing apoptosis in order to provide a neuroprotective effect in d-galactose-induced rats. Methods: A total of 100 male Wistar rats with randomized posttest-only control group design that met the eligibility criteria were included in this study. The treatment group was given 200 mg/kg BW/day of purple sweet potato water extract on days 1-70. d-galactose induction was administered in the treatment and control groups on days 15-70. Results: The independent t-test showed that the mean tumor necrosis factor-α (TNF-α) levels in the treatment group (735.36±139.74) was significantly lower than that in the control group (896.77±152.52). The p53 and glial fibrillary acidic protein (GFAP) expressions of astrocyte cells in the treatment group were significantly lower than that in the control group. The brain-derived neurotrophic factor (BDNF) levels in the treatment group (498.13±121.47) were higher than that in the control (391.93±140.28), and there was a significant increase in spatial working memory in the treatment group (72.01±10.22) than the control (59.77±11.87). Conclusions: The neuroprotective effect of purple sweet potato extract is due to d-galactose induction resulting from decrease in TNF-α levels, p53 expression, and GFAP expression and increase in BDNF levels and spatial working memory.
... We believe that the effectiveness of our experimental R13 therapy is the result of the gradual release of the BDNF mimetic 7,8-DHF over the 2-week treatment period. However, unlike BDNF, 7,8-DHF does not bind to and signal through the common neurotrophin receptor, p75 N TR (Wurzelmann et al., 2017). It is thus possible that our R13 treatments were so effective also because they avoided any anti-growth effects on regenerating axons resulting FIGURE 4 | (A) Direct muscle (M) responses recorded from gastrocnemius muscles in response to sciatic nerve stimulation are shown 4 weeks after sciatic nerve transection and repair from a mouse treated with oral R13 (upper trace), from a mouse treated with vehicle (middle trace), and from a mouse treated with oral 7,8-DHF (lower trace). ...
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Axon regeneration after peripheral nerve injury is slow and inefficient, leading to generally poor functional recovery. Activity-dependent experimental therapies that increase expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors enhance regeneration, suggesting that treatments with BDNF might also be effective. However, recombinant human BDNF (rhBDNF), as well as 7,8-dihydroxyflavone (7,8-DHF), a small molecular BDNF mimetic, may have limited treatment applications because of their modest oral bioavailability and pharmacokinetic profile. R13 is a 7,8-DHF prodrug. Upon oral administration, it is converted in the liver to 7,8-DHF. In immunoblots from tissues at the site of nerve injury, a single oral treatment with R13 to mice following sciatic nerve transection and repair produced a rapid and prolonged increase in immunoreactivity to phosphorylated TrkB, prolonged phosphorylation of mitogen activated protein kinase (MAPK/Erk1/2), and a rapid but transient increase in phosphorylated AKT (protein kinase B). Intramuscular injections of fluorescent retrograde tracers into the gastrocnemius and tibialis anterior muscles 4 weeks after nerve injury resulted in significantly greater numbers of labeled motoneurons and dorsal root ganglion neurons in R13-treated mice than in vehicle-treated controls. Direct electromyographic (EMG) responses (M waves) were significantly larger in R13-treated mice 4 weeks after injury than vehicle-treated controls or mice treated with oral 7,8-DHF. Oral treatments with the prodrug, R13, are a potent therapy for stimulating axon regeneration and functional recovery after peripheral nerve injury.
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Depression is a debilitating psychiatric disorder impacting an individual’s quality of life. It is the most prevalent mental illness across all age categories, incurring huge socio-economic impacts. Most depression treatments currently focus on the elevation of neurotransmitters according to the monoamine hypothesis. Conventional treatments include tricyclic antidepressants (TCAs), norepinephrine–dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SSRIs). Despite numerous pharmacological strategies utilising conventional drugs, the discovery of alternative medicines from natural products is a must for safer and beneficial brain supplement. About 30% of patients have been reported to show resistance to drug treatments coupled with functional impairment, poor quality of life, and suicidal ideation with a high relapse rate. Hence, there is an urgency for novel discoveries of safer and highly effective depression treatments. Stingless bee honey (SBH) has been proven to contain a high level of antioxidants compared to other types of honey. This is a comprehensive review of the potential use of SBH as a new candidate for antidepressants from the perspective of the monoamine, inflammatory and neurotrophin hypotheses.
Aims Prolonged Endoplasmic Reticulum Stress (ERS) is involved in the pathogenesis of metabolic syndrome, including type-2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. There have been significant efforts to discover molecules to treat ERS and/or to ameliorate associate symptoms. In this study, we investigated the effect of 7,8-Dihydroxyflavone (7,8-DHF) on ERS in liver and pancreas tissues in a cafeteria (CAF) diet induced metabolic syndrome model. Main methods Male C57BL/6 mice were fed CAF diet for 16 weeks and 7,8-DHF was administered intraperitoneally (5 mg/kg/day) for last four weeks. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in liver and pancreas tissues, insulin and interleukin-1β (IL-1β) in serum were analyzed by ELISA method and serum biochemistry parameters were analyzed with autoanalyzer. GRP78 and CHOP gene expression levels were determined by qRT-PCR. In addition, histopathological analyzes were performed on liver and pancreas tissues. Key findings Findings revealed that CAF diet caused metabolic abnormalities, insulin resistance and inflammation in serum and triggered ERS in pancreas and liver tissues. 7,8-DHF treatment significantly reduced metabolic abnormalities by reducing serum biochemical parameters, HOMO-IR and IL-1β levels. qRT-PCR and ELISA results indicated that 7,8-DHF treatment down-regulated GRP78 and CHOP expression and protein levels in the liver and GRP78 expression in pancreas. Efficiency of 7,8-DHF in these tissues was also demonstrated by histopathological tests. Significance In conclusion, CAF diet-induced metabolic syndrome model, 7,8-DHF suppressed ERS and ERS-induced metabolic disorders in both liver and pancreas. Therefore, 7,8-DHF may potentially be a novel therapeutic compound to ameliorate ERS and related metabolic symptoms.
Effective treatment for cognitive dysfunction after traumatic brain injury (TBI) is lacking in clinical practice. Increased brain-derived neurotrophic factor (BDNF) expression in cognitive circuits can significantly alleviate cognitive dysfunction in animal models of TBI. Selective 5-hydroxytryptamine receptor 6 (5-HT6R) agonists significantly increase BDNF expression and improve cognitive function. Therefore, we evaluated the protective effect of a highly selective 5-HT6R agonist, WAY-181187, on cognitive dysfunction after TBI. We established a controlled cortical impact model of moderate TBI in rats and performed drug intervention for five consecutive days. Rats had spatial reference memory impairment in the Morris water maze one and four weeks after TBI. BDNF expression in the medial prefrontal cortex (mPFC) and hippocampus decreased two and five weeks after TBI. Additionally, five weeks after TBI, decreases in neuronal dendritic spine density and the proportion of thin, mushroom-shaped dendritic spines and an increased proportion of stubby-type dendritic spines were observed. WAY-181187 administration (3 mg/kg) for five consecutive days after TBI significantly alleviated cognitive dysfunction at one and four weeks (P<0.001 and P<0.01), upregulated BDNF expression in the mPFC and hippocampus at two (P<0.01 and P<0.05) and five (P<0.01 and P<0.001) weeks and increased the dendritic spine density and the proportions of thin, mushroom-shaped dendrites in the mPFC (P<0.05, P<0.001 and P<0.01) and hippocampus (P<0.05, P<0.001 and P<0.05) at five weeks after TBI. Our results confirm that WAY-181187 administration (3 mg/kg) in the acute phase alleviated cognitive dysfunction after TBI, possibly by upregulating BDNF expression in the mPFC and hippocampus, enhancing neuroplasticity.
Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75NTR across perilesional cortex and higher expression of postsynaptic formations in LCN DBS-treated animals compared to untreated. Overall, these data suggest that LCN DBS is an effective treatment of cognitive deficits that result from TBI, possibly by activation of ascending, glutamatergic projections to thalamus and subsequent upregulation of thalamocortical activity that engages neuroplastic mechanisms for facilitation of functional re-organization. These results support a role for cerebellar output neuromodulation as a novel therapeutic approach to enhance rehabilitation for patients with chronic, post-TBI cognitive deficits that are unresponsive to traditional rehabilitative efforts.
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Currently, traumatic brain injury (TBI) is the leading cause of death or disabilities in young individuals worldwide. The multi-complexity of its pathogenesis as well as impermeability of the blood-brain barrier (BBB) makes 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 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. This study also showed using the passive avoidance (PA) test, that IV injection of NP-BDNF-PX 3 h 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 delivered BDNF into the brain, and improved neurological and cognitive deficits in TBI mice, thereby providing a neuroprotective effect.
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Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus.
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Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases.
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Traumatic brain injury (TBI) at the moderate level of impact induces massive cell death and results in extensive dendrite degeneration in the brain, leading to persistent cognitive, sensory, and motor dysfunction. Our previous reports have shown that the adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus after receiving a moderate TBI with a controlled cortical impact (CCI) device. There is no effective approach to prevent immature neuron death or degeneration following TBI. Our recent study found that pretreatment of 7, 8-dihydroxyflavone (DHF), a small molecule imitating brain derived neurotrophic factor (BDNF), protected immature neurons in the hippocampus from death following TBI. In the present study, we systemically treated moderate CCI-TBI mice or sham surgery mice with DHF once a day for 2 weeks via intraperitoneal injection, and then assessed the immature neurons in the hippocampus the second day after the last DHF injection. We found that post-injury treatment of DHF for 2 weeks not only increased the number of adult-born immature neurons in the hippocampus, but also promoted their dendrite arborization in the injured brain following TBI. Thus, DHF may be a promising compound that can promote neurogenesis and enhance immature neuron development following TBI.
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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.
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 [] 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.
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.
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.
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.
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.