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State of the Art of Brain-Derived Neurotrophic Factor

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 11216

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Special Issue Editors

Prof. Dr. Guiting Lin

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Guest Editor

Department of Urology, UCSF School of Medicine, San Francisco, CA 94143, USA
Interests: stem cell; urology; sexual medicine; cellular signaling pathway

Dr. Yuanyuan Zhang

E-Mail Website
Co-Guest Editor

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
Interests: stem cells; cell therapy; controlled release of growth factors; tissue specific extracellular matrix; tissue regeneration; 3D organoids for drug-induced mitochondrial toxicity testing and nephrotoxicity testing; treatment and biomarkers for diabetic nephropathy and kidney diseases
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Special Issue Information

Dear Colleagues,

This Special Issue, “State of the Art of Brain-Derived Neurotrophic Factor”, will cover a selection of recent research topics and current review articles in the field of neuroprotective effects of brain-derived neurotrophic factor in the central nerve and peripheral nerve system. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. It acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses. BDNF plays a significant role in neuroprotective effects. BDNF can promote protective pathways and inhibit damaging pathways that contribute to the brain’s neurogenic response by enhancing cell survival. This is especially evident following suppression of tropomyosin-related kinase B (TrkB) activity. BDNF recently was found to enhance survival and neuronal differentiation of human neural precursor cells in rat models of auditory neuronal damage. BDNF from bone marrow-derived cells promoted post-injury repair of sciatic nerve in mice. Therefore, BDNF would represent an attractive treatment modality for nerve injuries in addition to peripheral neuropathic disorders, such as diabetes mellitus.

Prof. Dr. Guiting Lin
Dr. Yuanyuan Zhang
Guest Editors

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Keywords

brain-derived neurotrophic factor (BDNF)
neuroprotection
nerve regeneration
survival and neuronal differentiation
central nerve system
peripheral nerve system
cellular signaling transduction
tropomyosin-related kinase B (TrkB)
clinical trials
state-of the-art technology

Published Papers (7 papers)

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Research

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14 pages, 3611 KiB

Open AccessArticle

Cannabidiol Modulates Emotional Function and Brain-Derived Neurotrophic Factor Expression in Middle-Aged Female Rats Exposed to Social Isolation

by Nadya Saad, Danielle Raviv, Tomer Mizrachi Zer-Aviv and Irit Akirav

Int. J. Mol. Sci. 2023, 24(20), 15492; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015492 - 23 Oct 2023

Viewed by 958

Abstract

Aging is associated with changes in cognitive and emotional function. Cannabidiol (CBD) has been reported to attenuate stress and anxiety in human and animal studies. In this study, we aimed to assess the therapeutic potential of CBD among middle-aged female rats exposed to social isolation (SI) and the potential involvement of brain-derived neurotrophic factor (BDNF) in these effects. Thirteen-month-old female rats were group-housed (GH) or exposed to social isolation (SI) and treated with vehicle or CBD (10 mg/kg). CBD restored the SI-induced immobility in the forced swim test and the SI-induced decrease in the expression of BDNF protein levels in the nucleus accumbens (NAc). CBD also increased the time that rats spent in the center in an open field, improved spatial training, and increased BDNF expression in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). BDNF expression was found to be correlated with an antidepressant (in the NAc) and an anxiolytic (in the mPFC, BLA, NAc) phenotype, and with learning improvement in the PFC. Together, our results suggest that CBD may serve as a beneficial agent for wellbeing in old age and may help with age-related cognitive decline. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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22 pages, 4001 KiB

Open AccessArticle

Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease

by Cristina Parrado Fernandez, Sanja Juric, Maria Backlund, Märta Dahlström, Nather Madjid, Veronica Lidell, Azita Rasti, Johan Sandin, Gunnar Nordvall and Pontus Forsell

Int. J. Mol. Sci. 2023, 24(13), 11159; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311159 - 06 Jul 2023

Cited by 2 | Viewed by 2571

Abstract

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect can possibly increase over time, there is still a need for alternative treatments that will improve cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease-modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons, or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells, and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed a neuroprotective effect against amyloid-beta or energy-deprivation-induced neurotoxicity, and increased the levels of brain-derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase in BDNF in the brains of 21 months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect, which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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14 pages, 4080 KiB

Open AccessArticle

BDNF Influence on Adult Terminal Axon Sprouting after Partial Deafferentation

by Beatriz Benítez-Temiño, Rosendo G. Hernández, Rosa R. de la Cruz and Angel M. Pastor

Int. J. Mol. Sci. 2023, 24(13), 10660; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310660 - 26 Jun 2023

Cited by 1 | Viewed by 754

Abstract

BDNF is a neurotrophin family member implicated in many different neuronal functions, from neuronal survival during development to synaptic plasticity associated with processes of learning and memory. Its presence in the oculomotor system has previously been demonstrated, as it regulates afferent composition of extraocular motoneurons and their firing pattern. Moreover, BDNF expression increases after extraocular motoneuron partial deafferentation, in parallel with terminal axon sprouting from the remaining axons. To elucidate whether BDNF could play an active role in this process, we performed partial deafferentation of the medial rectus motoneurons through transection of one of the two main afferents, that is, the ascending tract of Deiters, and injected BDNF into the motoneuron target muscle, the medial rectus. Furthermore, to check whether BDNF could stimulate axon sprouting without lesions, we performed the same experiment without any lesions. Axon terminal sprouting was assessed by calretinin immunostaining, which specifically labels the remaining afferent system on medial rectus motoneurons, the abducens internuclear neurons. The results presented herein show that exogenous BDNF stimulated terminal axon growth, allowing the total recovery of synaptic coverage around the motoneuron somata. Moreover, calretinin staining in the neuropil exceeded that present in the control situation. Thus, BDNF could also stimulate axonal sprouting in the neuropil of intact animals. These results point to an active role of BDNF in plastic adaptations that take place after partial deafferentation. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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20 pages, 5472 KiB

Open AccessArticle

Music with Different Tones Affects the Development of Brain Nerves in Mice in Early Life through BDNF and Its Downstream Pathways

by Jing Wang, Jianxing Wang, Yulai Wang, Yiwen Chai, Haochen Li, Deyang Miao, Honggui Liu, Jianhong Li and Jun Bao

Int. J. Mol. Sci. 2023, 24(9), 8119; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098119 - 01 May 2023

Cited by 4 | Viewed by 2281

Abstract

As a means of environmental enrichment, music environment has positive and beneficial effects on biological neural development. Kunming white mice (61 days old) were randomly divided into the control group (group C), the group of D-tone (group D), the group of A-tone (group A) and the group of G-tone (group G). They were given different tonal music stimulation (group A) for 14 consecutive days (2 h/day) to study the effects of tonal music on the neural development of the hippocampus and prefrontal cortex of mice in early life and its molecular mechanisms. The results showed that the number of neurons in the hippocampus and prefrontal cortex of mice increased, with the cell morphology relatively intact. In addition, the number of dendritic spines and the number of dendritic spines per unit length were significantly higher than those in group C, and the expressions of synaptic plasticity proteins (SYP and PSD95) were also significantly elevated over those in group C. Compared with group C, the expression levels of BDNF, TRKB, CREB, PI3K, AKT, GS3Kβ, PLCγ1, PKC, DAG, ERK and MAPK genes and proteins in the hippocampus and prefrontal cortex of mice in the music groups were up-regulated, suggesting that different tones of music could regulate neural development through BDNF and its downstream pathways. The enrichment environment of D-tone music is the most suitable tone for promoting the development of brain nerves in early-life mice. Our study provides a basis for screening the optimal tone of neuroplasticity in early-life mice and for the treatment of neurobiology and neurodegenerative diseases. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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12 pages, 2830 KiB

Open AccessArticle

Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model

by Brian M. Balog, Kangli Deng, Tessa Askew, Brett Hanzlicek, Mei Kuang and Margot S. Damaser

Int. J. Mol. Sci. 2023, 24(5), 4998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054998 - 05 Mar 2023

Cited by 2 | Viewed by 1279

Abstract

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague–Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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23 pages, 6322 KiB

Open AccessArticle

Acute Stress Induces Different Changes on the Expression of BDNF and trkB in the Mesocorticolimbic System of Two Lines of Rats Differing in Their Response to Stressors

by Maria Pina Serra, Francesco Sanna, Marianna Boi, Laura Poddighe, Lorenzo Secci, Marcello Trucas, Alberto Fernández-Teruel, Maria Giuseppa Corda, Osvaldo Giorgi and Marina Quartu

Int. J. Mol. Sci. 2022, 23(23), 14995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314995 - 30 Nov 2022

Cited by 4 | Viewed by 1600

Abstract

The present work was undertaken to investigate the effects of acute forced swimming (FS) on the levels of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (trkB) proteins in: the ventral tegmental area (VTA); the nucleus accumbens (Acb) shell and core compartments; and the anterior cingulate (ACg), prelimbic (PL) and infralimbic (IL) territories of the prefrontal cortex of genetic models of vulnerability (RLA, Roman low-avoidance rats) and resistance (RHA, Roman high-avoidance rats) to stress-induced depression. We report for the first time that FS induced very rapid and distinct changes in the levels of BDNF and trkB proteins in different areas of the mesocorticolimbic system of RHA and RLA rats. Thus, (1) in the VTA and Acb core, FS elicited a significant increase of both BDNF- and trkB-LI in RHA but not RLA rats, whereas in the Acb shell no significant changes in BDNF- and trkB-LI across the line and treatment were observed; (2) in RLA rats, the basal levels of BDNF-LI in the IL/PL cortex and of trkB-LI in the ACg cortex were markedly lower than those of RHA rats; moreover, BDNF- and trkB-LI in the IL/PL and ACg cortex were increased by FS in RLA rats but decreased in their RHA counterparts. These results provide compelling evidence that the genetic background influences the effects of stress on BDNF/trkB signaling and support the view that the same stressor may impact differently on the expression of BDNF in discrete brain areas. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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Review

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22 pages, 2282 KiB

Open AccessReview

An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease

by Tadahiro Numakawa and Ryutaro Kajihara

Int. J. Mol. Sci. 2024, 25(3), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25031596 - 27 Jan 2024

Viewed by 812

Abstract

Both the brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) play multiple roles in various aspects of neurons, including cell survival and synaptic function. BDNF and its receptor TrkB are extensively expressed in neurons of the central nervous system (CNS), and the contribution of the BDNF/TrkB system to neuronal function is evident; thus, its downregulation has been considered to be involved in the pathogenesis of Alzheimer’s disease (AD). GCs, stress-related molecules, and glucocorticoid receptors (GRs) are also considered to be associated with AD in addition to mental disorders such as depression. Importantly, a growing body of evidence suggests a close relationship between BDNF/TrkB-mediated signaling and the GCs/GR system in the CNS. Here, we introduce the current studies on the interaction between the neurotrophic system and stress in CNS neurons and discuss their involvement in the pathophysiology of AD. Full article

(This article belongs to the Special Issue State of the Art of Brain-Derived Neurotrophic Factor)

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