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Biomedicines
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BDNF in Brain Disorders: From Pathogenesis to Treatment
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BDNF in Brain Disorders: From Pathogenesis to Treatment

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 12133

Special Issue Editor

Dr. Tatiana Ilchibaeva

E-Mail Website
Guest Editor
The Federal Research Center Institute of Cytology and Genetics (ICG), Siberian Branch of Russian Academy of Sciences (SB RAS), 630090 Novosibirsk, Russia
Interests: eurodegeneration; neurotrophic factors; 5-HT system; 5-HT2A receptors; trkb receptor; GDNF; BDNF; CDNF; aggression; depression; 5-HT1A receptor

Special Issue Information

Dear Colleagues,

Brain-derived neurotrophic factor (BDNF) plays multiple roles in the nervous system, including in neuronal development, in long-term synaptic potentiation in different brain regions, and in neuronal survival. Alterations in these regulatory mechanisms account for several diseases of the nervous system. It is not surprising that BDNF and its receptors are also involved in many brain pathologies, including mood disorders, Alzheimer’s disease, autism spectrum disorder, and many others.

This Special Issue focuses on the current understanding and future research directions regarding BDNF and its receptors as key players in the pathobiology and treatment of different brain disorders. We warmly welcome original research and review articles relating to this hot topic.

Dr. Tatiana Ilchibaeva
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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17 pages, 1878 KiB  
Article
A Truncated Receptor TrkB Isoform (TrkB.T1) in Mechanisms of Genetically Determined Depressive-like Behavior of Mice
by Marah Alsalloum, Tatiana Ilchibaeva, Anton Tsybko, Dmitry Eremin and Vladimir Naumenko
Biomedicines 2023, 11(9), 2573; https://doi.org/10.3390/biomedicines11092573 - 19 Sep 2023
Cited by 1 | Viewed by 1432
Abstract
Depression is a mental disorder that significantly reduces quality of life, and the discovery of new drug targets is an urgent problem for modern neuroscience. Brain-derived neurotrophic factor (BDNF) and its receptors have been found to participate in mechanisms of depression and antidepressant [...] Read more.
Depression is a mental disorder that significantly reduces quality of life, and the discovery of new drug targets is an urgent problem for modern neuroscience. Brain-derived neurotrophic factor (BDNF) and its receptors have been found to participate in mechanisms of depression and antidepressant drugs’ action. In this study, we focused on a less-studied truncated isoform of receptor TrkB: TrkB.T1. Initially, we noticed that the level of TrkB.T1 is low in the hippocampus of Antidepressant-Sensitive Cataleptics (ASC) mice, which are characterized by genetically determined depressive-like behavior in contrast to “normal” C57BL/6J mice. Next, overexpression of TrkB.T1 receptor in hippocampal neurons of ACS mice was induced to clarify the role of this receptor in mechanisms of depressive-like behavior. TrkB.T1 overexpression lowered BDNF protein concentration in the hippocampus. On the behavioral level, TrkB.T1 overexpression severely decreased aggression and enhanced social behavior. Additionally, this excess of receptor TrkB.T1 slightly promoted anxiety and depressive-like behavioral traits without affecting learning and memory. Our results show that this TrkB isoform participates in the control of aggression, anxiety, and depressive-like behavior and in the regulation of BDNF system functioning in ASC mice (genetically predisposed to depressive-like behavior). Considering our findings, we believe that hippocampal receptor TrkB.T1 can be a drug target for the correction of behavioral pathologies. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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10 pages, 708 KiB  
Communication
BDNF rs962369 Is Associated with Major Depressive Disorder
by Aneta Bednářová, Viera Habalová and Ivan Tkáč
Biomedicines 2023, 11(8), 2243; https://doi.org/10.3390/biomedicines11082243 - 10 Aug 2023
Viewed by 797
Abstract
This study enrolled 291 patients diagnosed with depression and schizophrenia (F32, F33, and F20 according to ICD-10) and 227 ethnicity-matched control subjects. We analyzed the distribution of BDNF rs6265 and BDNF rs962369 genotypes, finding no significant associations between these and schizophrenia. We revealed [...] Read more.
This study enrolled 291 patients diagnosed with depression and schizophrenia (F32, F33, and F20 according to ICD-10) and 227 ethnicity-matched control subjects. We analyzed the distribution of BDNF rs6265 and BDNF rs962369 genotypes, finding no significant associations between these and schizophrenia. We revealed a significant increase in the risk of single-episode major depression disorder (MDD) for rs962369 minor allele homozygotes (CC vs. TT+TC), an association that persisted after adjusting for age and sex (OR 3.47; 95% CI 1.36–8.85; p = 0.009). Furthermore, rs962369 genotype was significantly associated with an increased risk of recurrent MDD in a log-additive model (OR per C-allele 1.65; 95% CI 1.11–2.45; p = 0.013). A comparative analysis between MDD subtypes and between MDD subtypes and schizophrenia showed no significant differences for BDNF rs6265. Notably, the frequency of minor allele C of BDNF rs962369 varied across subgroups, with the highest frequency in patients with recurrent MDD (0.32) and the lowest in schizophrenia patients (0.20). The presence of genotypes with at least one minor allele C was significantly higher in the recurrent MDD patient group compared to the schizophrenia group. In conclusion, the BDNF rs962369 variant was associated with MDD but not with schizophrenia. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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24 pages, 3844 KiB  
Article
Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System
by Tatiana Ilchibaeva, Anton Tsybko, Marina Lipnitskaya, Dmitry Eremin, Kseniya Milutinovich, Vladimir Naumenko and Nina Popova
Biomedicines 2023, 11(5), 1482; https://doi.org/10.3390/biomedicines11051482 - 19 May 2023
Cited by 2 | Viewed by 1803
Abstract
Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in [...] Read more.
Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus–mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF–DA crosstalk in the autistic-like phenotype of BTBR mice. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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27 pages, 2111 KiB  
Article
A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures
by Anastasia Levchenko, Sergey Malov, Alexey Antonik, Anastasia Protsvetkina, Kseniya V. Rybakova, Alexander Kanapin, Alexey N. Yakovlev, Anna Y. Nenasteva, Anton E. Nikolishin, Nikolay Cherkasov, Natalia A. Chuprova, Anna S. Blagonravova, Angelica V. Sergeeva, Tatyana V. Zhilyaeva, Maria K. Denisenko, Raul R. Gainetdinov, Alexander O. Kibitov and Evgeny M. Krupitsky
Biomedicines 2022, 10(12), 3007; https://doi.org/10.3390/biomedicines10123007 - 22 Nov 2022
Cited by 2 | Viewed by 1635
Abstract
At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional [...] Read more.
At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10−8 calculated with the Yates-corrected χ2 test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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19 pages, 11821 KiB  
Article
mTOR Signaling in BDNF-Treated Guinea Pigs after Ototoxic Deafening
by Annamaria Tisi, Dyan Ramekers, Vincenzo Flati, Huib Versnel and Rita Maccarone
Biomedicines 2022, 10(11), 2935; https://doi.org/10.3390/biomedicines10112935 - 15 Nov 2022
Cited by 1 | Viewed by 1604
Abstract
The mammalian target of rapamycin (mTOR) signaling plays a critical role in cell homeostasis, growth and survival. Here, we investigated the localization of the main mTOR signaling proteins in the organ of Corti of normal-hearing and deafened guinea pigs, as well as their [...] Read more.
The mammalian target of rapamycin (mTOR) signaling plays a critical role in cell homeostasis, growth and survival. Here, we investigated the localization of the main mTOR signaling proteins in the organ of Corti of normal-hearing and deafened guinea pigs, as well as their possible modulation by exogenously administered brain-derived neurotrophic factor (BDNF) in deafened guinea pigs. Animals were ototoxically deafened by systemic administration of kanamycin and furosemide, and one week later, the right cochleas were treated with gelatin sponge soaked in rhBDNF, while the left cochleas were used as negative controls. Twenty-four hours after treatment, animals were euthanized, and the cochleas were processed for subsequent analysis. Through immunofluorescence, we demonstrated the localization of AKT, pAKT, mTOR, pmTOR and PTEN proteins throughout the cochlea of guinea pigs for the first time, with a higher expression in supporting cells. Moreover, an increase in mTOR immunostaining was observed in BDNF-treated cochleas by means of fluorescence intensity compared to the other groups. Conversely, Western blot analysis showed no significant differences in the protein levels between groups, probably due to dilution of proteins in the neighboring tissues of the organ of Corti. Altogether, our data indicate that mTOR signaling proteins are expressed by the organ of Corti (with a major role for supporting cells) and that the modulation of mTOR may be a protective mechanism triggered by BDNF in the degenerating organ of Corti. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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11 pages, 1883 KiB  
Article
Urokinase-Type Plasminogen Activator Enhances the Neuroprotective Activity of Brain-Derived Neurotrophic Factor in a Model of Intracerebral Hemorrhage
by Stalik Dzhauari, Svetlana Litvinova, Anastasia Efimenko, Natalia Aleksandrushkina, Nataliya Basalova, Maxim Abakumov, Natalia Danilova, Pavel Malkov, Vadim Balabanyan, Tatiana Bezuglova, Viktor Balayants, Maxim Mnikhovich, Mikhail Gulyaev, Mariya Skryabina, Vladimir Popov, Dmitry Stambolsky, Tatiana Voronina, Vsevolod Tkachuk and Maxim Karagyaur
Biomedicines 2022, 10(6), 1346; https://doi.org/10.3390/biomedicines10061346 - 08 Jun 2022
Cited by 3 | Viewed by 2391
Abstract
Brain-derived neurotrophic factor (BDNF) is a classic neuroprotective and pro-regenerative factor in peripheral and central nervous tissue. Its ability to stimulate the restoration of damaged nerve and brain tissue after ischemic stroke and intraventricular hemorrhage has been demonstrated. However, the current concept of [...] Read more.
Brain-derived neurotrophic factor (BDNF) is a classic neuroprotective and pro-regenerative factor in peripheral and central nervous tissue. Its ability to stimulate the restoration of damaged nerve and brain tissue after ischemic stroke and intraventricular hemorrhage has been demonstrated. However, the current concept of regeneration allows us to assert that one factor, even if essential, cannot be the sole contributor to this complex biological process. We have previously shown that urokinase-type plasminogen activator (uPA) complements BDNF activity and stimulates restoration of nervous tissue. Using a model of intracerebral hemorrhage in rats, we investigated the neurotrophic and neuroprotective effect of BDNF combined with uPA. The local simultaneous administration of BDNF and uPA provided effective neuroprotection of brain tissue after intracerebral hemorrhage, promoted survival of experimental animals and their neurological recovery, and decreased lesion volume. The study of cellular mechanisms of the observed neurotrophic effect of BDNF and uPA combination revealed both known mechanisms (neuronal survival and neurite growth) and new ones (microglial activation) that had not been shown for BDNF and uPA. Our findings support the concept of using combinations of biological factors with diverse but complementary mechanisms of action as a promising regenerative approach. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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Review

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29 pages, 1493 KiB  
Review
Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington’s Disease: Mechanisms and Potential Therapeutics
by Andrew Speidell, Noman Bin Abid and Hiroko Yano
Biomedicines 2023, 11(8), 2275; https://doi.org/10.3390/biomedicines11082275 - 16 Aug 2023
Cited by 2 | Viewed by 1747
Abstract
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than [...] Read more.
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington’s disease (HD)—an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin’s importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals. Full article
(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)
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