Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (22 September 2023) | Viewed by 17453

Special Issue Editor


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Guest Editor
Division of Clinical Neuroscience, Center for Forensic Mental Health, Chiba University, Chiba, Japan
Interests: brain body axis; neuropsychiatric disorder; neurotrophic factors; neuroplasticity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Biomolecules invites submissions to a Special Issue focused on the chemistry, biology, and medical application of neurotrophic factors and growth factors in recognition of nature’s remarkable inspiration for gaining new ideas for future medicine.

Neurotrophic factors are a family of biomolecules that can support the growth, survival, and differentiation in the central and peripheral nerve system. Abnormalities in the expression of neurotrophic or growth factors (i.e., brain-derived neurotrophic factor, glial-cell-line-derived neurotrophic factor, epidermal growth factor, and transforming growth factor) might play a role in the pathogenesis of a variety of diseases. Numerous recent studies point to an increasing role of neurotrophic or growth factors as potential therapeutics for the treatment of a broad range of diseases.

For this Special Issue, we invite submissions focusing on understanding the challenges and opportunities for clinical development with this emerging therapeutic class.

Prof. Dr. Kenji Hashimoto
Guest Editor

Manuscript Submission Information

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Keywords

  • brain-derived neurotrophic factor (BDNF)
  • epidermal growth factor (EGF)
  • glial-cell line-derived neurotrophic factor (GDNF)
  • nerve growth factors (NGF)
  • transforming growth factors (TGF)

Published Papers (8 papers)

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Research

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16 pages, 2464 KiB  
Communication
Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility
by Laoise Casserly, Daniel R. Garton, Ana Montaño-Rodriguez and Jaan-Olle Andressoo
Biomolecules 2023, 13(9), 1428; https://doi.org/10.3390/biom13091428 - 21 Sep 2023
Cited by 1 | Viewed by 1001
Abstract
The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic [...] Read more.
The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists. Full article
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17 pages, 3039 KiB  
Article
Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction
by Daniel R. Garton, Giorgio Turconi, Vilma Iivanainen and Jaan-Olle Andressoo
Biomolecules 2023, 13(5), 761; https://doi.org/10.3390/biom13050761 - 27 Apr 2023
Viewed by 1172
Abstract
Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function [...] Read more.
Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment. Full article
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Review

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26 pages, 1408 KiB  
Review
The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers
by Tasuku Matsuoka and Masakazu Yashiro
Biomolecules 2023, 13(10), 1551; https://doi.org/10.3390/biom13101551 - 19 Oct 2023
Cited by 2 | Viewed by 1380
Abstract
Transforming growth factor-β (TGF-β) has attracted attention as a tumor suppressor because of its potent growth-suppressive effect on epithelial cells. Dysregulation of the TGF-β signaling pathway is considered to be one of the key factors in carcinogenesis, and genetic alterations affecting TGF-β signaling [...] Read more.
Transforming growth factor-β (TGF-β) has attracted attention as a tumor suppressor because of its potent growth-suppressive effect on epithelial cells. Dysregulation of the TGF-β signaling pathway is considered to be one of the key factors in carcinogenesis, and genetic alterations affecting TGF-β signaling are extraordinarily common in cancers of the gastrointestinal system, such as hereditary nonpolyposis colon cancer and pancreatic cancer. Accumulating evidence suggests that TGF-β is produced from various types of cells in the tumor microenvironment and mediates extracellular matrix deposition, tumor angiogenesis, the formation of CAFs, and suppression of the anti-tumor immune reaction. It is also being considered as a factor that promotes the malignant transformation of cancer, particularly the invasion and metastasis of cancer cells, including epithelial-mesenchymal transition. Therefore, elucidating the role of TGF-β signaling in carcinogenesis, cancer invasion, and metastasis will provide novel basic insight for diagnosis and prognosis and the development of new molecularly targeted therapies for gastrointestinal cancers. In this review, we outline an overview of the complex mechanisms and functions of TGF-β signaling. Furthermore, we discuss the therapeutic potentials of targeting the TGF-β signaling pathway for gastrointestinal cancer treatment and discuss the remaining challenges and future perspectives on targeting this pathway. Full article
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21 pages, 3919 KiB  
Review
Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors
by Xin-Yu Ma, Ting-Ting Yang, Lian Liu, Xiao-Chun Peng, Feng Qian and Feng-Ru Tang
Biomolecules 2023, 13(5), 754; https://doi.org/10.3390/biom13050754 - 27 Apr 2023
Viewed by 4004
Abstract
The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions [...] Read more.
The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood–brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases. Full article
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17 pages, 1152 KiB  
Review
VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases
by Amanda Louise White and Gregory Jaye Bix
Biomolecules 2023, 13(4), 702; https://doi.org/10.3390/biom13040702 - 20 Apr 2023
Cited by 5 | Viewed by 1387
Abstract
Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased [...] Read more.
Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased neuronal density, and improved outcome. However, VEGFA administration in clinical trials has thus far failed to replicate the promising results seen in animal models. The lack of beneficial effects in humans and the difficulty in medicinal translation may be due in part to administration methods and VEGFA’s ability to increase vascular permeability. One solution to mitigate the side effects of VEGFA may be found in the VEGFA isoforms. VEGFA is able to produce several different isoforms through alternative splicing. Each VEGFA isoform interacts differently with both the cellular components and the VEGF receptors. Because of the different biological effects elicited, VEGFA isoforms may hold promise as a tangible potential therapeutic for cerebrovascular diseases. Full article
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19 pages, 2944 KiB  
Review
Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System
by Hidekazu Sotoyama, Hisaaki Namba, Manavu Tohmi and Hiroyuki Nawa
Biomolecules 2023, 13(2), 372; https://doi.org/10.3390/biom13020372 - 15 Feb 2023
Cited by 3 | Viewed by 2609
Abstract
Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the [...] Read more.
Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors. Full article
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17 pages, 1349 KiB  
Review
Pathophysiology of Post-Traumatic Trigeminal Neuropathic Pain
by Olga A. Korczeniewska, Divya Kohli, Rafael Benoliel, Sita Mahalakshmi Baddireddy and Eli Eliav
Biomolecules 2022, 12(12), 1753; https://doi.org/10.3390/biom12121753 - 25 Nov 2022
Cited by 11 | Viewed by 2921
Abstract
Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and [...] Read more.
Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and clinical features associated with post-traumatic trigeminal neuropathic pain (PTNP). A cascade of events in the peripheral and central nervous system function is involved in the pathophysiology of pain following nerve injuries. Central and peripheral processes occur in tandem and may often be co-dependent. Due to the complexity of central mechanisms, only peripheral events contributing to the pathophysiology have been reviewed in this article. Future investigations will hopefully help gain insight into trigeminal-specific events in the pathophysiology of the development and maintenance of neuropathic pain secondary to nerve injury and enable the development of new therapeutic modalities. Full article
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13 pages, 3326 KiB  
Review
A Bibliometric Analysis of Research on the Role of BDNF in Depression and Treatment
by Teng He, Zifeng Wu, Xinying Zhang, Hanyu Liu, Yuanyuan Wang, Riyue Jiang, Cunming Liu, Kenji Hashimoto and Chun Yang
Biomolecules 2022, 12(10), 1464; https://doi.org/10.3390/biom12101464 - 12 Oct 2022
Cited by 7 | Viewed by 2131
Abstract
Brain-derived neurotrophic factor (BDNF), as the most widely distributed and widely studied neurotrophic factor in the mammalian brain, plays a key role in depression and the mechanisms of action for antidepressants. Currently, there is a large number of studies on the role of [...] Read more.
Brain-derived neurotrophic factor (BDNF), as the most widely distributed and widely studied neurotrophic factor in the mammalian brain, plays a key role in depression and the mechanisms of action for antidepressants. Currently, there is a large number of studies on the role of BDNF in the pathogenesis and therapeutic mechanism of depression. The quantity and quality of these studies, however, are unknown. To give beginners a quicker introduction to this research topic, we therefore performed a bibliometric analysis. A total of 5300 publications were included. We obtained the publications on this topic from the Web of Science database, and a variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. Moreover, we found that oxidative stress and neuroinflammation are the hotspots in the field in very recent years. Collectively, this study provides a comprehensive summary and analysis on the role of BDNF in depression and its treatment and offers meaningful values for beginners on this topic. Full article
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