Next Article in Journal
Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development
Previous Article in Journal
Unlocking the Green Gold: Exploring the Cancer Treatment and the Other Therapeutic Potential of Fucoxanthin Derivatives from Microalgae
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 17
Issue 7
10.3390/ph17070961
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases

by
George N. Chaldakov
1,*,
Luigi Aloe
2,
Stanislav G. Yanev
3,
Marco Fiore
4,*,
Anton B. Tonchev
1,
Manlio Vinciguerra
5,
Nikolai T. Evtimov
6,
Peter Ghenev
7 and
Krikor Dikranian
8
1
Departments of Anatomy and Cell Biology and Translational Stem Cell Biology, Research Institute, Medical University, 9002 Varna, Bulgaria
2
Fondazione Iret, Tecnopolo R. Levi-Montalcini, 40064 Ozzano dell’Emilia (BO), Italy
3
Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
4
Institute of Biochemistry and Cell Biology, National Research Council, IBBC-CNR, 00185 Rome, Italy
5
Department of Translational Stem Cell Biology, Research Institute, Medical University, 9002 Varna, Bulgaria
6
Department of Urology, University St Anna Hospital, 9002 Varna, Bulgaria
7
Department of General and Clinical Pathology, Medical University, 9002 Varna, Bulgaria
8
Department of Neuroscience, Medical School, Washington University, St. Louis, MO 63110, USA
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2024, 17(7), 961; https://doi.org/10.3390/ph17070961
Submission received: 27 May 2024 / Revised: 19 June 2024 / Accepted: 17 July 2024 / Published: 19 July 2024
(This article belongs to the Special Issue Synthetic Inhibitors of Nucleoside Monophosphate-Kinases)
Browse Figures
Versions Notes

Abstract

:
Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced “track”). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkBBDNF, TrkCNT−3, TrkANGF, and TrkApro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkANGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkANGF, TrkApro-NGF, TrkBBDNF, and TrkCNT−3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients.

1. Introduction

Thus, the task is not so much to see what no one has yet seen but to think what nobody has yet thought about that which everybody sees.
Arthur Schopenhauer
The discovery of nerve growth factor (NGF) in 1951 by Rita Levi-Montalcini was the Rosetta stone in understanding neural differentiation, survival, and functions [1,2]. Life, at both the local and systemic levels, requires nutritional, immune, neurotrophic, and metabotrophic support. Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapies for cardiometabolic diseases (CMD), neurodegenerative diseases, and cancers, thus extending human life expectancy and Quality of Life (QoL) [3,4,5,6]. The following pressing question thus remains: what are the pathogenic routes and how can they be counteracted for therapeutic purposes?

2. Neurotrophins and Their Receptors

At present, the neurotrophin family of proteins consists of NGF, pro-NGF, brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6 [5,6]. Of these, NGF, pro-NGF, BDNF, and NT-3 are multifunctional proteins, which, in addition to their neurotrophic action, exert various extraneuronal effects directed to immune, endothelial, beta-pancreatic, muscle, epithelial, and other nonneuronal cells [3,4,5,6,7,8,9,10]. As well as the metabolism of lipids and carbohydrates, we named metabotrophic effects and metabotrophic factors (MTF) [5,6].
Neurotrophins elicit their outcomes via ligation to p75NTR), the pan-neurotrophin receptor, and Trk receptors, namely, TrkANGF, TrkApro-NGF, TrkBBDNF, TrkBNT−4/5, and TrkCNT−3. The acronym Trk intends for tyrosine receptor kinases vs. non-receptor tyrosine kinases, which have no transmembrane domain (Figure 1, Table 1, Table 2 and Table 3).
In this connection, Figure 2 illustrates our own results of the potential significance of reduced local and/or blood levels of NGF and BDNF, functioning as metabotrophic factors (MTF) for the pathobiology of obesity and its related cardiometabolic and neurodegenerative diseases, particularly Alzheimer’s disease (AD), with the latter being considered a neurometabolic disease [3,4,5,6,8,9,10,18].

3. NGF, BDNF, and Their Trk Receptors: Druggable Targets for Disease Therapies

Druggability is a term used in drug discovery to describe biological targets [71,72]. In the context of the present article, these are the neurotrophins and their Trk receptors that are known or predicted to bind with high affinity to a drug [71,72]. Furthermore, by definition, the binding of the drug to a druggable target must alter the function of the target, with a therapeutic benefit to the patient [71,72]. The idea of druggability is most often constrained to low-molecular-weight chemicals (pharmaceuticals) but has also been revised to include biologicals such as therapeutic monoclonal antibodies, and nutraceuticals such as polyphenols extracted from vegetables [73,74].
There are numerous pathways that can cause the transition from a healthy to a diseased phenotype. In contrast, the pathways to reverse this process, such as treating conditions like CMD and cancers to extend human life expectancy, are limited. The critical question is as follows: what are these pathogenic pathways, and how can they be effectively countered for therapeutic purposes?
Human cells contain >500 protein kinases and nearly 200 protein phosphatases acting on thousands of proteins including cell growth factors in health and disease; see [3,4]. At present, BDNF, NGF, and pro-NGF play a crucial role in the pathogenesis of a wide spectrum of neuronal and non-neuronal disorders, such as Alzheimer’s and other neurodegenerative disorders, including obesity and related CMD [3,4,6]. The decreased presence of resident and/or blood circulating BDNF and NGF was described in metabolic syndrome, human coronary atherosclerosis, and acute coronary syndromes [3,4,5,6,7,9,10], suggestive of (i) a key function played by BDNF and NGF in the pathogenetic processes and (ii) a potential therapeutic action of TrkBBDNF and TrkANGF receptor agonists in CMD. Indeed, it is well known that BDNF acts in the leptin-mediated anorexigenic circuit to regulate the adipose-brain regulation of food intake; see [5,6]. Mice heterozygous for BDNF-targeted disruption and mice with a reduced expression of the TrkBBDNF receptor show hyperphagia and obesity; see [4,5,6].
Notably, short-term myocardial ischemia produces a sympathetic cardiac innervation dysfunction associated with a rapid elevation in NGF release, while the NGF exogenous administration acts against such neuronal dysfunction, indicating that the endogenous production of NGF is inadequate for efficient neural protection [75]. Since reduced local and/or circulating levels of NGF and BDNF were found to be related to atherogenesis [3,4,5,6,7,8,9,10], the stimulation of TkrANGF and TrkBBDNF receptors could create possible agonistic trackins with an anti-atherosclerotic effect.
Furthermore, recent studies show the therapeutic potential of NGF in the healing of corneal and cutaneous wounds [8,28,62,63,76,77], while TrkANGF receptor antagonists have been studied for new drugs for prostate, breast, and other malignant tumors, as well as for pain [20,29,30,78]. Stromal cells of the prostate and adipose stromal cells secrete NGF, which, in a paracrine way, can stimulate the carcinogenic proliferation of prostatic epithelial cells [79]. In support of such data, chemical substances that inhibit TrkANGF receptors are increasingly being investigated as potential anticancer drugs. For instance, TrkANGF receptor expression is positively associated with the invasion and malignancy of cancer cells in the prostate, and its antagonist Lestaurtinib (codename CEP-701) was included in some clinical trials focusing on prostate cancer [80]. This drug is the chemical substance indolocarbazole that specifically inhibits the TrkANGF receptor [19,80]. It should be noted that natural antibodies against NGF are also present in intravenous gammaglobulin (IVIg), which may inhibit the in vitro migration of prostate cancer cells; see [81]. Intriguingly, it was reported that tamoxifen, prescribed to breast cancer patients, may inhibit TrkANGF phosphorylation and, respectively, the NGF-elicited proliferation of epithelial cells from breast cancer [82]. Reflecting on the phenomenon of repurposed drugs (such as aspirin and colchicine), the findings about tamoxifen align with numerous other instances where an old drug has been found to have a new use.
Another “danger” arises from data showing that NGF-induced increases in the sympathetic innervation of the myocardium are implicated in the pathobiology of sudden cardiac death [83]. We consider these latter results as suggestive of a probable participation of NGF and its TrkA receptor in the pathogenetic mechanisms of arrhythmogenic right-ventricular dysplasia [24]. This is a genetic type of cardiomyopathy, characterized histologically by the substitution of deteriorated cardiomyocytes with NGF/BDNF-produced adipocytes documented in our immunohistochemical study [24]. Despite this, the possibility of TrkANGF and TrkCNT−3 receptor antagonists possessing an anti-arrhythmogenic action remains to further be investigated.
Intriguingly, high-pressure treatment with sterile physiological saline isotonic solution into the nasal cavity of individuals with sensorineural hearing loss and tinnitus potentiates NGF levels (in the nasal fluid), leading to improved hearing [84]. “Paradoxically”, recent experimental results obtained with a TrkANGF receptor inhibitor, GW441756, suggest that one component of an optimal therapy for Alzheimer’s disease may be a TrkANGF antagonist [20].

4. Conclusions and Perspectives

In science, the Apollonian tends to develop established lines to perfection, while the Dionysian rather relies on intuition and is more likely to open new, unexpected alleys for research. The future of mankind depends on the progress of science, and the progress of science depends on the support it can find. Support mostly takes the form of grants, and the present methods of distributing grants unduly favor the Apollonian.
Albert Szent-Gyorgyi (1972), Nobel Prize winner 1937 in Physiology or Medicine
This translational review highlighted the possible druggability of NGF-TrkANGF-TrkApro-NGF, BDNF-TrkBBDNF, and NT3-TrkCNT−3 through agonistic or antagonistic trackins for therapy for different pathologies (Table 4). This may contribute to the theoretical hypothesis of an innovative therapeutic frame for further translational investigations dealing with trackins.
Let us remember that the plasma membrane contains microdomains termed lipid rafts (LRs, existing as caveolae) that are enriched in lipids, such as glycosphingolipids, gangliosides, and cholesterol [86]; LRs are scaffolds for many receptors. Much evidence indicates that the functions of LRs depend upon the interactions with the cytoskeletal microtubules (MT) and MT-associated motor proteins [87]. NGF enhances the interaction between TrkA and MT at lipid rafts controlling different cellular responses including axonal growth [87]. These data suggest the existence of an intriguing quartet consisting of NGF-TrkNGF-MT-LR. In the brain, pro-NGF is the only detectable form of NGF; thus, the dysregulation of pro-NGF and/or its TrkApro-NGF receptor in the brain could be implicated in age-related memory loss, including AD [87]. Further, the current data suggest that an increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) reduces the expression of the TrkApro-NGF receptor; additionally, the dysfunction of the MT motors kinesin and dynein may lead to disruptions to the TrkApro-NGF receptor’s downstream survival signaling [88]. Conventional thinking immediately proposes antioxidant treatments as beneficial in restoring pro-NGF signaling and reducing brain neurodegeneration and related deficits in cognitive function. Since ROS-RNS also interferes with the abovementioned intriguing quartet [88], we wonder whether the murburn concept of the biology of oxygen [89,90,91] could explain such an association between Trk, ROS, RNS, MT, and AD.
Existing limits to Trk-targeting drug development include several critical tasks. One main issue is achieving a high specificity for Trk receptors without distressing similar kinases, leading to off-target results and unsolicited side effects. Furthermore, the progress of resistance mechanisms in the disease through mutations or unusual signaling pathways, obscures the long-term efficiency of these drugs. There are pharmacokinetic obstacles too, such as limited bioavailability and impairments in drug delivery to target tissues, restricting their therapeutic potential. Addressing these limits is crucial for advancing Trk-targeting treatments and improving outcomes for people with Trk-driven disorders.
In a nutshell
The concept of trackins highlighted herein is a promising step forward, but not the whole journey—however, it promises a reward in future translational research. Since 2016, see [3,4,5,7,22], we have been “pondering what no one else has yet considered about what everyone observes”, thus introducing the term trackins [4] with respect to the bivalent nature of the druggability of TrkANGF and TrkBBDNF receptors and, consequently, their stimulation or inhibition by trackins (pharmaceuticals, nutraceuticals, and/or biologicals), showing the relevance of this subject to therapies for the different diseases discussed in the present short review.
Doubtless, we remember René Descartes’ idea that “de omnibus dubitare, vel dubitare de ipsa” (from Latin—“everything must be doubted”).

5. Addendum

Human love of knowledge leads to the wish to “see inside” the body of organisms. Initially, this was achieved by Aristotle’s biology, the first in the history of science, which included five major processes:
  • A metabolic process, whereby animals take in matter, change its qualities, and distribute these to use to grow, live, and reproduce.
  • Temperature regulation, whereby animals maintain a steady state, which progressively fails in old age.
  • An information-processing model, whereby animals receive sensory information and use it to drive movements of the limbs.
  • The process of inheritance.
  • The processes of embryonic development and spontaneous generation
These five processes formed what Aristotle (384–322 BC) called the soul, as illustrated in Figure 3:

Author Contributions

G.N.C., L.A.; S.G.Y., M.F., N.T.E., A.B.T., M.V., K.D. and P.G.; writing—original draft preparation, G.N.C., L.A., M.F. and K.D.; writing—review and editing, G.N.C., L.A., K.D., S.G.Y., M.F., A.B.T., M.V. and P.G.; data acquisition, G.N.C., L.A.; K.D., S.G.Y., A.B.T., M.V., N.T.E., P.G. and M.F.; supervision, G.N.C., L.A., S.G.Y., M.F., A.B.T., M.V., K.D., N.T.E. and P.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable.

Acknowledgments

We sincerely thank our brain-and-heart friends (BHF) Luigi Manni, Federica Sornelli, Viviana Triaca, Mariana Hristova, Vesselka Nikolova, and Diana Vyagova for their useful assistance in our studies on the neurometabotrophins NGF and BDNF. We say sorry to the authors of other many pertinent studies that were not cited here for reasons of conciseness.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Levi-Montalcini, R. The nerve growth factor 35 years later. Science 1987, 237, 1154–1162. [Google Scholar] [CrossRef] [PubMed]
  2. Cohen, S.; Levi-Montalcini, R.; Hamburger, V. A Nerve Growth-Stimulating Factor Isolated from Sarcomas 37 and 180. Proc. Natl. Acad. Sci. USA 1954, 40, 1014–1018. [Google Scholar] [CrossRef] [PubMed]
  3. Yanev, S.; Aloe, L.; Fiore, M.; Chaldakov, G.N. Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: Linking cardiometabolic and neuropsychiatric diseases. World J. Pharmacol. 2013, 2, 92. [Google Scholar] [CrossRef]
  4. Yanev, S.; Fiore, M.; Hinev, A.; Ghenev, P.I.; Hristova, M.G.; Panayotov, P.; Tonchev, A.; Evtimov, N.; Aloe, L.; Chaldakov, G.N. From antitubulins to trackins. Biomed. Rev. 2016, 27, 59–67. [Google Scholar] [CrossRef]
  5. Chaldakov, G.; Fiore, M.; Tonchev, A.; Aloe, L. Adipopharmacology, a Novel Drug Discovery Approach: A Metabotrophic Perspective. Lett. Drug Des. Discov. 2008, 3, 503–505. [Google Scholar] [CrossRef]
  6. Frohlich, J.; Chaldakov, G.N.; Vinciguerra, M. Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy. Int. J. Mol. Sci. 2021, 22, 4137. [Google Scholar] [CrossRef] [PubMed]
  7. Chaldakov, G.N.; Fiore, M.; Stankulov, I.S.; Manni, L.; Hristova, M.G.; Antonelli, A.; Ghenev, P.I.; Aloe, L. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: A role for NGF and BDNF in cardiovascular disease? Prog. Brain Res. 2004, 146, 279–289. [Google Scholar] [CrossRef] [PubMed]
  8. Aloe, L.; Tirassa, P.; Lambiase, A. The topical application of nerve growth factor as a pharmacological tool for human corneal and skin ulcers. Pharmacol. Res. 2008, 57, 253–258. [Google Scholar] [CrossRef] [PubMed]
  9. Chaldakov, G.N.; Stankulov, I.S.; Fiore, M.; Ghenev, P.I.; Aloe, L. Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis. Atherosclerosis 2001, 159, 57–66. [Google Scholar] [CrossRef]
  10. Manni, L.; Nikolova, V.; Vyagova, D.; Chaldakov, G.N.; Aloe, L. Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. Int. J. Cardiol. 2005, 102, 169–171. [Google Scholar] [CrossRef]
  11. Gentry, J.J.; Barker, P.A.; Carter, B.D. The p75 neurotrophin receptor: Multiple interactors and numerous functions. Prog. Brain Res. 2004, 146, 25–39. [Google Scholar] [CrossRef]
  12. Jeanneteau, F.; Chao, M.V. Promoting neurotrophic effects by GPCR ligands. Novartis Found Symp. 2006, 276, 181–192, 233–237, 275–281. [Google Scholar]
  13. Sahay, A.; Kale, A.; Joshi, S. Role of neurotrophins in pregnancy and offspring brain development. Neuropeptides 2020, 83, 102075. [Google Scholar] [CrossRef]
  14. Galvez-Contreras, A.Y.; Campos-Ordonez, T.; Lopez-Virgen, V.; Gomez-Plascencia, J.; Ramos-Zuniga, R.; Gonzalez-Perez, O. Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders. Cytokine Growth Factor Rev. 2016, 32, 85–96. [Google Scholar] [CrossRef]
  15. Lamballe, F.; Klein, R.; Barbacid, M. The trk family of oncogenes and neurotrophin receptors. Princess Takamatsu Symp. 1991, 22, 153–170. [Google Scholar]
  16. French, S.J.; Humby, T.; Horner, C.H.; Sofroniew, M.V.; Rattray, M. Hippocampal neurotrophin and trk receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine. Mol. Brain Res. 1999, 67, 124–136. [Google Scholar] [CrossRef]
  17. Sinkevicius, K.W.; Kriegel, C.; Bellaria, K.J.; Lee, J.; Lau, A.N.; Leeman, K.T.; Zhou, P.; Beede, A.M.; Fillmore, C.M.; Caswell, D.; et al. Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis. Proc. Natl. Acad. Sci. USA 2014, 111, 10299–10304. [Google Scholar] [CrossRef]
  18. Aloe, L.; Rocco, M.L.; Balzamino, B.O.; Micera, A. Nerve growth factor: Role in growth, differentiation and controlling cancer cell development. J. Exp. Clin. Cancer Res. 2016, 35, 1–7. [Google Scholar] [CrossRef]
  19. Esteban-Villarrubia, J.; Soto-Castillo, J.J.; Pozas, J.; San Román-Gil, M.; Orejana-Martín, I.; Torres-Jiménez, J.; Carrato, A.; Alonso-Gordoa, T.; Molina-Cerrillo, J. Tyrosine kinase receptors in oncology. Int. J. Mol. Sci. 2020, 21, 1–48. [Google Scholar] [CrossRef]
  20. Zhang, Q.; Descamps, O.; Hart, M.J.; Poksay, K.S.; Spilman, P.; Kane, D.J.; Gorostiza, O.; John, V.; Bredesen, D.E. Paradoxical effect of TrkA inhibition in alzheimer’s disease models. J. Alzheimer’s Dis. 2014, 40, 605–617. [Google Scholar] [CrossRef]
  21. Ciafrè, S.; Ferraguti, G.; Tirassa, P.; Iannitelli, A.; Ralli, M.; Greco, A.; Chaldakov, G.N.; Rosso, P.; Fico, E.; Messina, M.P.; et al. Nerve growth factor in the psychiatric brain. Riv. Psichiatr. 2020, 55, 4–15. [Google Scholar] [CrossRef]
  22. Chaldakov, G.N. The metabotrophic NGF and BDNF: An emerging concept. Arch. Ital. Biol. 2011, 149, 257–263. [Google Scholar]
  23. Hirose, M.; Kuroda, Y.; Murata, E. NGF/TrkA Signaling as a Therapeutic Target for Pain. Pain Pract. 2016, 16, 175–182. [Google Scholar] [CrossRef]
  24. Ghenev, P.; Kitanova, M.; Popov, H.; Evtimov, N.; Stoev, S.; Tonchev, A.; Chaldakov, G. Neuroadipobiology of arrhythmogenic right ventricular dysplasia. An immunohistochemical study of neurotrophins. Adipobiology 2017, 8, 55. [Google Scholar] [CrossRef]
  25. Voronin, M.V.; Vakhitova, Y.V.; Seredenin, S.B. Chaperone Sigma1R and antidepressant effect. Int. J. Mol. Sci. 2020, 21, 1–33. [Google Scholar] [CrossRef]
  26. Alizadeh Pahlavani, H. Possible role of exercise therapy on depression: Effector neurotransmitters as key players. Behav. Brain Res. 2024, 459, 114791. [Google Scholar] [CrossRef]
  27. Hochstrasser, T.; Ehrlich, D.; Sperner-Unterweger, B.; Humpel, C. Antidepressants and anti-inflammatory drugs differentially reduce the release of NGF and BDNF from rat platelets. Pharmacopsychiatry 2013, 46, 29–34. [Google Scholar] [CrossRef]
  28. Angelucci, F.; Mathé, A.A.; Aloe, L. Neurotrophic factors and CNS disorders: Findings in rodent models of depression and schizophrenia. Prog. Brain Res. 2004, 146, 151–165. [Google Scholar] [CrossRef]
  29. Kozisek, M.E.; Middlemas, D.; Bylund, D.B. Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol. Ther. 2008, 117, 30–51. [Google Scholar] [CrossRef]
  30. Jiang, C.; Salton, S.R. The role of neurotrophins in major depressive disorder. Transl. Neurosci. 2013, 4, 46–58. [Google Scholar] [CrossRef]
  31. Raap, U.; Ständer, S.; Metz, M. Pathophysiology of itch and new treatments. Curr. Opin Allergy Clin. Immunol. 2011, 11, 420–427. [Google Scholar] [CrossRef]
  32. Raap, U.; Papakonstantinou, E.; Metz, M.; Lippert, U.; Schmelz, M. Update on the cutaneous neurobiology of pruritus. Hautarzt 2016, 67, 595–600. [Google Scholar] [CrossRef]
  33. Zisiadis, G.A.; Alevyzaki, A.; Nicola, E.; Rodrigues, C.F.D.; Blomgren, K.; Osman, A.M. Memantine increases the dendritic complexity of hippocampal young neurons in the juvenile brain after cranial irradiation. Front. Oncol. 2023, 13, 1202200. [Google Scholar] [CrossRef]
  34. Minoretti, P.; Santiago Sáez, A.S.; García Martín, Á.F.; Riera, M.; Gómez Serrano, M.; Lahmar, A.; Emanuele, E. Impact of Job Types on Plasma Neurotrophins Levels: A Preliminary Study in Airline Pilots, Construction Workers, and Fitness Instructors. Neuro Endocrinol. Lett. 2023, 44, 439–443. [Google Scholar]
  35. Khodabakhsh, P.; Asgari Taei, A.; Shafaroodi, H.; Pournajaf, S.; Dargahi, L. Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype. Stem Cell Rev. Rep. 2024, 20, 394–412. [Google Scholar] [CrossRef]
  36. Chen, W.; Ren, Q.; Zhou, J.; Liu, W. Mesenchymal Stem Cell-Induced Neuroprotection in Pediatric Neurological Diseases: Recent Update of Underlying Mechanisms and Clinical Utility. Appl. Biochem. Biotechnol. 2024. [Google Scholar] [CrossRef]
  37. Moghadasi, M.; Akbari, F.; Najafi, P. Interaction of aerobic exercise and crocin improves memory, learning and hypocampic tau and neurotrophins gene expression in rats treated with trimethytin as a model of Alzheimer’s disease. Mol. Biol. Rep. 2024, 51, 111. [Google Scholar] [CrossRef]
  38. Shafiee, A.; Rafiei, M.A.; Jafarabady, K.; Eskandari, A.; Abhari, F.S.; Sattari MAAmini, M.J.; Bakhtiyari, M. Effect of cannabis use on blood levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF): A systematic review and meta-analysis. Brain Behav. 2024, 14, e3340. [Google Scholar] [CrossRef]
  39. Tu, Y.; Han, D.; Liu, Y.; Hong, D.; Chen, R. Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF. Brain Behav. 2024, 14, e3356. [Google Scholar] [CrossRef]
  40. Liu, J.; Guan, J.; Xiong, J.; Wang, F. Effects of Transcranial Magnetic Stimulation Combined with Sertraline on Cognitive Level, Inflammatory Response and Neurological Function in Depressive Disorder Patients with Non-suicidal Self-injury Behavior. Actas Esp. Psiquiatr. 2024, 52, 28–36. [Google Scholar]
  41. Crews, F.T.; Macht, V.; Vetreno, R.P. Epigenetic regulation of microglia and neurons by proinflammatory signaling following adolescent intermittent ethanol (AIE) exposure and in human AUD. Adv. Drug Alcohol. Res. 2024, 4, 12094. [Google Scholar] [CrossRef]
  42. Sun, L.; Xiao, K.; Shen, X.-Y.; Wang, S. Impact of transcranial electrical stimulation on serum neurotrophic factors and language function in patients with speech disorders. World J. Clin. Cases 2024, 12, 1742–1749. [Google Scholar] [CrossRef]
  43. Yu, Z.; Joy, S.; Mi, T.; Yazdanpanah, G.; Burgess, K.; de Paiva, C.S. New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease. Front. Med. 2022, 9, 937142. [Google Scholar] [CrossRef]
  44. Ricci, A.; Salvucci, C.; Castelli, S.; Carraturo, A.; de Vitis, C.; D’Ascanio, M. Adenocarcinomas of the Lung and Neurotrophin System: A Review. Biomedicines 2022, 10, 2531. [Google Scholar] [CrossRef]
  45. Sullivan, I.; Kc, R.; Singh, G.; Das, V.; Ma, K.; Li, X.; Mwale, F.; Votta-Velis, G.; Bruce, B.; Natarajan Anbazhagan, A.; et al. Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization. Int. J. Mol. Sci. 2022, 23, 12076. [Google Scholar] [CrossRef]
  46. Qin, S.; Zhang, Z.; Zhao, Y.; Liu, J.; Qiu, J.; Gong, Y.; Fan, W.; Guo, Y.; Guo, Y.; Xu, Z.; et al. The impact of acupuncture on neuroplasticity after ischemic stroke: A literature review and perspectives. Front. Cell Neurosci. 2022, 16, 817732. [Google Scholar] [CrossRef]
  47. Arutjunyan, A.V.; Kerkeshko, G.O.; Milyutina, Y.P.; Shcherbitskaia, A.D.; Zalozniaia, I.V.; Mikhel, A.V.; Inozemtseva, D.B.; Vasilev, D.S.; Kovalenko, A.A.; Kogan, I.Y. Imbalance of Angiogenic and Growth Factors in Placenta in Maternal Hyperhomocysteinemia. Biochemistry 2023, 88, 262–279. [Google Scholar] [CrossRef]
  48. Lutfi Ismaeel, G.; Makki AlHassani, O.J.; Alazragi, R.S.; Hussein Ahmed, A.; Mohamed, A.H.; Yasir Jasim, N.; Hassan Shari, F.; Almashhadani, H.A. Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state-of-the-art. Biotechnol. Prog. 2023, 39, e3363. [Google Scholar] [CrossRef]
  49. Redigolo, L.; Sanfilippo, V.; La Mendola, D.; Forte, G.; Satriano, C. Bioinspired Nanoplatforms Based on Graphene Oxide and Neurotrophin-Mimicking Peptides. Membranes 2023, 13, 50489. [Google Scholar] [CrossRef]
  50. Jashire Nezhad, N.; Safari, A.; Namavar, M.R.; Nami, M.; Karimi-Haghighi, S.; Pandamooz, S.; Dianatpour, M.; Azarpira, N.; Khodabandeh, Z.; Zare, S.; et al. Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke. J. Stroke Cerebrovasc. Dis. 2023, 32, 107202. [Google Scholar] [CrossRef]
  51. Pahlavani, H.A. Exercise therapy to prevent and treat Alzheimer’s disease. Front. Aging Neurosci. 2023, 15, 1243869. [Google Scholar] [CrossRef]
  52. Wan, T.; Zhang, F.S.; Qin, M.Y.; Jiang, H.R.; Zhang, M.; Qu, Y.; Wang, Y.L.; Zhang, P.X. Growth factors: Bioactive macromolecular drugs for peripheral nerve injury treatment—Molecular mechanisms and delivery platforms. Biomed. Pharmacother. 2024, 170, 116024. [Google Scholar] [CrossRef] [PubMed]
  53. Giri, S.S.; Tripathi, A.S.; Erkekoğlu, P.; Zaki, M.E.A. Molecular pathway of pancreatic cancer-associated neuropathic pain. J. Biochem. Mol. Toxicol. 2024, 38, e23638. [Google Scholar] [CrossRef] [PubMed]
  54. Stabile, A.M.; Pistilli, A.; Moretti, E.; Bartolini, D.; Ruggirello, M.; Rende, M.; Castellini, C.; Mattioli, S.; Ponchia, R.; Tripodi, S.A.; et al. A Possible Role for Nerve Growth Factor and Its Receptors in Human Sperm Pathology. Biomedicines 2023, 11, 3345. [Google Scholar] [CrossRef]
  55. Rosso, P.; Fico, E.; Mesentier-Louro, L.A.; Triaca, V.; Lambiase, A.; Rama, P.; Tirassa, P. NGF eye administration recovers the trkb and glutamate/GABA marker deficit in the adult visual cortex following optic nerve crush. Int. J. Mol. Sci. 2021, 22, 10014. [Google Scholar] [CrossRef]
  56. D’Souza, S.; Vaidya, T.; Nair, A.P.; Shetty, R.; Kumar, N.R.; Bisht, A.; Panigrahi, T.; J, T.S.; Khamar, P.; Dickman, M.M.; et al. Altered Ocular Surface Health Status and Tear Film Immune Profile Due to Prolonged Daily Mask Wear in Health Care Workers. Biomedicines 2022, 10, 1160. [Google Scholar] [CrossRef]
  57. Shu, J.; He, X.; Li, H.; Liu, X.; Qiu, X.; Zhou, T.; Wang, P.; Huang, X. The beneficial effect of human amnion mesenchymal cells in inhibition of inflammation and induction of neuronal repair in EAE mice. J. Immunol. Res. 2018, 2018, 5083797. [Google Scholar] [CrossRef] [PubMed]
  58. Sun, S.; Diggins, N.H.; Gunderson, Z.J.; Fehrenbacher, J.C.; White, F.A.; Kacena, M.A. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone 2020, 131, 115109. [Google Scholar] [CrossRef]
  59. Valente, S.; Curti, N.; Giampieri, E.; Randi, V.; Donadei, C.; Buzzi, M.; Versura, P. Impact of blood source and component manufacturing on neurotrophin content and in vitro cell wound healing. Blood Transfus. 2022, 20, 213–222. [Google Scholar] [CrossRef]
  60. Sipione, R.; Liaudet, N.; Rousset, F.; Landis, B.N.; Hsieh, J.W.; Senn, P. Axonal Regrowth of Olfactory Sensory Neurons In Vitro. Int. J. Mol. Sci. 2023, 24, 12863. [Google Scholar] [CrossRef]
  61. Zhang, Y.; Zhao, X.; Ge, D.; Huang, Y.; Yao, Q. The impact and mechanism of nerve injury on bone metabolism. Biochem. Biophys. Res. Commun. 2024, 704, 149699. [Google Scholar] [CrossRef] [PubMed]
  62. Lambiase, A.; Rama, P.; Bonini, S.; Caprioglio, G.; Aloe, L. Topical Treatment with Nerve Growth Factor for Corneal Neurotrophic Ulcers. N. Engl. J. Med. 1998, 338, 1174–1180. [Google Scholar] [CrossRef] [PubMed]
  63. Aloe, L. Nerve growth factor, human skin ulcers and vascularization. Our experience. Prog. Brain Res. 2004, 146, 515–522. [Google Scholar] [CrossRef]
  64. Raap, U.; Kapp, A. Neurotrophins in healthy and diseased skin. G. Ital. Dermatol. Venereol. Organo Uff. Soc. Ital. Dermatol. Sifilogr. 2010, 145, 205–211. [Google Scholar]
  65. Scuri, M.; Samsell, L.; Piedimonte, G. The role of neurotrophins in inflammation and allergy. Inflamm. Allergy Drug Targets 2010, 9, 173–180. [Google Scholar] [CrossRef]
  66. D’Amico, F.; Lugarà, C.; Luppino, G.; Giuffrida, C.; Giorgianni, Y.; Patanè, E.M.; Manti, S.; Gambadauro, A.; La Rocca, M.; Abbate, T. The Influence of Neurotrophins on the Brain-Lung Axis: Conception, Pregnancy, and Neonatal Period. Curr. Issues Mol. Biol. 2024, 46, 2528–2543. [Google Scholar] [CrossRef]
  67. Pham, T.L.; He, J.; Kakazu, A.H.; Jun, B.; Bazan, N.G.; Bazan, H.E.P. Defining a mechanistic link between pigment epithelium–derived factor, docosahexaenoic acid, and corneal nerve regeneration. J. Biol. Chem. 2017, 292, 18486–18499. [Google Scholar] [CrossRef] [PubMed]
  68. Ghosh, T.; Maity, N.; Sur, V.P.; Konar, A.; Hazra, S. Mitigating fibrosis-An impediment to corneal re-innervation following lamellar flap surgery. Exp. Eye Res. 2020, 194, 108009. [Google Scholar] [CrossRef]
  69. Micera, A.; Jirsova, K.; Esposito, G.; Balzamino, B.O.; Zazzo ADi Bonini, S. Mast cells populate the corneoscleral limbus: New insights for our understanding of limbal microenvironment. Investig. Ophthalmol. Vis. Sci. 2020, 61, 43. [Google Scholar] [CrossRef]
  70. Moramarco, A.; Sacchetti, M.; Franzone, F.; Segatto, M.; Cecchetti, D.; Miraglia, E.; Roberti, V.; Iacovino, C.; Giustini, S. Ocular surface involvement in patients with neurofibromatosis type 1 syndrome. Graefe’s Arch. Clin. Exp. Ophthalmol. 2020, 258, 1757–1762. [Google Scholar] [CrossRef]
  71. Owens, J. Determining druggability. Nat. Rev. Drug Discov. 2007, 6, 187. [Google Scholar] [CrossRef]
  72. Dixon, S.J.; Stockwell, B.R. Identifying druggable disease-modifying gene products. Curr. Opin. Chem. Biol. 2009, 13, 549–555. [Google Scholar] [CrossRef]
  73. Carito, V.; Ceccanti, M.; Cestari, V.; Natella, F.; Bello, C.; Coccurello, R.; Mancinelli, R.; Fiore, M. Olive polyphenol effects in a mouse model of chronic ethanol addiction. Nutrition 2017, 33, 65–69. [Google Scholar] [CrossRef] [PubMed]
  74. Fiore, M.; Messina, M.P.; Petrella, C.; D’Angelo, A.; Greco, A.; Ralli, M.; Ferraguti, G.; Tarani, L.; Vitali, M.; Ceccanti, M. Antioxidant properties of plant polyphenols in the counteraction of alcohol-abuse induced damage: Impact on the Mediterranean diet. J. Funct. Foods 2020, 71, 104012. [Google Scholar] [CrossRef]
  75. Abe, T.; Morgan, D.A.; Gutterman, D.D. Protective role of nerve growth factor against postischemic dysfunction of sympathetic coronary innervation. Circulation 1997, 95, 213–220. [Google Scholar] [CrossRef] [PubMed]
  76. Aloe, L.; Rocco, M.L.; Bianchi, P.; Manni, L. Nerve growth factor: From the early discoveries to the potential clinical use. J. Transl. Med. 2012, 10, 239. [Google Scholar] [CrossRef] [PubMed]
  77. Chiaretti, A.; Piastra, M.; Caresta, E.; Nanni, L.; Aloe, L. Improving ischaemic skin revascularisation by nerve growth factor in a child with crush syndrome. Arch. Dis. Child 2002, 87, 446–448. [Google Scholar] [CrossRef] [PubMed]
  78. Watanabe, T.; Inoue, M.; Sasaki, K.; Araki, M.; Uehara, S.; Monden, K.; Saika, T.; Nasu, Y.; Kumon, H.; Chancellor, M.B. Nerve growth factor level in the prostatic fluid of patients with chronic prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment. BJU Int. 2011, 108, 248–251. [Google Scholar] [CrossRef]
  79. Warrington, R.J.; Lewis, K.E. Natural antibodies against nerve growth factor inhibit in vitro prostate cancer cell metastasis. Cancer Immunol. Immunother. 2011, 60, 187–195. [Google Scholar] [CrossRef]
  80. Festuccia, C.; Muzi, P.; Gravina, G.L.; Millimaggi, D.; Speca, S.; Dolo, V.; Ricevuto, E.; Vicentini, C.; Bologna, M. Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro. Int. J. Oncol. 2007, 30, 193–200. [Google Scholar] [CrossRef]
  81. Thiele, C.J.; Li, Z.; McKee, A.E. On Trk—The TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin. Cancer Res. 2009, 15, 5962–5967. [Google Scholar] [CrossRef]
  82. Chiarenza, A.; Lazarovici, P.; Lempereur, L.; Cantarella, G.; Bianchi, A.; Bernardini, R. Tamoxifen inhibits nerve growth factor-induced proliferation of the human breast cancerous cell line MCF-7. Cancer Res. 2001, 61, 3002–3008. [Google Scholar]
  83. Chen, P.S.; Chen, L.S.; Cao, J.M.; Sharifi, B.; Karagueuzian, H.S.; Fishbein, M.C. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc. Res. 2001, 50, 409–416. [Google Scholar] [CrossRef] [PubMed]
  84. Salvinelli, F.; Frari, V.; Rocco, M.L.; Rosso, P.; Aloe, L. Enhanced presence of NGF and mast cells number in nasal cavity after autologous stimulation: Relation with sensorineural hearing deficit. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 381–391. [Google Scholar]
  85. Povarnina, P.Y.; Vorontsova, O.N.; Gudasheva, T.A.; Ostrovskaya, R.U.; Seredenin, S.B. Original nerve growth factor mimetic dipeptide GK-2 restores impaired cognitive functions in rat models of Alzheimer’s disease. Acta Naturae 2013, 5, 84–91. [Google Scholar] [CrossRef]
  86. Head, B.P.; Patel, H.H.; Insel, P.A. Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function: Membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim. Biophys. Acta Biomembr. 2014, 1838, 532–545. [Google Scholar] [CrossRef] [PubMed]
  87. Pryor, S.; McCaffrey, G.; Young, L.R.; Grimes, M.L. NGF causes TrKA to specifically attract microtubules to lipid rafts. PLoS ONE 2012, 7, e35163. [Google Scholar] [CrossRef]
  88. Kropf, E.; Fahnestock, M. Effects of reactive oxygen and nitrogen species on trka expression and signalling: Implications for prongf in aging and alzheimer’s disease. Cells 2021, 10, 1983. [Google Scholar] [CrossRef]
  89. Manoj, K.M. Murburn concept: Murzyme roles of redox proteins in xenobiotic metabolism and ATP-synthesis. Biomed. Rev. 2023, 34, 27. [Google Scholar] [CrossRef]
  90. Manoj, K.M.; Jaeken, L. Synthesis of theories on cellular powering, coherence, homeostasis and electro-mechanics: Murburn concept and evolutionary perspectives. J. Cell Physiol. 2023, 238, 931–953. [Google Scholar] [CrossRef]
  91. Francati, S.; Fiore, M.; Ferraguti, G. The janus face of oxidative stress in health and disease: The cause or the cure? Biomed. Rev. 2023, 34, 13. [Google Scholar] [CrossRef]
  92. Lurz, J.; Ladwig, K.H. Mind and body interventions in cardiology: The importance of the brain–heart connection. Herz 2022, 47, 103–109. [Google Scholar] [CrossRef] [PubMed]
Pharmaceuticals 17 00961 g001
Figure 1. Neurotrophins and their Trk receptors. Redrawn from [11].
Figure 1. Neurotrophins and their Trk receptors. Redrawn from [11].
Pharmaceuticals 17 00961 g001
Pharmaceuticals 17 00961 g002
Figure 2. Metabotrophic factors (MTF) and their Trk receptors on the crossroads of the pathogenesis of and therapy for cardiometabolic diseases (CMD) and neurometabolic diseases (NMD), particularly Alzheimer’s disease (AD). Credit Nikifor N. Chaldakov.
Figure 2. Metabotrophic factors (MTF) and their Trk receptors on the crossroads of the pathogenesis of and therapy for cardiometabolic diseases (CMD) and neurometabolic diseases (NMD), particularly Alzheimer’s disease (AD). Credit Nikifor N. Chaldakov.
Pharmaceuticals 17 00961 g002
Pharmaceuticals 17 00961 g003
Figure 3. Structure of the soul of plants, animals, and humans. In this vision, humans are unique in having all three types of souls symbiotically. Here, it is reasonable to quote Socrates—“Man is a soul that serves his body”—as a first conceptual step to envisage the soul-and-body interaction [92].
Figure 3. Structure of the soul of plants, animals, and humans. In this vision, humans are unique in having all three types of souls symbiotically. Here, it is reasonable to quote Socrates—“Man is a soul that serves his body”—as a first conceptual step to envisage the soul-and-body interaction [92].
Pharmaceuticals 17 00961 g003
Table 1. Neurotrophin receptors and ligands. * Notably, the Trk receptor’s transactivation through the G protein-coupled receptor has lately arisen as an original perspective on neurotrophin functions [12].
Table 1. Neurotrophin receptors and ligands. * Notably, the Trk receptor’s transactivation through the G protein-coupled receptor has lately arisen as an original perspective on neurotrophin functions [12].
Receptors * Neurotrophins
p75NTR NGF, BDNF, NT-3. NT-4/5
TrkA NGF, pro-NGF
TrkB BDNF, pro-BDNF, NT-4/5
TrkC NT-3
Table 2. Multiple effects of NGF and BDNF. * Arrhythmogenic right-ventricular dysplasia (ARVD) is characterized by the accumulation and dysfunction of adipose tissue in the right ventricle of the heart, leading to ventricular arrhythmias and progressive right-ventricular failure, and often sudden cardiac death.
Table 2. Multiple effects of NGF and BDNF. * Arrhythmogenic right-ventricular dysplasia (ARVD) is characterized by the accumulation and dysfunction of adipose tissue in the right ventricle of the heart, leading to ventricular arrhythmias and progressive right-ventricular failure, and often sudden cardiac death.
PhysiotherapeuticPathogenic
Neurotrophic [13,14,15,16]Oncotrophic (cancerogenic) [17,18,19,20]
Immunotrophic [21,22]Nociceptogenic [23]
Меtabotrophic [5,6,22]Arrhythmogenic [24] *
Psychotrophic [20,25,26,27,28,29,30]Pruritus [31,32]
Cognitogenic [33,34,35,36,37,38,39,40,41,42]Dry-eye disease [43]
Angiogenic [44,45,46,47,48,49,50,51,52,53]
Sperm vitality, mobility, fertility [54]
Skin, cornea, axon and bone wound/fracture healing [31,32,43,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]
Table 3. Metabotrophic effects of NGF and BDNF [5,6,22,54].
Table 3. Metabotrophic effects of NGF and BDNF [5,6,22,54].
NGF and BDNF are released by pancreatic beta cells and have an insulinotropic effect
NGF has homology with proinsulin
BDNF-deficient mice may develop metabolic syndrome-like abnormalities
NGF up-regulates the expression of PPAR-gamma
NGF and BDNF are trophic factors for pancreatic beta cells
BDNF improves cognition
NGF up-regulates the expression of LDL receptor-related proteins
NGF increases skin and corneal wound healing
NGF inhibits glucose-induced down-regulation of caveolin-1
NGF increases diabetic erectile dysfunction
NGF may rescue silent myocardial ischemia in diabetes mellitus
A healthy lifestyle potentiates brain and/or circulating BDNF and NGF
An atherogenic diet reduces brain BDNF
BDNF potentiates cognitive processes
BDNF-deficient mice may develop abnormalities similar to the metabolic syndrome
Table 4. Trackins and therapy for different diseases; see [3,4,6,23,27,28,29,30,31,32,57,58,59,62,63,64,78,79,85]. * T2/3DM, type 2/3 diabetes mellitus.
Table 4. Trackins and therapy for different diseases; see [3,4,6,23,27,28,29,30,31,32,57,58,59,62,63,64,78,79,85]. * T2/3DM, type 2/3 diabetes mellitus.
Agonists Antagonists
TrkANGF, TrkApro-NGF, TrkBBDNF, TrkCNT−3TrkANGF
Cardiometabolic diseasesCancers
Atherosclerosis, hypertension Prostate, Breast
Obesity, T2DM *, metabolic syndrome Brain, Pancreas, Lung
Atrial fibrillation
Diabetic erectile dysfunction
Cardiovascular diseases
Arrhythmogenic right ventricular dysplasia
Sudden cardiac death
Neurometabolic diseases
Alzheimer’s disease (T3DM) * Pain
Parkinson’s diseasePruritus
Multiple sclerosis
Wounds
Skin, cornea, bone, axon
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chaldakov, G.N.; Aloe, L.; Yanev, S.G.; Fiore, M.; Tonchev, A.B.; Vinciguerra, M.; Evtimov, N.T.; Ghenev, P.; Dikranian, K. Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases. Pharmaceuticals 2024, 17, 961. https://doi.org/10.3390/ph17070961

AMA Style

Chaldakov GN, Aloe L, Yanev SG, Fiore M, Tonchev AB, Vinciguerra M, Evtimov NT, Ghenev P, Dikranian K. Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases. Pharmaceuticals. 2024; 17(7):961. https://doi.org/10.3390/ph17070961

Chicago/Turabian Style

Chaldakov, George N., Luigi Aloe, Stanislav G. Yanev, Marco Fiore, Anton B. Tonchev, Manlio Vinciguerra, Nikolai T. Evtimov, Peter Ghenev, and Krikor Dikranian. 2024. "Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases" Pharmaceuticals 17, no. 7: 961. https://doi.org/10.3390/ph17070961

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop