Acta Scientific Ophthalmology (ISSN: 2582-3191)

Research Article Volume 5 Issue 5

Targeting of Signal Transduction Pathway Components to Mitigate Selected Ocular Disorders

Najam A Sharif1-7*

1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
2Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA
3Department of Pharmacy Sciences, Creighton University, Omaha, Nebraska, USA
4Singapore Eye Research Institute (SERI), Singapore
5Department of Surgery and Cancer, Imperial College of Science and Technology, St. Mary’s Campus, London, UK
6Duke-NUS Medical School, Singapore
7Global Alliances and External Research, Ophthalmology Innovation Center, Santen Inc., Emeryville, CA, USA

*Corresponding Author: Najam Sharif, Vice President and Head, Global Alliances and External Research, Ophthalmology Innovation Center, Santen Incorporated, Emeryville, CA, USA.

Received: September 06, 2021; Published: April 04, 2022

Abstract

Coordinated communication between and within cells forms the basis for life in health and disease of all tissues and organs. Such relaying of information is mediated by neurotransmitters, hormones, bacteria, viruses, steroids and a host of cyto- and chemokines via specific receptors, ion-channels, and transporters located in cellular membranes and on intracellular organelles including the nuclear membrane and within the nucleus itself. Activation of such transmembrane components generates intracellular second messengers such as cAMP, cGMP, inositol phosphates, diacyl glycerol, Ca2+, and gaseous transmitters such as nitric oxide, carbon monoxide and hydrogen sulfide that modulate activity of cytoplasmic proteins, lipids and other substances via phosphorylation, dephosphorylation, glycation, and acetylation. Additional communication is achieved by modulation of genetic machinery, via transcription factors, various chaperones, and through secretome/exosome-mediated release of growth factors, microRNAs, and via direct transfer of many of the afore-mentioned chemicals between neighboring cells down nanotunnels. Dysfunctions within any component of this signal transduction machinery, whether in excess or deficiency or by mutation, results in some form of disease and thus represent targets for intervention by small molecule drugs, peptides, antibodies, genetic manipulation and/or via cell-replacement therapeutics. A brief outline of some of these elements will be discussed.

Keywords: Receptors; Signal Transduction; Ion-channels; GPCRs; Enzyme; Agonist; Antagonist; Inhibitor

References

  1. Overington JP., et al. “How many drug targets are there?”. Nature Reviews Drug Discovery12 (2006): 993-996.
  2. Brunton L., et al. “Goodman and Gilman's”. The Pharmacological Basis of Therapeutics (12th). New York: McGraw-Hill Professional (2010).
  3. Alexander SPH., et al. “The concise guide to pharmacology 2019/20: G protein-coupled receptors”. British Journal of Pharmacology1 (2019): S21-S141.
  4. Alexander SPH., et al. “The concise guide to pharmacology 2019/20: Nuclear hormone receptors”. British Journal of Pharmacology 1 (2019): S229-S246.
  5. Alexander SPH., et al. “The concise guide to pharmacology 2019/20: Enzymes”. British Journal of Pharmacology1 (2019): S297-S396.
  6. Alexander SPH., et al. “The concise guide to pharmacology 2019/20: Transporters”. British Journal of Pharmacology1 (2019): S397-S493.
  7. Alexander SPH., et al. “The concise guide to pharmacology 2019/20: Ion channels”. British Journal of Pharmacology1 (2019): S142-S228.
  8. Cavet ME., et al. “Nitric oxide (NO): an emerging target for the treatment of glaucoma”. Investigative Ophthalmology and Visual Science 55 (2014): 5005-5015.
  9. Ohia SE., et al. “Regulation of aqueous humor dynamics by hydrogen sulfide: potential role in glaucoma pharmacotherapy”. Journal of Ocular Pharmacology and Therapeutics 1-2 (2014): 61-69.
  10. Sharif NA., et al. “Pharmacological analysis of mast cell mediator and neurotransmitter receptors coupled to adenylate cyclase and phospholipase C on immunocytochemically-defined human conjunctival epithelial cells”. Journal of Ocular Pharmacology and Therapeutics 13 (1997): 321-336.
  11. Sharif NA. “Glaucomatous optic neuropathy treatment options: the promise of novel therapeutics, techniques and tools to help preserve vision”. Neural Regeneration Research 13 (2018): 1145-1150.
  12. Sharif NA. “iDrugs and iDevices discovery and development - preclinical assays, techniques and animal model studies for ocular hypotensives and neuroprotectants”. Journal of Ocular Pharmacology and Therapeutics 34 (2018): 7-39.
  13. Sharif NA. “Discovery to launch of anti-allergy (Emadine; Patanol/Pataday/Pazeo) and anti-glaucoma (Travatan; Simbrinza) ocular drugs, and generation of novel pharmacological tools such as AL-8810”. ACS Pharmacology and Translational Science 3 (2020): 1391-1421.
  14. Sharif NA. “Therapeutic drugs and devices for tackling ocular hypertension and glaucoma, and need for neuroprotection and cytoprotective therapies”. Frontiers in Pharmacology 12 (2021):
  15. Sharif NA., et al. “Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation”. Journal of Ocular Pharmacology and Therapeutics 19 (2003): 437-455.
  16. Husain S., et al. “Acute effects of PGF on MMP-2 secretion from human ciliary muscle cells: a PKC- and ERK-dependent process”. Investigative Ophthalmology and Visual Science 46 (2005): 1706-1713.
  17. Sharif NA., et al. “Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues”. Investigative Ophthalmology and Visual Science 44 (2003): 715-721.
  18. Sharif NA., et al. “Characterization of the ocular anti allergic and anti-histaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases”. Journal of Pharmacology and Experimental Therapeutics 278 (1996): 1251-1260.
  19. Katoli P., et al. “NPR-B natriuretic peptide receptors in human corneal epithelium: mRNA, immunohistochemical, protein and biochemical pharmacology studies”. Molecular Vision 16 (2010): 1241-1252.
  20. Claesson-Welsh L. “VEGF receptor signal transduction - A brief update”. Vascular Pharmacology 86 (2016): 14-17.
  21. Stevens M and Oltean S. “Modulation of receptor tyrosine kinase activity through alternative splicing of ligands and receptors in the VEGF-A/VEGFR axis”. Cells 8 (4): 288.
  22. Schwappach B. “An overview of trafficking and assembly of neurotransmitter receptors and ion channels (Review)”. Molecular Membrane Biology 4 (2008): 270-278.
  23. Sharif NA., et al. “Pharmacological characterization of NMDA‑receptor‑channel in rodent and dog brain and rat spinal cord using [3H]MK‑801 binding”. Neurochemistry Research 16 (1991): 563‑569.
  24. Brown DA. “Regulation of neural ion channels by muscarinic receptors”. Neuropharmacology 136 (2018): 383-400.
  25. Albalawi F., et al. “The P2X7 Receptor primes IL-1β and the NLRP3 inflammasome in astrocytes exposed to mechanical strain”. Frontiers in Cell Neuroscience 11 (2017): 227.
  26. Liu K., et al. “The association between nuclear receptors and ocular diseases”. Oncotargete16 (2017): 27603-27615.
  27. Roskoski R Jr. “Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update”. Pharmacology Research 152 (2020): 104609.
  28. Rassi DM., et al. “Review: microRNAs in ocular surface and dry eye diseases”. Ocular Surface 4 (2017): 660-669.
  29. Yamashita T., et al. “Possibility of exosome-based therapeutics and challenges in production of exosomes eligible for therapeutic application”. Biological and Pharmaceutical Bulletin 6 (2018): 835-842.
  30. Chinnery HR and Keller KE. “Tunneling nanotubes and the eye: intercellular communication and implications for ocular health and disease”. BioMed Research International 2020 (2020): 7246785.
  31. Abelson MB., et al. “Advances in pharmacotherapy for allergic conjunctivitis”. Expert Opinion on Pharmacotherapy 16 (2015): 1219-1231.
  32. Wiernas TK., et al. “Effects of bradykinin on signal transduction, cell proliferation, and cytokine, prostaglandin E2 and collagenase-1 release from human corneal epithelial cells”. British Journal of Pharmacology 123 (1998): 1127-1137.
  33. Yanni JM., et al. “A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs”. Acta Ophthalmologica Scandinavica 77 (1999): 33-37.
  34. Platanitis E., et al. “Regulatory networks involving STATs, IRFs, and NFκB in inflammation”. Frontiers in Immunology 9 (2018): 2542.
  35. Nguyen QD., et al. “Intravitreal sirolimus for the treatment of noninfectious uveitis: evolution through preclinical and clinical studies”. 125.12 (2018): 1984-1993.
  36. Blindness and vision impairment- https://www.who.int › News › Fact sheets. WHO Priority eye diseases (2019).
  37. Acott TS., et al. “Normal and glaucomatous outflow regulation”. Progress in Retinal and Eye Research 11 (2020): 100897.
  38. Burgoyne CF., et al. “The optic nerve head as a biomechanical structure; a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage”. Progress in Retinal and Eye Research 24 (2005): 39-73.
  39. Lee EJ., et al. “Reversal of lamina cribrosa displacement after intraocular pressure reduction in open-angle glaucoma”. Ophthalmology 120 (2013): 553-559.
  40. Xu G., et al. “Optic nerve head deformation in glaucoma: the temporal relationship between optic nerve head surface depression and retinal nerve fiber layer thinning”. Ophthalmology 121 (2014): 2362-2370.
  41. Wilson GN., et al. “Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma”. Journal of Neuroinflammation 12 (2015): 176.
  42. Wei X., et al. “Neuroinflammation and microglia in glaucoma: time for a paradigm shift”. Journal of Neuroscience Research1 (2019): 70-76.
  43. Tribble JR., et al. “Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice”. Molecular Brain1 (2020): 8.
  44. Flammer J., et al. “The impact of ocular blood flow in glaucoma”. Progress in Retinal and Eye Research4 (2002): 359-393.
  45. Yao A., et al. “Metabolic pathways in context: mTOR signaling in the retina and optic nerve - A review”. Clinical and Experimental Ophthalmology 8 (2020): 1072-1084.
  46. Guo L., et al. “Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix”. Investigative Ophthalmology and Visual Science 1 (2005): 175-182.
  47. Calkins DJ and Horner PJ. “The cell and molecular biology of glaucoma: axonopathy and the brain”. Investigative Ophthalmology and Visual Science 53 (2012): 2482-2484.
  48. Neufeld AH., et al. “Nitric oxide synthase in the human glaucomatous optic nerve head”. Archives of Ophthalmology 115 (1997): 497–503.
  49. He S., et al. “Targets of neuroprotection in glaucoma”. Journal of Ocular Pharmacology and Therapeutics 1-2 (2018): 85-106.
  50. Hollander H., et al. “Evidence of constriction of optic axons at the lamina cribrosa in the normotensive eye in humans and other mammals”. Ophthalmic Research 127 (1995): 296-309.
  51. Ha Y., et al. “Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma”. Cell Death Disease 10 (2015): e1900.
  52. Geyer O and Levo Y. “Glaucoma is an autoimmune disease”. Autoimmune Review6 (2020): 102535.
  53. Sehi M., et al. “Reversal of retinal ganglion cell dysfunction after surgical reduction of intraocular pressure”. Ophthalmology 117 (2010): 2329-2336.
  54. Sharif NA., et al. “Levobetaxolol (Betaxon®) and other β–adrenergic antagonists: preclinical pharmacology, IOP-lowering activity and sites of action in human eyes”. Journal of Ocular Pharmacology and Therapeutics 17 (2001): 305-317.
  55. Hellberg MR., et al. “Identification and characterization of the ocular hypotensive efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist, and AL-6598, a DP prostaglandin receptor agonist”. Survey of Ophthalmology 47 (2002): S13-S33.
  56. Klimko P and Sharif NA. “Discovery, characterization and clinical utility of prostaglandin agonists for treatment of glaucoma”. British Journal of Pharmacology 176 (2019): 1051-1058.
  57. Kirihara T., et al. “Pharmacologic characterization of omidenepag isopropyl, a novel selective EP2 receptor agonist, as an ocular hypotensive agent”. Investigative Ophthalmology and Visual Science 59 (2018): 145–153.
  58. Aihara M., et al. “Omidenepag isopropyl versus latanoprost in primary open-angle glaucoma and ocular hypertension: the phase 3 AYAME study”. American Journal of Pharmacology 220 (2020): 53-63.
  59. Sato K., et al. “The sustained release of tafluprost with a drug delivery system prevents the axonal injury-induced loss of retinal ganglion cells in rats”. Current Eye Research 9 (2020): 1114-1123.
  60. Nagano N., et al. “Development of a novel intraocular-pressure-lowering therapy targeting ATX”. Biological and Pharmaceutical Bulletin 11 (2019): 1926-1935.
  61. Al-Zamil WM and Yassin SA. “Recent developments in age-related macular degeneration: a review”. Clinical Interventions in Aging 12 (2017): 1313-1330.
  62. Li L., et al. “Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD”. Journal of Cellular Physiology 2 (2020): 1259-1273.

Citation

Citation: Najam A Sharif. “Targeting of Signal Transduction Pathway Components to Mitigate Selected Ocular Disorders".Acta Scientific Ophthalmology 5.5 (2022): 03-17.

Copyright

Copyright: © 2022 Najam A Sharif. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.




Metrics

Acceptance rate35%
Acceptance to publication20-30 days
ISI- IF1.042
JCR- IF0.24

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