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Sharif NA, Kulkarni-Chitnis M, Okolie A, Njie-Mbye YF, Ohia SE. Kinin B1- and B2-Receptor Subtypes Contract Isolated Bovine Ciliary Muscle: Their Role in Ocular Lens Function and Intraocular Pressure Reduction. Pharmaceuticals (Basel) 2024; 17:1501. [PMID: 39598412 PMCID: PMC11597478 DOI: 10.3390/ph17111501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Bradykinin is an endogenously produced nonapeptide with many physiological and pathological functions that are mediated by two pharmacologically defined receptor subtypes, B1- and B2-receptors. Current studies sought to characterize the functional bradykinin (BK) receptors present in freshly isolated bovine ciliary muscle (BCM) using an organ-bath tissue contraction system. Methods: Cumulative longitudinal isometric tension responses of BCM strips (4-5 mm) were recorded before and after the addition of test compounds to BCM strips hooked up to an isometric strain gauge transducer system. Results: BK and its analogs (7-11 concentrations) contracted BCM in a biphasic concentration-dependent manner. The first high affinity/potency phase accounted for 40-60% of the maximal contraction by each of BK (potency, EC50 = 0.9 ± 0.3 nM), Lys-BK (EC50 = 0.7 ± 0.1 nM), Met-Lys-BK (EC50 = 1 ± 0.1 nM), Hyp3-BK (EC50 = 1 ± 0.2 nM), RMP-7 (EC50 = 3.5 ± 0.5 nM), and Des-Arg9-BK (EC50 = 10 ± 0.4nM) (mean ± SEM, n = 3-8). The second lower activity phase of contraction potency values for these peptides ranged between 100 nM and 3 µM. In the presence of a selective B1-receptor antagonist (R715; 0.1-10 µM), the concentration-response curves to Des-Arg9-BK (B1-receptor agonist) were still observed, indicating activation of B2-receptors by this kinin. Likewise, when B2-receptors were completely blocked by using a B2-selective antagonist (WIN-64338; 1-10 µM), BK still induced BCM contraction, now by stimulating B1-receptors. Conclusions: This agonist/antagonist profile of BCM receptors indicated the presence of both B1- and B2-receptor subtypes, both being responsible for contracting this smooth muscle. The BCM kinin receptors may be involved in changing the shape of the ocular lens to influence accommodation, and since the ciliary muscle is attached to the trabecular meshwork through which aqueous humor drains, endogenously released kinins may regulate intraocular pressure.
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Affiliation(s)
- Najam A. Sharif
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA (Y.F.N.-M.); (S.E.O.)
- Singapore Eye Research Institute (SERI), Singapore 169856, Singapore
- Institute of Ophthalmology, University College London (UCL), London WC1E6BT, UK
- Department of Ophthalmology, Imperial College of Science and Technology, St. Mary’s Campus, London SW72AZ, UK
- Department of Pharmacy Sciences, Creighton University, Omaha, NE 68178, USA
- Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, TX 76107, USA
- Department of Ophthalmology, Eye-ACP Duke-National University of Singapore Medical School, Singapore 169857, Singapore
| | - Madura Kulkarni-Chitnis
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA (Y.F.N.-M.); (S.E.O.)
| | - Anthonia Okolie
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA (Y.F.N.-M.); (S.E.O.)
| | - Ya Fatou Njie-Mbye
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA (Y.F.N.-M.); (S.E.O.)
| | - Sunny E. Ohia
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA (Y.F.N.-M.); (S.E.O.)
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Wisniewski P, Gangnus T, Burckhardt BB. Recent advances in the discovery and development of drugs targeting the kallikrein-kinin system. J Transl Med 2024; 22:388. [PMID: 38671481 PMCID: PMC11046790 DOI: 10.1186/s12967-024-05216-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The kallikrein-kinin system is a key regulatory cascade involved in blood pressure maintenance, hemostasis, inflammation and renal function. Currently, approved drugs remain limited to the rare disease hereditary angioedema. However, growing interest in this system is indicated by an increasing number of promising drug candidates for further indications. METHODS To provide an overview of current drug development, a two-stage literature search was conducted between March and December 2023 to identify drug candidates with targets in the kallikrein-kinin system. First, drug candidates were identified using PubMed and Clinicaltrials.gov. Second, the latest publications/results for these compounds were searched in PubMed, Clinicaltrials.gov and Google Scholar. The findings were categorized by target, stage of development, and intended indication. RESULTS The search identified 68 drugs, of which 10 are approved, 25 are in clinical development, and 33 in preclinical development. The three most studied indications included diabetic retinopathy, thromboprophylaxis and hereditary angioedema. The latter is still an indication for most of the drug candidates close to regulatory approval (3 out of 4). For the emerging indications, promising new drug candidates in clinical development are ixodes ricinus-contact phase inhibitor for thromboprophylaxis and RZ402 and THR-149 for the treatment of diabetic macular edema (all phase 2). CONCLUSION The therapeutic impact of targeting the kallikrein-kinin system is no longer limited to the treatment of hereditary angioedema. Ongoing research on other diseases demonstrates the potential of therapeutic interventions targeting the kallikrein-kinin system and will provide further treatment options for patients in the future.
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Affiliation(s)
- Petra Wisniewski
- Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Münster, Germany
| | - Tanja Gangnus
- Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Münster, Germany
| | - Bjoern B Burckhardt
- Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Münster, Germany.
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Sharif NA. Human experience and efficacy of omidenepag isopropyl (Eybelis®; Omlonti®): Discovery to approval of the novel non-prostaglandin EP2-receptor-selective agonist ocular hypotensive drug. Curr Opin Pharmacol 2024; 74:102426. [PMID: 38168596 DOI: 10.1016/j.coph.2023.102426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
More than 75 million people worldwide suffer from ocular hypertension (OHT)-associated retinal and optic nerve degenerative diseases that cause visual impairment and can lead to blindness. In an effort to find novel pharmaceutical therapeutics to combat OHT with reduced side-effect potential, several emerging drug candidates have advanced to human proof-of-concept in recent years. One such compound is a nonprostaglandin (non-PG) EP2-receptor-selective agonist (omidenepag isopropyl ester). Omidenepag (OMD; free acid form) is a novel non-PG that selectively binds to and activates the human EP2-prostglandin receptor (EP2R) with a high affinity (Ki = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC50 = 3.9-8.3 nM). OMD significantly downregulated COL12A1 and COL13A1 mRNAs in human trabecular meshwork (TM) cells, a tissue involved in the pathogenesis of OHT. Omidenepag isopropyl (OMDI) potently and efficaciously lowered intraocular pressure (IOP) in ocular normotensive rabbits, dogs, and monkeys, and also in ocular hypertension (OHT) Cynomolgus monkeys, after a single topical ocular (t.o.) instillation at doses of 0.0001-0.01%. No reduction in IOP-lowering response to OMDI was observed after repeated t.o. dosing with OMDI in dogs and monkeys. Additive IOP reduction to OMDI was noted with brinzolamide, timolol, and brimonidine in rabbits and monkeys. OMDI 0.002% t.o. decreased IOP by stimulating the conventional (TM) and uveoscleral (UVSC) outflow of aqueous humor (AQH) in OHT monkeys. In a Phase-III clinical investigation, 0.002% OMDI (once daily t.o.) reduced IOP by 5-6 mmHg in OHT/primary open-angle glaucoma (POAG) patients (22-34 mmHg baseline IOPs) that was maintained over 12-months. In an additional month-long clinical study, 0.002% OMDI induced IOP-lowering equivalent to that of latanoprost (0.005%), a prostanoid FP-receptor agonist, thus OMDI was noninferior to latanoprost. Additive IOPreduction was also noted in OHT/OAG patients when OMDI (0.002%, once daily t.o.) and timolol (0.05%, twice daily t.o.) were administered. Patients with OHT/POAG who were low responders or nonresponders to latanoprost (0.005%, q.d.; t.o.) experienced significant IOP-lowering (additional approximately 3 mmHg) when they were switched over to OMDI 0.002% (q.d.; t.o.). No systemic or ocular adverse reactions (e.g. iris color changes/deepening of the upper eyelid sulcus/abnormal eyelash growth) were noted after a year-long, once-daily t.o. dosing with 0.002 % OMDI in OHT/POAG patients. However, OMDI caused transient conjunctival hyperemia. These characteristics of OMDI render it a suitable new medication for treating OHT and various types of glaucoma, especially where elevated IOP is implicated.
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Affiliation(s)
- Najam A Sharif
- Eye-ACP Duke-National University of Singapore Medical School, Singapore; Singapore Eye Research Institute (SERI), Singapore; Institute of Ophthalmology, University College London (UCL), London UK; Imperial College of Science and Technology, St. Mary's Campus, London UK; Department of Pharmacy Sciences, Creighton University, Omaha, NE USA; Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX USA.
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Sharif NA. Identifying new drugs and targets to treat rapidly elevated intraocular pressure for angle closure and secondary glaucomas to curb visual impairment and prevent blindness. Exp Eye Res 2023; 232:109444. [PMID: 36958427 DOI: 10.1016/j.exer.2023.109444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/23/2023] [Accepted: 03/16/2023] [Indexed: 03/25/2023]
Abstract
A multitude of pharmacological compounds have been shown to lower and control intraocular pressure (IOP) in numerous species of animals and human subjects after topical ocular dosing or via other routes of administration. Most researchers have been interested in finding drug candidates that exhibit a relatively long duration of action from a chronic therapeutic use perspective, for example to treat ocular hypertension (OHT), primary open-angle glaucoma and even normotensive glaucoma. However, it is equally important to seek and characterize treatment modalities which offer a rapid onset of action to help provide fast relief from quickly rising IOP that occurs in certain eye diseases. These include acute angle-closure glaucoma, primary angle-closure glaucoma, uveitic and inflammatory glaucoma, medication-induced OHT, and other secondary glaucomas induced by eye injury or infection which can cause partial or complete loss of eyesight. Such fast-acting agents can delay or prevent the need for ocular surgery which is often used to lower the dangerously raised IOP. This research survey was therefore directed at identifying agents from the literature that demonstrated ocular hypotensive activity, normalizing and unifying the data, determining their onset of action and rank ordering them on the basis of rapidity of action starting within 30-60 min and lasting up to at least 3-4 h post topical ocular dosing in different animal species. This research revealed a few health authority-approved drugs and some investigational compounds that appear to meet the necessary criteria of fast onset of action coupled with significant efficacy to reduce elevated IOP (by ≥ 20%, preferably by >30%). However, translation of the novel animal-based findings to the human conditions remains to be demonstrated but represent viable targets, especially EP2-receptor agonists (e.g. omidenepag isopropyl; AL-6598; butaprost), mixed activity serotonin/dopamine receptor agonists (e.g. cabergoline), rho kinase inhibitors (e.g. AMA0076, Y39983), CACNA2D1-gene product inhibitors (e.g. pregabalin), melatonin receptor agonists, and certain K+-channel openers (e.g. nicorandil, pinacidil). Other drug candidates and targets were also identified and will be discussed.
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Affiliation(s)
- Najam A Sharif
- Institute of Ophthalmology, University College London (UCL), London, UK; Imperial College of Science and Technology, St. Mary's Campus, London, UK; Eye-ACP Duke-National University of Singapore Medical School, Singapore; Singapore Eye Research Institute (SERI), Singapore; Department of Pharmacy Sciences, Creighton University, Omaha, NE, USA; Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA; Ophthalmology Innovation Center, Santen Inc USA, Emeryville, CA, USA.
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Vachlioti E, Ferikoglou S, Georgiou X, Karampatsis V, Afratis K, Bafiti V, Savard M, Papaioannou D, Katsila T, Gobeil F, Rassias G. Development of a multigram synthesis of the bradykinin receptor 2 agonist FR-190997 and analogs thereof. Arch Pharm (Weinheim) 2023; 356:e2200610. [PMID: 36720040 DOI: 10.1002/ardp.202200610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/24/2022] [Accepted: 01/13/2023] [Indexed: 02/02/2023]
Abstract
Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.
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Affiliation(s)
- Eleanna Vachlioti
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
| | - Spyridon Ferikoglou
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
| | - Xenios Georgiou
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
| | - Vasilios Karampatsis
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
| | - Konstantinos Afratis
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
| | - Vivi Bafiti
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Martin Savard
- Institute of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | | | - Theodora Katsila
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Fernand Gobeil
- Institute of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Gerasimos Rassias
- Department of Chemistry, University of Patras, Rio University Campus, Patra, Greece
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Sharif NA. Degeneration of retina-brain components and connections in glaucoma: Disease causation and treatment options for eyesight preservation. CURRENT RESEARCH IN NEUROBIOLOGY 2022; 3:100037. [PMID: 36685768 PMCID: PMC9846481 DOI: 10.1016/j.crneur.2022.100037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 01/25/2023] Open
Abstract
Eyesight is the most important of our sensory systems for optimal daily activities and overall survival. Patients who experience visual impairment due to elevated intraocular pressure (IOP) are often those afflicted with primary open-angle glaucoma (POAG) which slowly robs them of their vision unless treatment is administered soon after diagnosis. The hallmark features of POAG and other forms of glaucoma are damaged optic nerve, retinal ganglion cell (RGC) loss and atrophied RGC axons connecting to various brain regions associated with receipt of visual input from the eyes and eventual decoding and perception of images in the visual cortex. Even though increased IOP is the major risk factor for POAG, the disease is caused by many injurious chemicals and events that progress slowly within all components of the eye-brain visual axis. Lowering of IOP mitigates the damage to some extent with existing drugs, surgical and device implantation therapeutic interventions. However, since multifactorial degenerative processes occur during aging and with glaucomatous optic neuropathy, different forms of neuroprotective, nutraceutical and electroceutical regenerative and revitalizing agents and processes are being considered to combat these eye-brain disorders. These aspects form the basis of this short review article.
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Affiliation(s)
- Najam A. Sharif
- Duke-National University of Singapore Medical School, Singapore,Singapore Eye Research Institute (SERI), Singapore,Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA,Department of Pharmaceutical Sciences, Texas Southern University, Houston, TX, USA,Department of Surgery & Cancer, Imperial College of Science and Technology, St. Mary's Campus, London, UK,Department of Pharmacy Sciences, School of School of Pharmacy and Health Professions, Creighton University, Omaha, NE, USA,Ophthalmology Innovation Center, Santen Incorporated, 6401 Hollis Street (Suite #125), Emeryville, CA, 94608, USA,Ophthalmology Innovation Center, Santen Incorporated, 6401 Hollis Street (Suite #125), Emeryville, CA, 94608, USA.
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Ghanim AM, Girgis AS, Kariuki BM, Samir N, Said MF, Abdelnaser A, Nasr S, Bekheit MS, Abdelhameed MF, Almalki AJ, Ibrahim TS, Panda SS. Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates. Bioorg Chem 2021; 119:105557. [PMID: 34952242 DOI: 10.1016/j.bioorg.2021.105557] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/13/2021] [Accepted: 12/09/2021] [Indexed: 01/17/2023]
Abstract
A new set of ibuprofen-quinoline conjugates comprising quinolinyl heterocycle and ibuprofen moieties linked by an alkyl chain were synthesized in good yields utilizing an optimized reaction procedure in a molecular hybridization approach to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. The synthesized conjugates were screened for their anti-inflammatory, and ulcerogenic properties. Several conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test without showing any ulcerogenic liability. In addition, most conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate test. The most promising conjugates were the unsubstituted and 6-substituted fluoro- and chloro-derivatives of 2-(trifluoromethyl)quinoline linked to ibuprofen by a propyl chain. Their anti-inflammatory activity was evaluated against LPS-stimulated inflammatory reactions in RAW264.7 mouse macrophages. In this regard, it was found that most of the conjugates were able to significantly reduce the release and production of nitric oxide in the LPS-stimulated macrophages. The secretion and expression of the pro-inflammatory cytokines IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) were also significantly suppressed.
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Affiliation(s)
- Amany M Ghanim
- Department of Chemistry & Physics, Augusta University, Augusta, GA 30912, USA; Department of Pharmaceutical Organic Chemistry Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Adel S Girgis
- Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
| | - Benson M Kariuki
- School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
| | - Nermin Samir
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Mona F Said
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo (AUC), Cairo 11835, Egypt
| | - Soad Nasr
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo (AUC), Cairo 11835, Egypt; Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany
| | - Mohamed S Bekheit
- Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
| | | | - Ahmad J Almalki
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Tarek S Ibrahim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Siva S Panda
- Department of Chemistry & Physics, Augusta University, Augusta, GA 30912, USA.
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Sharif NA. Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies. Front Pharmacol 2021; 12:729249. [PMID: 34603044 PMCID: PMC8484316 DOI: 10.3389/fphar.2021.729249] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
Damage to the optic nerve and the death of associated retinal ganglion cells (RGCs) by elevated intraocular pressure (IOP), also known as glaucoma, is responsible for visual impairment and blindness in millions of people worldwide. The ocular hypertension (OHT) and the deleterious mechanical forces it exerts at the back of the eye, at the level of the optic nerve head/optic disc and lamina cribosa, is the only modifiable risk factor associated with glaucoma that can be treated. The elevated IOP occurs due to the inability of accumulated aqueous humor (AQH) to egress from the anterior chamber of the eye due to occlusion of the major outflow pathway, the trabecular meshwork (TM) and Schlemm’s canal (SC). Several different classes of pharmaceutical agents, surgical techniques and implantable devices have been developed to lower and control IOP. First-line drugs to promote AQH outflow via the uveoscleral outflow pathway include FP-receptor prostaglandin (PG) agonists (e.g., latanoprost, travoprost and tafluprost) and a novel non-PG EP2-receptor agonist (omidenepag isopropyl, Eybelis®). TM/SC outflow enhancing drugs are also effective ocular hypotensive agents (e.g., rho kinase inhibitors like ripasudil and netarsudil; and latanoprostene bunod, a conjugate of a nitric oxide donor and latanoprost). One of the most effective anterior chamber AQH microshunt devices is the Preserflo® microshunt which can lower IOP down to 10–13 mmHg. Other IOP-lowering drugs and devices on the horizon will be also discussed. Additionally, since elevated IOP is only one of many risk factors for development of glaucomatous optic neuropathy, a treatise of the role of inflammatory neurodegeneration of the optic nerve and retinal ganglion cells and appropriate neuroprotective strategies to mitigate this disease will also be reviewed and discussed.
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Affiliation(s)
- Najam A Sharif
- Global Alliances and External Research, Ophthalmology Innovation Center, Santen Inc., Emeryville, CA, United States
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Othman R, Cagnone G, Joyal JS, Vaucher E, Couture R. Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies. Cells 2021; 10:1913. [PMID: 34440682 PMCID: PMC8391508 DOI: 10.3390/cells10081913] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 12/29/2022] Open
Abstract
The kallikrein-kinin system (KKS) contributes to retinal inflammation and neovascularization, notably in diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Bradykinin type 1 (B1R) and type 2 (B2R) receptors are G-protein-coupled receptors that sense and mediate the effects of kinins. While B2R is constitutively expressed and regulates a plethora of physiological processes, B1R is almost undetectable under physiological conditions and contributes to pathological inflammation. Several KKS components (kininogens, tissue and plasma kallikreins, and kinin receptors) are overexpressed in human and animal models of retinal diseases, and their inhibition, particularly B1R, reduces inflammation and pathological neovascularization. In this review, we provide an overview of the KKS with emphasis on kinin receptors in the healthy retina and their detrimental roles in DR and AMD. We highlight the crosstalk between the KKS and the renin-angiotensin system (RAS), which is known to be detrimental in ocular pathologies. Targeting the KKS, particularly the B1R, is a promising therapy in retinal diseases, and B1R may represent an effector of the detrimental effects of RAS (Ang II-AT1R).
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Affiliation(s)
- Rahmeh Othman
- School of Optometry, Université de Montréal, Montreal, QC H3T 1P1, Canada
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Gael Cagnone
- Department of Pediatry, Faculty of Medicine, CHU St Justine, Université de Montréal, Montreal, QC H3T 1J4, Canada; (G.C.); (J.-S.J.)
| | - Jean-Sébastien Joyal
- Department of Pediatry, Faculty of Medicine, CHU St Justine, Université de Montréal, Montreal, QC H3T 1J4, Canada; (G.C.); (J.-S.J.)
| | - Elvire Vaucher
- School of Optometry, Université de Montréal, Montreal, QC H3T 1P1, Canada
| | - Réjean Couture
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
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A Robust Bioassay of the Human Bradykinin B 2 Receptor that Extends Molecular and Cellular Studies: The Isolated Umbilical Vein. Pharmaceuticals (Basel) 2021; 14:ph14030177. [PMID: 33668382 PMCID: PMC7996148 DOI: 10.3390/ph14030177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 11/18/2022] Open
Abstract
Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.
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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 Pharmacol Transl Sci 2020; 3:1391-1421. [PMID: 33344909 DOI: 10.1021/acsptsci.0c00137] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Indexed: 02/07/2023]
Abstract
The eye and eyesight are exquistly designed and are precious, and yet we often take them for granted. Good vision is critical for our long-term survival and for humanity's enduring progress. Unfortunately, since ocular diseases do not culminate in life-and-death scenarios, awareness of the plight of millions of people suffering from such eye ailments is not publicized as other diseases. However, losing eyesight or falling victim to visual impairment is a frightening outlook for most people. Glaucoma, a collection of chronic optic neuropathies, of which the most prevalent form, primary open-angle glaucoma (POAG), is the second leading cause of irreversible blindness. POAG currently afflicts >70 million people worldwide and is an insidious, progressive, silent thief of sight that is asymptomatic. On the other hand, allergic conjunctivitis (AC), and the associated rhinitis ("hay-fever"), frequently victimizes a huge number of people worldwide, especially during seasonal changes. While not life-threatening, sufferers of AC soon learn the value of drugs to treat their signs and symptoms of AC as they desire rapid relief to overcome the ocular itching/pain, redness, and tearing AC causes. Herein, I will describe the collective efforts of many researchers whose industrious, diligent, and dedicated team work resulted in the discovery, biochemical/pharmacological characterization, development and eventual launch of drugs to treat AC (e.g., olopatadine [Patanol/Pataday/Pazeo] and emedastine [Emedine]), and for treating ocular hypertension and POAG (e.g., travoprost [Travatan ] and Simbrinza). This represents a personal perspective.
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Affiliation(s)
- Najam A Sharif
- Department of Pharmacology & Neuroscience University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
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Rassias G, Leonardi S, Rigopoulou D, Vachlioti E, Afratis K, Piperigkou Z, Koutsakis C, Karamanos NK, Gavras H, Papaioannou D. Potent antiproliferative activity of bradykinin B2 receptor selective agonist FR-190997 and analogue structures thereof: A paradox resolved? Eur J Med Chem 2020; 210:112948. [PMID: 33139111 DOI: 10.1016/j.ejmech.2020.112948] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/24/2020] [Accepted: 10/14/2020] [Indexed: 12/26/2022]
Abstract
Βradykinin stimulation of B2 receptor is known to activate the oncogenic ERK pathway and overexpression of bradykinin receptors B1 and B2 has been reported to occur in glioma, colorectal and cervical cancers. B1R and B2R antagonists have been shown to reverse tumor proliferation and invasion. Paradoxically, B1R and B2R agonism has also been reported to elicit antiproliferative benefits. In order to complement the data accumulated to date with the natural substrate bradykinin and peptidic B2R antagonists, we decided to examine for the first time the response elicited by B2R stimulation in breast cancer lines with a non-peptidic small molecule B2R agonist. We synthesized and assessed the highly selective and potent B2R partial agonist FR-190997 in MCF-7 and MDA-MBA-231 breast cancer lines and found it possessed significant antiproliferative activity (IC50 2.14 and 0.08 μΜ, respectively). The modular nature of FR-190997 allowed us to conduct a focused SAR study and discover compound 10 which exhibits subnanomolar antiproliferative activity (IC 50 0.06 nΜ) in the TNBC MDA-MBA-231 cell line. This performance surpasses, in most cases by several orders of magnitude, those of established anticancer agents and FDA-approved breast cancer drugs. In line with the established literature we suggest that this remarkable activity precipitates from a dual mode of action involving agonist-induced receptor internalization/degradation combined with sequestration of functional intracellular B2 receptors and inhibition of the associated endosomal signaling. The latter mode may be realized by appropriate ligands regardless of B2R agonist/antagonist designation which only relates to membrane residing GCPRs. Under this prism the controversy over the antiproliferative effects of B2 agonists and antagonists is potentially neutralized.
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Affiliation(s)
- Gerasimos Rassias
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece.
| | - Sofia Leonardi
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece
| | - Dionisia Rigopoulou
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece
| | - Eleanna Vachlioti
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece
| | - Konstantinos Afratis
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece
| | - Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece; Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Christos Koutsakis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece; Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Haralambos Gavras
- Hypertension and Atherosclerosis Section, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
| | - Dionissios Papaioannou
- Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504, Patras, Greece.
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In Vitro Screening and Transfection Concentration Optimization of Cynomolgus Monkey I κB α-siRNA. J Ophthalmol 2020; 2020:1848540. [PMID: 32377413 PMCID: PMC7180988 DOI: 10.1155/2020/1848540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 03/09/2020] [Indexed: 12/04/2022] Open
Abstract
Purpose To seek for a small interfering RNA (siRNA) sequence targeting a cynomolgus monkey inhibitor of nuclear factor kappa B α (IκBα) that can specifically and effectively suppress IκBα gene expression of cynomolgus monkey ciliary muscle (CM) cells and trabecular meshwork (TM) cells in vitro and screen for optimal siRNA transfection concentration. Methods Three IκBα-specific double-stranded siRNAs were designed and synthesized. They were transfected into primarily cultured cynomolgus monkey CM cells and TM cells. The mRNA and protein levels of IκBα were examined by using real-time quantitative polymerase chain reaction (real-time PCR) and western blot to screen a pair of candidate valid sequences with the highest inhibitory rate. Both cells were transfected with Cy5-labeled nonspecific control-siRNA (NC-siRNA) of four different concentrations (10, 20, 50, and 100 nmol/L(nM)), and flow cytometry was used to assess transfection efficiency. Then, cells were transfected with the candidate valid IκBα -siRNA of the same four concentrations, and the cytotoxicity was detected by using Cell Counting Kit-8 (CCK8), and the inhibitory efficiency of IκBα was identified via real-time PCR to find out optimal siRNA transfection concentration. Results The suppression effect of the siRNA targeting the GCACTTAGCCTCTATCCAT of IκBα gene was most obvious by in vitro screening. The inhibitory rate of IκBα was 82% for CM cells and 82% for TM cells on the mRNA level and 98% for CM cells and 93% for TM cells on the protein level, respectively. The results of flow cytometry showed that the transfection efficiency was the highest at 100 nM, which was 89.0% for CM cells and 48.2% for TM cells, respectively. The results of CCK8 showed that there was no statistically significant difference in cell viability after transfection of different concentrations of IκBα-siRNA. The results of real-time PCR indicated that there was no statistical difference in the inhibitory efficiency of IκBα after transfection of different concentrations of IκBα-siRNA. Conclusion It proves that the siRNA targeting the GCACTTAGCCTCTATCCAT of IκBα gene is the valid sequence to suppress cynomolgus monkey IκBα expression of CM cells and TM cells by RNAi. 10 nM is the optimal transfection concentration.
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Sharif NA. iDrugs and iDevices Discovery Research: Preclinical Assays, Techniques, and Animal Model Studies for Ocular Hypotensives and Neuroprotectants. J Ocul Pharmacol Ther 2018; 34:7-39. [PMID: 29323613 DOI: 10.1089/jop.2017.0125] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Discovery ophthalmic research is centered around delineating the molecular and cellular basis of ocular diseases and finding and exploiting molecular and genetic pathways associated with them. From such studies it is possible to determine suitable intervention points to address the disease process and hopefully to discover therapeutics to treat them. An investigational new drug (IND) filing for a new small-molecule drug, peptide, antibody, genetic treatment, or a device with global health authorities requires a number of preclinical studies to provide necessary safety and efficacy data. Specific regulatory elements needed for such IND-enabling studies are beyond the scope of this article. However, to enhance the overall data packages for such entities and permit high-quality foundation-building publications for medical affairs, additional research and development studies are always desirable. This review aims to provide examples of some target localization/verification, ocular drug discovery processes, and mechanistic and portfolio-enhancing exploratory investigations for candidate drugs and devices for the treatment of ocular hypertension and glaucomatous optic neuropathy (neurodegeneration of retinal ganglion cells and their axons). Examples of compound screening assays, use of various technologies and techniques, deployment of animal models, and data obtained from such studies are also presented.
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Affiliation(s)
- Najam A Sharif
- 1 Global Alliances & External Research , Santen Incorporated, Emeryville, California.,2 Department of Pharmaceutical Sciences, Texas Southern University , Houston, Texas.,3 Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center , Fort Worth, Texas
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Sharif NA, Patil R, Li L, Husain S. Human ciliary muscle cell responses to kinins: Activation of ERK1/2 and pro-matrix metalloproteinases secretion. World J Ophthalmol 2016; 6:20-27. [DOI: 10.5318/wjo.v6.i3.20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/24/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To study activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and pro-matrix metalloproteinases (pro-MMPs) secretion from isolated primary human ciliary muscle (h-CM) cells in response to bradykinin (BK) and other agonists.
METHODS Serum-starved h-CM cells were challenged with vehicle, BK agonists or antagonists. Cell lysates were evaluated for phosphorylated ERK1/2 using homogeneous time-resolved fluorescence technology based on a sandwich immunoassay. Rabbit polyclonal anti-pro-MMP antibodies were used to measure pro-MMPs using immunoblot analysis.
RESULTS A 10 min incubation time using 5 × 104 h-CM cells/well was optimum condition for studying stimulation of ERK1/2 phosphorylation. BK (100 nmol/L) caused a 1.86 ± 0.26 fold (n = 3) increase in ERK1/2 phosphorylation above baseline. BK analogs, Met-Lys-BK and RMP-7 (100 nmol/L), also stimulated ERK1/2 phosphorylation by 1.57 ± 0.04 and 1.55 ± 0.09 fold, respectively. However, Des-Arg9-Bradykinin, a B1 receptor-selective agonist (0.1-1 μmol/L), was essentially inactive. HOE-140 or WIN-64338 (B2-antagonists) appreciably blocked phosphorylation of ERK1/2 induced by various BK agonists. Pre-treatment of cells with a prostaglandin (PG) synthase inhibitor (bromfenac; 1 μmol/L) failed to alter kinin-induced ERK1/2 activation. BK and a non-peptide BK agonist (FR-190997) (10 nmol/L-1 μmol/L) also enhanced pro-MMPs secretion (pro-MMP-1 > pro-MMP-3 > pro-MMP-2; 1.45-1.75-fold over baseline) from h-CM cells.
CONCLUSION These collective data suggest that B2 kinin receptors initiate signaling in h-CM cells by a relatively rapid mechanism (within minutes) involving ERK1/2 activation which in turn regulates MMPs production (within hours). The latter process does not involve PGs.
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Sharif NA. Novel potential treatment modalities for ocular hypertension: focus on angiotensin and bradykinin system axes. J Ocul Pharmacol Ther 2015; 31:131-45. [PMID: 25599263 DOI: 10.1089/jop.2014.0114] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite the availability of modern surgical procedures, new drug delivery techniques, health authority-approved single topical ocular drugs, and combination products thereof, there continues to be an unmet medical need for novel treatment modalities for preserving vision. This is especially true for the treatment of glaucoma and the high risk factor often associated with this ocular disease, elevated intraocular pressure (IOP). Undesirable local or systemic side effects, frequency of dosing, lack of sustained IOP lowering, and lack of prevention of diurnal IOP spikes are among the greatest challenges. The very recent discovery, characterization, and publication of 2 novel IOP-lowering agents that pertain to the renin-angiotensin and kallikrein-kinin axes potentially offer novel means to treat and control ocular hypertension (OHT). Here, some contextual introductory information is provided first, followed by more detailed discussion of the properties and actions of diminazene aceturate (DIZE; a novel angiotensin-converting enzyme-2 activator) and FR-190997 (a nonpeptide bradykinin receptor-2 agonist) in relation to their anti-OHT activities in rodent and cynomolgus monkey eyes, respectively. It is anticipated that these compounds will pave the way for future discovery, development, and marketing of novel drugs to treat glaucoma and thus help save sight for millions of people afflicted with this slow progressive optic neuropathy.
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Affiliation(s)
- Najam A Sharif
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University , Houston, Texas
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Masuda T, Shimazawa M, Hara H. The kallikrein system in retinal damage/protection. Eur J Pharmacol 2014; 749:161-3. [PMID: 25448306 DOI: 10.1016/j.ejphar.2014.10.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 09/29/2014] [Accepted: 10/03/2014] [Indexed: 12/27/2022]
Abstract
Kallikrein is a serine protease involved in the kallikrein-kinnin system. Kallikrein is derived from the blood plasma or tissue, and is correlated with aggravation and improvement in eye diseases, such as, glaucoma, diabetic retinopathy, age-related macular degeneration, and ocular ischemic syndrome. The plasma kallikrein stimulates retinal vascular permeability and intraocular hemorrhage. On the other hand, we had reported that the tissue kallikrein normalizes retinal vasopermeability and inhibited retinal neovascularization and retinal ischemic injury. The protective mechanisms of the tissue-derived kallikrein include the cleavage of vascular endothelial growth factor (VEGF), which suggests that the tissue kallikrein could be potentially-effective against any disease involving the VEGF production.
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Affiliation(s)
- Tomomi Masuda
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
| | - Masamitsu Shimazawa
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
| | - Hideaki Hara
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
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