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Neuroaxonal and cellular damage/protection by prostanoid receptor ligands,fatty acid derivatives and associated enzyme inhibitors

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Neural Regeneration Research 2023年第1期18卷 5-17页

作者： najam a.sharif Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesTexas Southern UniversityHoustonTXUSA Department of Pharmacology and Neuroscience University of North Texas Health Sciences CenterFort WorthTXUSA Department of Pharmacy Sciences School of Pharmacy and Health ProfessionsCreighton UniversityOmahaNEUSA Singapore Eye Research Institute(SERI) SingaporeSingapore Duke-NUS Medical School SingaporeSingapore Department of Surgery&Cancer Imperial College of Science and TechnologySt.Mary’s CampusLondonUK Global Alliances and External Research Ophthalmology Innovation CenterSanten Inc USAEmeryvilleCAUSA

Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical,mechanical,noxious and other *** D_(2),prostaglandin E_(2),prostaglandin F_(2)α,prostaglandin I_(2)and thromboxane-A_(2)interact with five major receptors(and their sub-types)to elicit specific downstream cellular and tissue *** general,prostaglandins have been associated with pain,inflammation,and edema when they are present at high local concentrations and involved on a chronic ***,in acute settings,certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation,providing cellular protection,regulating sleep,and enhancing blood flow,to lowering intraocular pressure to prevent the development of glaucoma,a blinding *** classes of prostaglandins are implicated(or are considered beneficial)in certain central nervous system dysfunctions(e.g.,Alzheimer’s,Parkinson’s,and Huntington’s diseases;amyotrophic lateral sclerosis and multiple sclerosis;stroke,traumatic brain injuries and pain)and in ocular disorders(e.g.,ocular hypertension and glaucoma;allergy and inflammation;edematous retinal disorders).This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease,and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists,polyunsaturated fatty acids,and cyclooxygenase inhibitors.

关键词： AL-8810 axon brain central nervous system cyclooxygenase inhibitors neuron neuroprotection ocular polyunsaturated fatty acids prostaglandins

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Glaucomatous optic neuropathy treatment options:the promise of novel therapeutics,techniques and tools to help preserve vision

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Neural Regeneration Research 2018年第7期13卷 1145-1150页

作者： najam a.sharif Department of Global Alliances & External Research Global Ophthalmology Research & DevelopmentSanten Incorporated Department of Pharmaceutical Sciences Texas Southern University Department of Pharmacology and Neuroscience University of North Texas Health Sciences Center Department of Pharmacy Sciences Creighton University Department of Surgery & Cancer Imperial College of Science and TechnologySt.Mary's Campus

Peripheral vision loss followed by ＂tunnel vision＂ and eventual irreversible blindness is the fate of patients afflicted by various forms of glaucoma including primary open-angle glaucoma（POAG） and normotensive glaucoma（NTG）.These complex and heterogeneous diseases are characterized by extensive death of retinal ganglion cells（RGCs） accompanied by retraction and severance of their axonal connections to the brain and thus damage to and thinning of the optic *** patients suffering from this glaucomatous optic neuropathy（GON） first notice visual impairment when they have lost 〉 40% of their RGCs,early diagnosis is the key to retard the progression of *** intraocular pressure（IOP）,low cerebrospinal and/or low intracranial fluid pressure,advancing age,and ethnicity are major risk factors associated with ***,retinal vascular abnormalities and a high sensitivity of RGCs and optic nerve head components to neurotoxic,inflammatory,oxidative and mechanical insults also contribute to vision loss in POAG/*** treatment modalities for POAG and NTG involve lowering IOP using topical ocular drugs,combination drug products,and surgical *** recently approved multi-pharmacophoric drugs（e.g.,rho kinase inhibitor,Netarsudil;a drug conjugate,Latanoprostene Bunod） and novel aqueous humor drainage devices（i Stent and Cy Pass） are also gaining acceptance for treating POAG/*** and regenerative agents,coupled with electroceutical,mechanical support systems,stem cell transplantation and gene therapy are emerging therapeutics on the horizon to help combat *** latter techniques and approaches hope to rejuvenate RGCs and repair the optic nerve structures,thereby providing a gain of function of the visual system for the glaucoma patients.

关键词： glaucoma ocular hypertension glaucomatous optic neuropathy drainage device optic nerve degeneration retinal ganglion cells nerve regeneration neuroprotection

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Human ciliary muscle cell responses to kinins:Activation of ERK1/2 and pro-matrix metalloproteinases secretion

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World Journal of Ophthalmology 2016年第3期6卷 20-27页

作者： najam a.sharif Rajkumar Patil Linya Li Shahid Husain Pharmaceutical Research Alcon Research Ltd. (A Novartis Company) Ophthalmology Medical University of South Carolina

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 timeresolved fluorescence technology based on a sandwich immunoassay. Rabbit polyclonal anti-pro-MMP antibodies were used to measure pro-MMPs using immunoblot *** 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, DesArg9-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-treatmentof 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.

关键词： Extracellular signal-regulated kinase-1/2 Bradykinin Ciliary muscle Matrix metalloproteinases B2-receptor

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