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1
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Argiolas A, Argiolas FM, Argiolas G, Melis MR. Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies. Brain Sci 2023; 13:802. [PMID: 37239274 PMCID: PMC10216368 DOI: 10.3390/brainsci13050802] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Erectile dysfunction (ED) is the inability to get and maintain an adequate penile erection for satisfactory sexual intercourse. Due to its negative impacts on men's life quality and increase during aging (40% of men between 40 and 70 years), ED has always attracted researchers of different disciplines, from urology, andrology and neuropharmacology to regenerative medicine, and vascular and prosthesis implant surgery. Locally and/or centrally acting drugs are used to treat ED, e.g., phosphodiesterase 5 inhibitors (first in the list) given orally, and phentolamine, prostaglandin E1 and papaverine injected intracavernously. Preclinical data also show that dopamine D4 receptor agonists, oxytocin and α-MSH analogues may have a role in ED treatment. However, since pro-erectile drugs are given on demand and are not always efficacious, new strategies are being tested for long lasting cures of ED. These include regenerative therapies, e.g., stem cells, plasma-enriched platelets and extracorporeal shock wave treatments to cure damaged erectile tissues. Although fascinating, these therapies are laborious, expensive and not easily reproducible. This leaves old vacuum erection devices and penile prostheses as the only way to get an artificial erection and sexual intercourse with intractable ED, with penile prosthesis used only by accurately selected patients.
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Affiliation(s)
- Antonio Argiolas
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
| | - Francesco Mario Argiolas
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
| | - Giacomo Argiolas
- General Medicine Unit, Hospital San Michele, ARNAS“G. Brotzu”, Piazzale Ricchi 1, 09100 Cagliari, Italy;
| | - Maria Rosaria Melis
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy; (F.M.A.); (M.R.M.)
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2
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Pakpahan C, Ibrahim R, William W, Faizah Z, Juniastuti J, Lusida MI, Oceandy D. Stem cell therapy and diabetic erectile dysfunction: A critical review. World J Stem Cells 2021; 13:1549-1563. [PMID: 34786157 PMCID: PMC8567456 DOI: 10.4252/wjsc.v13.i10.1549] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.
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Affiliation(s)
- Cennikon Pakpahan
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Raditya Ibrahim
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - William William
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
- Department of Medical Biology, School of Medicine and Health Sciences Atma Jaya Catholic University of Indonesia, Jakarta 14440, Indonesia
| | - Zakiyatul Faizah
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
| | | | - Maria I Lusida
- Institute for Tropical Disease, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom
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3
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Luo C, Ampomah-Wireko M, Wang H, Wu C, Wang Q, Zhang H, Cao Y. Isoquinolines: Important Cores in Many Marketed and Clinical Drugs. Anticancer Agents Med Chem 2021; 21:811-824. [PMID: 32329698 DOI: 10.2174/1871520620666200424132248] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/07/2020] [Accepted: 02/19/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Isoquinoline analogs are an important, structurally diverse class of compounds that are extensively used as pharmaceuticals. Derivatives containing the isoquinoline scaffold have become a focus of therapeutic research because of their wide range of biological characteristics. Examples of these drugs, many of which are in clinical application or at the pre-clinical stage, are used to treat a broad swathe of ailments, such as tumors, respiratory diseases, infections, nervous system diseases, cardiovascular and cerebrovascular diseases, endocrine and metabolic diseases. METHODS Data were collected from PubMed, Web of Science, and SciFinder, through searches of drug names. RESULTS At least 38 isoquinoline-based therapeutic drugs are in clinical application or clinical trials, and their chemical structure and pharmacokinetics are described in detail. CONCLUSION The isoquinoline ring is a privileged scaffold which is often preferred as a structural basis for drug design, and plays an important role in drug discovery. This review provides a guide for pharmacologists to find effective preclinical/clinical drugs and examines recent progress in the application of the isoquinoline scaffold.
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Affiliation(s)
- Chunying Luo
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | | | - Huanhuan Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Chunli Wu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Hui Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yaquan Cao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
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de Sousa GR, Vieira GM, das Chagas PF, Pezuk JA, Brassesco MS. Should we keep rocking? Portraits from targeting Rho kinases in cancer. Pharmacol Res 2020; 160:105093. [PMID: 32726671 DOI: 10.1016/j.phrs.2020.105093] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/15/2020] [Accepted: 07/19/2020] [Indexed: 12/12/2022]
Abstract
Cancer targeted therapy, either alone or in combination with conventional chemotherapy, could allow the survival of patients with neoplasms currently considered incurable. In recent years, the dysregulation of the Rho-associated coiled-coil kinases (ROCK1 and ROCK2) has been associated with increased metastasis and poorer patient survival in several tumor types, and due to their essential roles in regulating the cytoskeleton, have gained popularity and progressively been researched as targets for the development of novel anti-cancer drugs. Nevertheless, in a pediatric scenario, the influence of both isoforms on prognosis remains a controversial issue. In this review, we summarize the functions of ROCKs, compile their roles in human cancer and their value as prognostic factors in both, adult and pediatric cancer. Moreover, we provide the up-to-date advances on their pharmacological inhibition in pre-clinical models and clinical trials. Alternatively, we highlight and discuss detrimental effects of ROCK inhibition provoked not only by the action on off-targets, but most importantly, by pro-survival effects on cancer stem cells, dormant cells, and circulating tumor cells, along with cell-context or microenvironment-dependent contradictory responses. Together these drawbacks represent a risk for cancer cell dissemination and metastasis after anti-ROCK intervention, a caveat that should concern scientists and clinicians.
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Affiliation(s)
| | | | | | | | - María Sol Brassesco
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Brazil.
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Grice PT, Liu J, Gabrielson AT, Pearce I, Bivalacqua TJ, Modgil V. Drug delivery options and therapeutic advances in the management of erectile dysfunction. Expert Opin Drug Deliv 2020; 17:1259-1268. [PMID: 32531183 DOI: 10.1080/17425247.2020.1782383] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. It is estimated that 20-30% of adult men will have at least one episode of ED during their lifetime and the prevalence increases with age. ED is known to have significant negative psychological implications for men, resulting in impaired functional status and a greater prevalence of anxiety and depression. AREAS COVERED Medications for the treatment of erectile dysfunction largely revolve around oral, injection, and topical therapies. Though all three modalities are widely used, each delivery option has its own advantages and specific indications. Likewise, there are several new developing treatments for ED that may change the landscape of treatment. The goal of this review is to summarize contemporary drug delivery options used in the treatment of ED and highlight future promising pharmacological developments. EXPERT OPINION There are a myriad of new developments on the horizon including new PDE5Is and drug targets, nanotechnology enhancements, stem cell and gene therapy, shockwave therapy, and platelet-rich plasma injections. These are all promising new methods to not only treat ED but also to address the pathology and prevent or eliminate further damage.
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Affiliation(s)
- P T Grice
- Nottingham Urology Centre, Nottingham University Hospitals NHS Trust , Nottingham, UK
| | - J Liu
- James Buchanan Brady Urological Institute, Johns Hopkins Hospital , Baltimore, Maryland, United States
| | - A T Gabrielson
- James Buchanan Brady Urological Institute, Johns Hopkins Hospital , Baltimore, Maryland, United States
| | - I Pearce
- Manchester Andrology Centre, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust , UK
| | - T J Bivalacqua
- James Buchanan Brady Urological Institute, Johns Hopkins Hospital , Baltimore, Maryland, United States
| | - V Modgil
- Manchester Andrology Centre, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust , UK
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6
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Pharmacology and perspectives in erectile dysfunction in man. Pharmacol Ther 2020; 208:107493. [PMID: 31991196 DOI: 10.1016/j.pharmthera.2020.107493] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/05/2019] [Indexed: 12/15/2022]
Abstract
Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal, and hormonal systems. Therefore, the fine coordination of these events is essential to maintain penile flaccidity or allow erection; an alteration of these events leads to erectile dysfunction (ED). ED is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity. A great boost to this research field was given by commercialization of phosphodiesterase-5 (PDE5) inhibitors. Indeed, following the discovery of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost, and many preclinical and clinical papers have been published in the last 10 years. This review is structured to provide an overview of the mediators and peripheral mechanism(s) involved in penile function in men, the drugs used in therapy, and the future prospective in the management of ED. Indeed, 30% of patients affected by ED are classified as "nonresponders," and there is still an unmet need for therapeutic alternatives. A flowchart suggesting the guidelines for ED evaluation and the ED pharmacological treatment is also provided.
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7
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Shahbazi R, Baradaran B, Khordadmehr M, Safaei S, Baghbanzadeh A, Jigari F, Ezzati H. Targeting ROCK signaling in health, malignant and non-malignant diseases. Immunol Lett 2020; 219:15-26. [PMID: 31904392 DOI: 10.1016/j.imlet.2019.12.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/15/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022]
Abstract
A Rho-associated coiled-coil kinase (ROCK) is identified as a critical downstream effector of GTPase RhoA which contains two isoforms, ROCK1 (also known as p160ROCK and ROKβ) and ROCK2 (also known as Rho-kinase and ROKα), the gene of which is placed on chromosomes 18 (18q11.1) and 2 (2p24), respectively. ROCKs have a principal function in the generation of actin-myosin contractility and regulation of actin cytoskeleton dynamics. They represent a chief role in regulating various cellular functions, such as apoptosis, growth, migration, and metabolism through modulation of cytoskeletal actin synthesis, and cellular contraction through phosphorylation of numerous downstream targets. Emerging evidence has indicated that ROCKs present a significant function in cardiac physiology. Of note, dysregulation of ROCKs involves in several cardiac pathological processes like cardiac hypertrophy, cardiac fibrosis, systemic blood pressure disorder, and pulmonary hypertension. Moreover, ROCKs, in addition to their role in regulating renal arteriolar contraction, glomerular blood flow, and filtration, can also play a role in controlling podocytes, tubular cells, and mesangial cell structure and function. Hyperactivity disorder and over-gene expression of Rho/ROCK have been indicated in different cancers. Furthermore, it seems that increasing the expression of mRNA or ROCK protein has an undesirable effect on patient survival and has a positive impact on the progression and worsening of disease prognosis. This review focuses on the physiological and pathological functions of ROCKs with a particular view on its possible value of ROCK inhibitors as a new therapy in cancers and non-cancer diseases.
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Affiliation(s)
- Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran.
| | - Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran.
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran.
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran.
| | - Farinaz Jigari
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran.
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran.
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8
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Chung E. A Review of Current and Emerging Therapeutic Options for Erectile Dysfunction. Med Sci (Basel) 2019; 7:medsci7090091. [PMID: 31470689 PMCID: PMC6780857 DOI: 10.3390/medsci7090091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/20/2019] [Accepted: 08/23/2019] [Indexed: 12/23/2022] Open
Abstract
Contemporary treatment algorithms for erectile dysfunction (ED) involve the use of medical therapies such as phosphodiesterase type 5 (PDE5) inhibitors and intracavernosal injection therapy of vasoactive agents, as well as vacuum erection devices and penile prosthesis implants in medically refractory cases. However, the current therapeutic options only address the symptoms of ED and not the underlying pathogenesis that results in ED. Newer and novel ED therapies aspire to reverse ED conditions by preventing cavernosal fibrosis, promoting endothelial revascularization and modulating various neuro-hormonal pathways. Regenerative therapeutic strategies such as low-intensity shock wave, gene and cellular-based therapies, and penile transplants are designed to improve penile hemodynamics and revitalize the cavernosal smooth muscle to mitigate and/or reverse underlying ED. This state-of-art article evaluates current and emerging therapeutic options for ED.
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Affiliation(s)
- Eric Chung
- AndroUrology Centre, Brisbane, QLD 4000, Australia.
- University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.
- Macquarie University Hospital, Sydney, NSW 2109, Australia.
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9
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Patel DP, Pastuszak AW, Hotaling JM. Emerging Treatments for Erectile Dysfunction: a Review of Novel, Non-surgical Options. Curr Urol Rep 2019; 20:44. [PMID: 31214818 DOI: 10.1007/s11934-019-0908-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW To review novel, non-surgical therapies for erectile dysfunction (ED). RECENT FINDINGS Recently, a landmark study identified the SIM1 locus, involved in the leptin-melanocortin pathway, as an independent risk factor for ED and a potential target for novel therapies. The recent literature otherwise has focused on low-intensity shock wave therapy (LiSWT), with several randomized trials and meta-analyses suggesting therapeutic efficacy. There are few novel oral agents for ED. There is growing evidence suggesting efficacy of intracavernosal stem cells therapy and low-intensity shock wave therapy (LiSWT), although these therapies are still investigational. A better understanding of the pathophysiologic spectrum of ED will offer new opportunities for novel, non-surgical therapies for ED.
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Affiliation(s)
- Darshan P Patel
- Division of Urology, Department of Surgery, University of Utah School of Medicine, 30 N 1900 E, Rm # 3B420, Salt Lake City, UT, 84132, USA
| | - Alexander W Pastuszak
- Division of Urology, Department of Surgery, University of Utah School of Medicine, 30 N 1900 E, Rm # 3B420, Salt Lake City, UT, 84132, USA
| | - James M Hotaling
- Division of Urology, Department of Surgery, University of Utah School of Medicine, 30 N 1900 E, Rm # 3B420, Salt Lake City, UT, 84132, USA.
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10
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Dee RA, Mangum KD, Bai X, Mack CP, Taylor JM. Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure. Pharmacol Ther 2019; 193:121-134. [PMID: 30189292 PMCID: PMC7235948 DOI: 10.1016/j.pharmthera.2018.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The prevalence of high blood pressure (also known as hypertension) has steadily increased over the last few decades. Known as a silent killer, hypertension increases the risk for cardiovascular disease and can lead to stroke, heart attack, kidney failure and associated sequela. While numerous hypertensive therapies are currently available, it is estimated that only half of medicated patients exhibit blood pressure control. This signifies the need for a better understanding of the underlying cause of disease and for more effective therapies. While blood pressure homeostasis is very complex and involves the integrated control of multiple body systems, smooth muscle contractility and arterial resistance are important contributors. Strong evidence from pre-clinical animal models and genome-wide association studies indicate that smooth muscle contraction and BP homeostasis are governed by the small GTPase RhoA and its downstream target, Rho kinase. In this review, we summarize the signaling pathways and regulators that impart tight spatial-temporal control of RhoA activity in smooth muscle cells and discuss current therapeutic strategies to target these RhoA pathway components. We also discuss known allelic variations in the RhoA pathway and consider how these polymorphisms may affect genetic risk for hypertension and its clinical manifestations.
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Affiliation(s)
- Rachel A Dee
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Kevin D Mangum
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Xue Bai
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Christopher P Mack
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Joan M Taylor
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
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Abstract
INTRODUCTION Numerous studies have highlighted the intimate association between erectile dysfunction (ED) and diabetes mellitus (DM). However, the true pathogenesis of ED among diabetic men has not yet been fully discovered. The treatment of ED in diabetic patients remains an interesting area of research. The last two decades have witnessed phenomenal advances in the management of ED with the efficacy of pharmacotherapy for ED in diabetic patients encouraging, especially with introduction of innovative conservative tools for treatment. AREAS COVERED The aim of this review is to discuss the currently available information on ED pharmacotherapy in diabetic males and provide an expert perspective on the current treatment strategies. EXPERT OPINION Conservative treatment remains the initial step for the treatment of ED in diabetic patients. This kind of therapy consists of different modalities including: oral treatments, intracavernosal pharmacotherapy, and evolving modalities such as soluble guanylate cyclase activators, stem cells (SCs), and alternative treatments such as herbal treatment and transdermal/topical pharmacotherapy. However, it should be noted that the currently available pharmacotherapy is still far from ideal. One hopes to witness new drugs and technologies that may revolutionize ED treatment in the future, especially in such complex cases as DM.
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Affiliation(s)
- Ahmed I El-Sakka
- a Department of Urology , Suez Canal University , Ismailia , Egypt
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12
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Uvin P, Albersen M, Bollen I, Falter M, Weyne E, Linsen L, Tinel H, Sandner P, Bivalacqua TJ, De Ridder DJMK, Van der Aa F, Brône B, Van Renterghem K. Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure. BJU Int 2016; 119:325-332. [DOI: 10.1111/bju.13691] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Pieter Uvin
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Urology; Jessa Hospital; Hasselt University; Hasselt Belgium
- Department of Development and Regeneration; Cluster Organ Systems; Faculty of Medicine; Group Biomedical Sciences; KU Leuven; Leuven Belgium
| | - Maarten Albersen
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Development and Regeneration; Cluster Organ Systems; Faculty of Medicine; Group Biomedical Sciences; KU Leuven; Leuven Belgium
| | - Ine Bollen
- Physiology Group; University of Hasselt; Hasselt Belgium
| | - Maarten Falter
- Physiology Group; University of Hasselt; Hasselt Belgium
| | - Emmanuel Weyne
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Development and Regeneration; Cluster Organ Systems; Faculty of Medicine; Group Biomedical Sciences; KU Leuven; Leuven Belgium
| | - Loes Linsen
- Jessa Hospital; University Biobank Limburg; Hasselt Belgium
| | - Hanna Tinel
- Bayer HealthCare; Global Drug Discovery; Wuppertal Germany
- Institute of Pharmacology; Hannover Medical School; Hannover Germany
| | - Peter Sandner
- Bayer HealthCare; Global Drug Discovery; Wuppertal Germany
- Institute of Pharmacology; Hannover Medical School; Hannover Germany
| | - Trinity J. Bivalacqua
- Department of Urology; James Buchanan Brady Urological Institute; Johns Hopkins Medical Institutions; Baltimore MD USA
| | - Dirk J. M. K. De Ridder
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Development and Regeneration; Cluster Organ Systems; Faculty of Medicine; Group Biomedical Sciences; KU Leuven; Leuven Belgium
| | - Frank Van der Aa
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Development and Regeneration; Cluster Organ Systems; Faculty of Medicine; Group Biomedical Sciences; KU Leuven; Leuven Belgium
| | - Bert Brône
- Physiology Group; University of Hasselt; Hasselt Belgium
| | - Koenraad Van Renterghem
- Department of Urology; University Hospitals Leuven; Leuven Belgium
- Department of Urology; Jessa Hospital; Hasselt University; Hasselt Belgium
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13
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Wei L, Surma M, Shi S, Lambert-Cheatham N, Shi J. Novel Insights into the Roles of Rho Kinase in Cancer. Arch Immunol Ther Exp (Warsz) 2016; 64:259-78. [PMID: 26725045 PMCID: PMC4930737 DOI: 10.1007/s00005-015-0382-6] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 11/24/2015] [Indexed: 12/12/2022]
Abstract
Rho-associated coiled-coil kinase (ROCK) is a major downstream effector of the small GTPase RhoA. The ROCK family, consisting of ROCK1 and ROCK2, plays a central role in the organization of the actin cytoskeleton, and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Since the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored in numerous diseases, including cancer. Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance as well. This review focuses on the new advances of the most recent 5 years from the studies on the roles of ROCK in cancer development and progression; the discussion is mainly focused on the potential value of ROCK inhibitors in cancer therapy.
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Affiliation(s)
- Lei Wei
- Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 Building, Room 332, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA. .,Department of Cellular and Integrative Physiology, Indiana University, School of Medicine, 1044 West Walnut Street, R4-370, Indianapolis, IN, 46202-5225, USA.
| | - Michelle Surma
- Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 Building, Room 332, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA
| | - Stephanie Shi
- Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 Building, Room 332, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA
| | - Nathan Lambert-Cheatham
- Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 Building, Room 332, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA
| | - Jianjian Shi
- Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 Building, Room 332, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA.
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Feng Y, LoGrasso PV, Defert O, Li R. Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J Med Chem 2015; 59:2269-300. [PMID: 26486225 DOI: 10.1021/acs.jmedchem.5b00683] [Citation(s) in RCA: 268] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiological and biological functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.
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Affiliation(s)
| | | | - Olivier Defert
- Amakem Therapeutics , Agoralaan A bis, 3590 Diepenbeek, Belgium
| | - Rongshi Li
- Center for Drug Discovery and Department of Pharmaceutical Sciences, College of Pharmacy, Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center , 986805 Nebraska Medical Center, Omaha, Nebraska 68198, United States
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Knezevic NN, Cicmil N, Knezevic I, Candido KD. Discontinued neuropathic pain therapy between 2009-2015. Expert Opin Investig Drugs 2015; 24:1631-46. [PMID: 26472477 DOI: 10.1517/13543784.2015.1099627] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Studies have shown that neuropathic pain remains imprecisely responsive to conventional therapies, therefore posing an ongoing, vexing clinical conundrum for healthcare resource utilization. This manuscript reflects the stark reality of the limited pharmacological choices available to clinicians and is a reflective of an ongoing need for more extensive neuropathic pain clinical research. AREAS COVERED The authors review a total of 33 potential drugs for neuropathic pain which were discontinued in the period between 01/01/2009 and 12/31/2014. Eleven drugs were terminated in the first phase of clinical trials; nineteen were discontinued in the second phase, while only three drugs reached the third phase. EXPERT OPINION Since only 40-60% of patients obtain partial pain relief from current neuropathic pain treatment options, assuring that they receive new medications for this complex disorder is imperative. However, the authors believe that future studies should not only focus on the discovery of new compounds. Efforts should also be devoted to developing a better understanding of the therapeutic challenges of neuropathic pain, as well as to designing and carrying out clinical trials in collaboration between pharmaceutical companies, physicians and scientists. Furthermore, the authors believe that other outcome measures besides pain intensity, such as functionality and quality of life, should receive more attention.
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Affiliation(s)
- Nebojsa Nick Knezevic
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL 60657 , USA.,b College of Medicine , University of Illinois , Chicago , IL 60612 , USA
| | - Nenad Cicmil
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL 60657 , USA
| | - Ivana Knezevic
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL 60657 , USA
| | - Kenneth D Candido
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL 60657 , USA.,b College of Medicine , University of Illinois , Chicago , IL 60612 , USA
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Peak TC, Yafi FA, Sangkum P, Hellstrom WJG. Emerging drugs for the treatment of erectile dysfunction. Expert Opin Emerg Drugs 2015; 20:263-75. [PMID: 25740087 DOI: 10.1517/14728214.2015.1021682] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Erectile dysfunction adversely affects the lives of millions of men, and is the most commonly treated sexual disorder today. The erectile process has been extensively investigated, with major advances made in elucidating many of the complex molecular pathways involved. These advances have allowed researchers to design and study drug formulations that target various aspects of this complex process. The initial culmination of this research was the introduction of phosphodiesterase 5-inhibitors. While effective in many patients, they are not satisfactory for all afflicted men. As a result, researchers are developing novel drugs that target different molecular pathways. AREAS COVERED The paper will review these pathways, and the potential agents that target them. More specifically, first dopaminergic and melanocortin receptor agonists that act centrally will be covered. Then, the paper will examine the "second-generation" phosphodiesterase 5-inhibitors, soluble guanylate cyclases, rho-kinase inhibitors, and maxi-k channel activators that act peripherally. EXPERT OPINION Most of these novel drugs have yet to reach Phase III studies. However, it is likely that in years to come, patients will be selectively treated with these novel agents as a monotherapy or in combination with others acting in a synergistic manner.
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Affiliation(s)
- Taylor C Peak
- Tulane University School of Medicine , New Orleans, LA , USA
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Choi WS, Kwon OS, Cho SY, Paick J, Kim SW. Effect of Chronic Administration of PDE5 Combined with Glycemic Control on Erectile Function in Streptozotocin‐Induced Diabetic Rats. J Sex Med 2015; 12:600-10. [DOI: 10.1111/jsm.12752] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nat Rev Urol 2014; 11:622-8. [PMID: 25311680 DOI: 10.1038/nrurol.2014.278] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA-Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA-ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA-ROCK signalling and inhibition suggest that the RhoA-ROCK pathway could prove to be a new therapeutic target for the treatment of ED.
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Goodman JR, Chandna A, Borch C. Does accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) ensure greater compliance with animal welfare laws? J APPL ANIM WELF SCI 2014; 18:82-91. [PMID: 25174609 DOI: 10.1080/10888705.2014.948625] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Accreditation of nonhuman animal research facilities by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) is widely considered the "gold standard" of commitment to the well being of nonhuman animals used in research. AAALAC-accredited facilities receive preferential treatment from funding agencies and are viewed favorably by the general public. Thus, it bears investigating how well these facilities comply with U.S. animal research regulations. In this study, the incidences of noncompliance with the Animal Welfare Act (AWA) at AAALAC-accredited facilities were evaluated and compared to those at nonaccredited institutions during a period of 2 years. The analysis revealed that AAALAC-accredited facilities were frequently cited for AWA noncompliance items (NCIs). Controlling for the number of animals at each facility, AAALAC-accredited sites had significantly more AWA NCIs on average compared with nonaccredited sites. AAALAC-accredited sites also had more NCIs related to improper veterinary care, personnel qualifications, and animal husbandry. These results demonstrate that AAALAC accreditation does not improve compliance with regulations governing the treatment of animals in laboratories.
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Affiliation(s)
- Justin R Goodman
- a Laboratory Investigations Department , People for the Ethical Treatment of Animals , Norfolk , Virginia
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20
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Sezen SF, Lagoda G, Musicki B, Burnett AL. Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: a role for neuronal ROCK. J Sex Med 2014; 11:2164-71. [PMID: 24919622 DOI: 10.1111/jsm.12613] [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] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The pathogenesis of diabetic erectile dysfunction (ED) includes neuropathy, but the molecular basis for neurogenic ED is incompletely understood. The RhoA/ROCK pathway has been implicated in diabetic neuropathy and in ED, but its role in diabetic neurogenic ED is not known. AIMS The aim of this study was to determine whether hydroxyl fasudil, a ROCK inhibitor, affects diabetic neuropathy-related ED. METHODS Type 1 diabetes mellitus was induced in male rats by streptozotocin (75 mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10 mg/kg/day, intraperitoneally) or vehicle, for 4 weeks. Age-matched control, nondiabetic, rats were treated intraperitoneally for 4 weeks with saline. At week 12, after a 2 day washout, neuro-stimulated erectile function was evaluated. Major pelvic ganglia (MPG) were collected for Western blot analysis of RhoA, ROCK-1, ROCK-2, phospho (P)-AKT (Ser(473) ), and P-phosphatase and tensin homolog (P-PTEN) (Ser(380) /Thr(382/383) ). MAIN OUTCOME MEASURES Effect of ROCK inhibitor hydroxyl fasudil on erectile function and ROCK/P-AKT/P-PTEN pathway in the MPG of diabetic rats. RESULTS Erectile response was significantly (P < 0.05) reduced in diabetic rats compared with nondiabetic rats and was preserved (P < 0.05) in diabetic rats treated with hydroxyl fasudil. In diabetic rats, RhoA and ROCK-2 protein expressions in MPG were increased (P < 0.05) and remained increased in hydroxyl fasudil-treated rats. P-AKT (Ser(473) ) expression was decreased (P < 0.05), whereas P-PTEN (Ser(380) /Thr(382/383) ) expression was increased (P < 0.05) in MPG of diabetic rats compared with nondiabetic rats, and both were reversed (P < 0.05) in diabetic rats treated with hydroxyl fasudil. CONCLUSION Improved erectile function and restored P-AKT and P-PTEN in the MPG with hydroxyl fasudil treatment suggest the role of Rho signaling via PTEN/AKT pathway in neurogenic diabetic ED.
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Affiliation(s)
- Sena F Sezen
- The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
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Decaluwé K, Pauwels B, Boydens C, Van de Voorde J. Treatment of erectile dysfunction: new targets and strategies from recent research. Pharmacol Biochem Behav 2013; 121:146-57. [PMID: 24291648 DOI: 10.1016/j.pbb.2013.11.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 11/18/2013] [Indexed: 12/15/2022]
Abstract
In recent years, research on penile erection has increasingly been centered on the molecular mechanisms involved. Major progress has been made in the field and at present a whole number of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex process of erection. This knowledge has led to the discovery of several new therapeutic targets and multiple medical approaches for the treatment of erectile dysfunction (ED). This review focuses on the progress made in this field within the last few years.
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Affiliation(s)
- K Decaluwé
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - B Pauwels
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - C Boydens
- Department of Pharmacology, Ghent University, Ghent, Belgium
| | - J Van de Voorde
- Department of Pharmacology, Ghent University, Ghent, Belgium.
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Targeting of Rho kinase ameliorates impairment of diabetic endothelial function in intrarenal artery. Int J Mol Sci 2013; 14:20282-98. [PMID: 24129169 PMCID: PMC3821615 DOI: 10.3390/ijms141020282] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 07/11/2013] [Accepted: 09/09/2013] [Indexed: 02/04/2023] Open
Abstract
Endothelial dysfunction in kidney vasculature is the initial and key element for nephropathy in diabetes mellitus. Accumulating evidence suggests the protective role of Rho kinase inhibitors in endothelial dysfunction via modulating eNOS activity and NO production. However, the role of Rho kinase in diabetes-related endothelial dysfunction in kidney vasculature and the relevant mechanisms remain unknown. We assessed whether pharmacological inhibition of Rho kinase attenuates endothelial dysfunction in intrarenal arteries from type 1 diabetic rats. Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney. Fasudil treatment showed no improvement in diabetes-related abnormality in metabolic indices, but it significantly ameliorated endothelial dysfunction in intrarenal arteries and lessened the mesangial matrix expansion in the kidney cortex. Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor. In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.
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Yin Y, Lin L, Ruiz C, Khan S, Cameron MD, Grant W, Pocas J, Eid N, Park H, Schröter T, Lograsso PV, Feng Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J Med Chem 2013; 56:3568-81. [PMID: 23570561 DOI: 10.1021/jm400062r] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (∼7 mmHg). (22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered.
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Affiliation(s)
- Yan Yin
- Medicinal Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States
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Lasker GF, Pankey EA, Allain AV, Murthy SN, Stasch JP, Kadowitz PJ. The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat. Urology 2013; 81:465.e7-14. [PMID: 23374844 DOI: 10.1016/j.urology.2012.10.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 09/11/2012] [Accepted: 10/24/2012] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To investigate the effects of the selective Rho-associated protein kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat. METHODS The effect of intracavernosal (i.c.) injections of azaindole-1 on change in intracavernous pressure (ICP), ICP/mean arterial pressure (MAP), area under the curve (AUC), and response duration were investigated in the anesthetized rat under control conditions and when nonadrenergic noncholinergic neurotransmission and cholinergic function or soluble guanylyl cyclase (sGC) were inhibited or after cavernosal nerve crush injury. RESULTS The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long-lasting at the highest doses studied compared with the prototypical ROCK inhibitor fasudil. Erectile responses were not altered by 7-nitroindazole and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside, indicating that they were independent of an action on sGC. The erectile response to i.c. injections of azaindole-1 or Y-27632, which was reported to be NO/cyclic guanosine monophosphate-dependent, was not attenuated after cavernosal nerve crush injury. CONCLUSION The present studies indicate that azaindole-1 has long-lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.
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Affiliation(s)
- George F Lasker
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA
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