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Ishihara Y, Ando M, Goto Y, Kotani S, Watanabe N, Nakatani Y, Ishii S, Miyamoto N, Mano Y, Ishikawa Y. A novel selective phosphodiesterase 9 inhibitor, irsenontrine (E2027), enhances GluA1 phosphorylation in neurons and improves learning and memory via cyclic GMP elevation. Neuropharmacology 2025; 273:110428. [PMID: 40147639 DOI: 10.1016/j.neuropharm.2025.110428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/22/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
Phosphodiesterase 9 (PDE9) plays a critical role in synaptic plasticity and cognitive function by modulating cyclic GMP (cGMP). Many reports have shown that PDE9 inhibition improves cognitive function and synaptic plasticity in rodents. Several studies have found that the NO/cGMP/PKG pathway is downregulated in patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) and in older individuals. A PDE9 inhibitor could therefore be a potential therapeutic approach for improving cognitive dysfunction in dementia, including in AD and DLB. We previously discovered a novel PDE9 inhibitor, irsenontrine (E2027). In the current study, irsenontrine showed highly selective affinity for PDE9 with more than 1800-fold selectivity over other PDEs. Irsenontrine maleate significantly increased intracellular cGMP levels in rat cortical primary neurons, and phosphorylation of AMPA receptor subunit GluA1 was induced following cGMP elevation. Oral administration of irsenontrine significantly upregulated cGMP levels in the hippocampus and cerebrospinal fluid (CSF) of naïve rats, and a novel object recognition test showed that irsenontrine administration also significantly improved learning and memory. The effects of irsenontrine were confirmed in rats treated with Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), a model of learning and memory impairment due to downregulation of the cGMP pathway. l-NAME downregulated cGMP in the CSF and hippocampus and impaired novel object recognition, but oral administration of irsenontrine clearly attenuated these phenotypes. These results indicate that irsenontrine improves learning and memory via the elevation of cGMP levels, and they strongly suggest that irsenontrine could be a novel therapeutic approach against cognitive dysfunction.
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Affiliation(s)
- Yasuharu Ishihara
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan; Laboratory of Genomics-based Drug Discovery, Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, Degree Program in Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
| | - Mai Ando
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
| | - Yasuaki Goto
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
| | - Sadaharu Kotani
- Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, Japan
| | - Naoto Watanabe
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
| | - Yosuke Nakatani
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
| | - Satoko Ishii
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
| | - Norimasa Miyamoto
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan; Laboratory of Genomics-based Drug Discovery, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan
| | - Yuji Mano
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan; Laboratory of Genomics-based Drug Discovery, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan
| | - Yukio Ishikawa
- Deep Human Biology Learning, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan
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Zarante Bahamón AM, Navarro Marroquin S, Suarez-Obando F, Ramón Gómez JL. Recomendaciones de manejo de la hiperamonemia en neonatos. UNIVERSITAS MÉDICA 2023. [DOI: 10.11144/javeriana.umed63-4.rmhn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
La hiperamonemia se define como el aumento de las concentraciones de amonio en el plasma, de forma aguda o crónica. Frecuentemente, se presenta en diversos tipos de errores innatos del metabolismo, enfermedades que deben diagnosticarse y manejarse de manera inmediata y adecuada, debido a que el retraso en su manejo genera secuelas neurológicas graves y permanentes, así como desenlaces fatales. El objetivo del artículo es aportar herramientas al clínico para la sospecha, el abordaje diagnóstico y el manejo del recién nacido con hiperamonemia primaria, teniendo en cuenta la correlación entre fisiopatología, etiología, aproximación clínica y de laboratorio, así como recomendaciones de manejo farmacológico y no farmacológico.
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Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int J Mol Sci 2021; 22:10372. [PMID: 34638713 PMCID: PMC8508925 DOI: 10.3390/ijms221910372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/10/2023] Open
Abstract
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Markus Grosse Perdekamp
- Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
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El-Baz FK, Elgohary R, Salama A. Amelioration of Hepatic Encephalopathy Using Dunaliella salina Microalgae in Rats: Modulation of Hyperammonemia/TLR4. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8843218. [PMID: 33855084 PMCID: PMC8021475 DOI: 10.1155/2021/8843218] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 02/27/2021] [Accepted: 03/19/2021] [Indexed: 12/28/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disease that is developed as a complication of both acute and chronic liver failure affecting psychomotor dysfunction, memory, and concentration. This study is aimed at evaluating the therapeutic effects of Dunaliella salina (D. salina) microalgae in thioacetamide- (TAA-) induced HE in rats. HE was induced by TAA (200 mg/kg; i.p.) for three successive days. Forty male Wister albino rats were divided into 4 groups; the first group was served as a normal, and the second group was injected with TAA and served as TAA control. The third and fourth groups were administered D. salina (100 and 200 mg/kg; p.o.), respectively, after TAA injection for 7 days. The behavioral and biochemical markers as well as histological aspects of HE were estimated. This study revealed that TAA caused behavioral changes, oxidative stress, neuroinflammation, nuclear pyknosis, and neurons degeneration. D. salina improved liver function and decreased oxidative stress and inflammatory mediator as TLR4 protein expression. Also, D. salina elevated HSP-25 and IGF-1 as well as improved brain histopathological alterations. In conclusion, D. salina exerted a therapeutic potential against HE via its antioxidant, antiinflammatory and cytoprotective effects.
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Affiliation(s)
- Farouk K. El-Baz
- Plant Biochemistry Department, National Research Centre (NRC), 33 El Buhouth St., Dokki, Cairo 12622, Egypt
| | - Rania Elgohary
- Narcotics, Ergogenics and Poisons Department, National Research Centre (NRC), 33 El Buhouth St., Dokki, Cairo 12622, Egypt
| | - Abeer Salama
- Pharmacology Department, National Research Centre (NRC), 33 El Buhouth St., Dokki, Cairo 12622, Egypt
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Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
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França MER, Ramos RKLG, Oliveira WH, Duarte-Silva E, Araújo SMR, Lós DB, Peixoto CA. Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy. Toxicol Appl Pharmacol 2019; 379:114673. [PMID: 31323263 DOI: 10.1016/j.taap.2019.114673] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/10/2019] [Accepted: 07/15/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Tadalafil displays important neuroprotective effects in experimental models of neurodegenerative diseases, however its mechanisms of action remain poorly understood. The aim of the present study was to investigate the action of Tadalafil on learning and memory, neuroinflammation, glial cell activation and neuroprotection in the experimental model of hepatic encephalopathy (HE) induced by Thioacetamide (TAA) in mice. METHODS Mice received intraperitoneal injections of TAA, for 3 consecutive days, reaching the final dose of 600 mg/kg. Tadalafil 15 mg/kg body weight was administered by gavage during 15 days after TAA induction. Mice underwent a Barnes maze for learning and memory evaluation. RESULTS Animals with hepatic encephalopathy showed reduced learning and spatial memory in the Barnes Maze, presented astrocyte and microglia activation and increased neuroinflammatory markers such as TNF-α, IL-1β, IL-6, p-p38, p-ERK and p-NF-kB. In addition, the signaling pathway PKA/PKG/CREB/BDNF/NeuN/synaptophysin and glutamate receptors were deregulated by TAA. Tadalafil treatment regulated the inflammation signaling pathways restoring learning and spatial memory. CONCLUSION Tadalafil significantly reduced neuroinflammation, promoted neuroprotection and plasticity, regulated the expression of hippocampal glutamate receptor and restored spatial learning ability and memory.
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Affiliation(s)
- Maria Eduarda Rocha França
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil.
| | | | - Wilma Helena Oliveira
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil
| | - Eduardo Duarte-Silva
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/ Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil
| | - Shyrlene Meyre Rocha Araújo
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil
| | - Deniele Bezerra Lós
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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Kosenkov AM, Gaidin SG, Sergeev AI, Teplov IY, Zinchenko VP. Fast changes of NMDA and AMPA receptor activity under acute hyperammonemia in vitro. Neurosci Lett 2018; 686:80-86. [PMID: 30195972 DOI: 10.1016/j.neulet.2018.08.054] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 08/18/2018] [Indexed: 12/14/2022]
Abstract
It was established in experiments on cell cultures of neurons and astrocytes that ammonium ions at concentrations of 4-8 mM cause hyperexcitation of the neuronal network, as a result of which there is a disturbance of calcium homeostasis, which can lead to the death of neurons. In the present study, we investigated the effect of toxic doses of ammonium (8 mM NH4Cl) on the activity of NMDA and AMPA receptors and the role of these receptors in spontaneous synchronous activity (SSA). In a control experiment in the absence of NH4Cl, SSA is not suppressed by NMDA receptor inhibitors, but is suppressed by AMPA receptor antagonists. In the presence of toxic doses of NH4Cl, SSA is completely inhibited by NMDA receptor inhibitors in 63% of neurons and by AMPA receptor inhibitors in 33% of neurons. After short-term applications of toxic doses of ammonium, the amplitude of the Ca2+ response to 10 μM NMDA increases, and decreases in response to 500 nM FW (agonist of AMPA receptors). NMDA receptor blocker MK-801 (20 μM), competitive antagonist D-AP5 (10 μM) and competitive AMPA receptor antagonist NBQX (2 μM) abolished the activating ammonium mediated effect on the NMDA receptors while only MK-801, but not NBQX, abolished the inhibiting ammonium mediated effect on AMPA receptors. These data indicate that under acute hyperammonemia, the activity of NMDA receptors increases, while the activity of AMPA receptors decreases. This phenomenon could explain such a wide range of toxic effects of ammonium ions mediated by NMDA receptors.
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Affiliation(s)
- Artem M Kosenkov
- Institute of Cell Biophysics, RAS, Pushchino, Moscow Region, 142290, Russia.
| | - Sergei G Gaidin
- Institute of Cell Biophysics, RAS, Pushchino, Moscow Region, 142290, Russia
| | | | - Ilia Y Teplov
- Institute of Cell Biophysics, RAS, Pushchino, Moscow Region, 142290, Russia
| | - Valery P Zinchenko
- Institute of Cell Biophysics, RAS, Pushchino, Moscow Region, 142290, Russia
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Murad HA, Gazzaz ZJ, Ali SS, Ibraheem MS. Candesartan, rather than losartan, improves motor dysfunction in thioacetamide-induced chronic liver failure in rats. ACTA ACUST UNITED AC 2017; 50:e6665. [PMID: 28953991 PMCID: PMC5609604 DOI: 10.1590/1414-431x20176665] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 07/24/2017] [Indexed: 12/16/2022]
Abstract
Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg-1·day-1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg-1·day-1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower "off-rate" from angiotensin-II receptors. Clinical trials are recommended.
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Affiliation(s)
- H A Murad
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Z J Gazzaz
- Department of Medicine, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - S S Ali
- Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - M S Ibraheem
- Department of Microbiology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
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Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity. Neurochem Res 2016; 42:721-736. [PMID: 27286679 DOI: 10.1007/s11064-016-1966-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 05/20/2016] [Accepted: 05/24/2016] [Indexed: 12/12/2022]
Abstract
Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH4+ and K+ in their effects on the Na+,K+-ATPase and the Na+,K+, 2 Cl- and water transporter NKCC1. Stimulation of the Na+,K+-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na+,K+-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.
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Tenorio-Laranga J, Montoliu C, Urios A, Hernandez-Rabaza V, Ahabrach H, García-Horsman JA, Felipo V. The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients. J Neuroinflammation 2015; 12:183. [PMID: 26420028 PMCID: PMC4589196 DOI: 10.1186/s12974-015-0404-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 09/23/2015] [Indexed: 12/22/2022] Open
Abstract
Background Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. Methods PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. Results In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. Conclusions These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response.
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Affiliation(s)
- Jofre Tenorio-Laranga
- Real-time Imaging Laboratory, Divisions of Pharmacology and Toxicology and Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, PO Box 56, Helsinki, 00014, Finland.
| | - Carmina Montoliu
- Fundación Investigación Hospital Clínico Universitario, INCLIVA, Valencia, Spain.
| | - Amparo Urios
- Fundación Investigación Hospital Clínico Universitario, INCLIVA, Valencia, Spain.
| | - Vicente Hernandez-Rabaza
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain.
| | - Hanan Ahabrach
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain.
| | - J Arturo García-Horsman
- Real-time Imaging Laboratory, Divisions of Pharmacology and Toxicology and Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, PO Box 56, Helsinki, 00014, Finland.
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain.
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Mondal P, Trigun SK. Bacopa monnieri Extract (CDRI-08) Modulates the NMDA Receptor Subunits and nNOS-Apoptosis Axis in Cerebellum of Hepatic Encephalopathy Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2015; 2015:535013. [PMID: 26413124 PMCID: PMC4564645 DOI: 10.1155/2015/535013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 02/09/2015] [Accepted: 02/09/2015] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE), characterized by impaired cerebellar functions during chronic liver failure (CLF), involves N-methyl-D-aspartate receptor (NMDAR) overactivation in the brain cells. Bacopa monnieri (BM) extract is a known neuroprotectant. The present paper evaluates whether BM extract is able to modulate the two NMDAR subunits (NR2A and NR2B) and its downstream mediators in cerebellum of rats with chronic liver failure (CLF), induced by administration of 50 mg/kg bw thioacetamide (TAA) i.p. for 14 days, and in the TAA group rats orally treated with 200 mg/kg bw BM extract from days 8 to 14. NR2A is known to impart neuroprotection and that of NR2B induces neuronal death during NMDAR activation. Neuronal nitric oxide synthase- (nNOS-) apoptosis pathway is known to mediate NMDAR led excitotoxicity. The level of NR2A was found to be significantly reduced with a concomitant increase of NR2B in cerebellum of the CLF rats. This was consistent with significantly enhanced nNOS expression, nitric oxide level, and reduced Bcl2/Bax ratio. Moreover, treatment with BM extract reversed the NR2A/NR2B ratio and also normalized the levels of nNOS-apoptotic factors in cerebellum of those rats. The findings suggest modulation of NR2A and NR2B expression by BM extract to prevent neurochemical alterations associated with HE.
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Affiliation(s)
- Papia Mondal
- Biochemistry Section, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | - Surendra Kumar Trigun
- Biochemistry Section, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
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Jördens MS, Keitel V, Karababa A, Zemtsova I, Bronger H, Häussinger D, Görg B. Multidrug resistance-associated protein 4 expression in ammonia-treated cultured rat astrocytes and cerebral cortex of cirrhotic patients with hepatic encephalopathy. Glia 2015; 63:2092-2105. [PMID: 26102310 DOI: 10.1002/glia.22879] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 06/08/2015] [Indexed: 12/30/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome frequently accompanying liver cirrhosis and reflects the clinical manifestation of a low grade cerebral edema associated with cerebral oxidative/nitrosative stress. The multidrug resistance-associated protein (Mrp) 4 is an export pump which transports metabolites that were recently suggested to play a major role in the pathogenesis of HE such as neurosteroids and cyclic nucleotides. We therefore studied Mrp4 expression changes in ammonia-exposed cultured astrocytes and postmortem human brain samples of cirrhotic patients with HE. NH4 Cl increased Mrp4 mRNA and protein levels in astrocytes in a dose- and time-dependent manner up to threefold after 72 h of exposure and concurrently inhibited N-glycosylation of Mrp4 protein. Upregulation of Mrp4 mRNA and protein as well as impaired N-glycosylation of Mrp4 protein by ammonia were sensitive towards the glutamine-synthetase inhibitor l-methionine-S-sulfoximine and were not induced by CH3 NH3 Cl (5 mmol/L). Upregulation of Mrp4 mRNA required ammonia-induced activation of nitric oxide synthases or NADPH oxidase and p38MAPK -dependent activation of PPARα. Inhibition of Mrp4 by ceefourin 1 synergistically enhanced both, inhibition of astrocyte proliferation as well as transcription of the oxidative stress surrogate marker heme oxygenase 1 by forskolin (10 µmol/L, 72 h) or NH4 Cl (5 mmol/L, 72 h) in cultured rat astrocytes. Increased Mrp4 mRNA and protein levels were also found in postmortem brain samples from patients with liver cirrhosis with HE but not in those without HE. The data show that Mrp4 is upregulated in HE, which may be relevant for the handling of neurosteroids and cyclic nucleotides in response to ammonia. GLIA 2015;63:2092-2105.
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Affiliation(s)
- Markus S Jördens
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Ayse Karababa
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Irina Zemtsova
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Holger Bronger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
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Dhanda S, Sandhir R. Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy. Behav Brain Res 2015; 286:222-35. [PMID: 25639545 DOI: 10.1016/j.bbr.2015.01.042] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 01/17/2015] [Accepted: 01/22/2015] [Indexed: 02/06/2023]
Abstract
The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE.
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Affiliation(s)
- Saurabh Dhanda
- Department of Biochemistry, Basic Medical Science Block, Panjab University, Chandigarh 160014, India
| | - Rajat Sandhir
- Department of Biochemistry, Basic Medical Science Block, Panjab University, Chandigarh 160014, India.
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Mondal P, Trigun SK. Pannexin1 as a novel cerebral target in pathogenesis of hepatic encephalopathy. Metab Brain Dis 2014; 29:1007-15. [PMID: 24807590 DOI: 10.1007/s11011-014-9556-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 04/28/2014] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) represents a nervous system disorder caused due to liver dysfunction. HE is broadly classified as acute/overt and moderate-minimal HE. Since HE syndrome severely affects quality of life of the patients and it may be life threatening, it is important to develop effective therapeutic strategy against HE. Mainly ammonia neurotoxicity is considered accountable for HE. Increased level of ammonia in the brain activates glutamate-NMDA (N-methyl-D-aspartate) receptor (NMDAR) pathway leading to Ca(2+) influx, energy deficit and oxidative stress in the post synaptic neurons. Moreover, NMDAR blockage has been found to be a poor therapeutic option, as this neurotransmitter receptor plays important role in maintaining normal neurophysiology of the brain. Thus, searching new molecular players in HE pathogenesis is of current concern. There is an evolving concept about roles of the trans-membrane channels in the pathogenesis of a number of neurological complications. Pannexin1 (Panx1) is one of them and has been described to be implicated in stroke, epilepsy and ischemia. Importantly, the pathogenesis of these complications relates to some extent with NMDAR over activation. Thus, it is speculated that HE pathogenesis might also involve Panx1. Indeed, some recent observations in the animal models of HE provide support to this argument. Since opening of Panx1 channel is mostly associated with the neuronal dysfunctions, down regulation of this channel could serve as a relevant therapeutic strategy without producing any serious side effects. In the review article an attempt has been made to summarize the current information on implication of Panx1 in the brain disorders and its prospects for being examined as pharmacological target in HE pathogenesis.
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Affiliation(s)
- Papia Mondal
- Biochemistry Section Centre of Advanced Study in Zoology, Banaras Hindu university, Varanasi, 221005, India
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Wang XY, Xie RX, Zhang JG, Zhang DK. Role of neurosteroids in hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2014; 22:5086-5091. [DOI: 10.11569/wcjd.v22.i33.5086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric manifestation of chronic or acute liver disease. Neurosteroids are synthesized from cholesterol and its precursors by glial cells, oligodendrocytes and neurons in the brain. The mechanisms by which neurosteroids affect brain function may involve both genetic and non-genetic effects. On one hand, neurosteroids bind and modulate different types of neuronal membrane receptors, including gamma-amino butyric acid-A receptor (GABA-A), N-methyl-D-aspartic acid receptor (NMDA), 5-hydroxytryptamine 3 (5-HT3) and opioid receptors which have been showed to be involved in HE. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression. Of note, neurosteroids play a role in the pathogenesis of HE through inhibiting long-term potentiation. Neurosteroids might provide a new avenue for HE treatment.
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Zhang SN, Li XZ, wang Y, zhang N, Yang ZM, Liu SM, Lu F. Neuroprotection or neurotoxicity? new insights into the effects of Acanthopanax senticosus harms on nervous system through cerebral metabolomics analysis. JOURNAL OF ETHNOPHARMACOLOGY 2014; 156:290-300. [PMID: 25223591 DOI: 10.1016/j.jep.2014.08.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 08/30/2014] [Accepted: 08/31/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acanthopanax senticosus harms (AS), also called "Ciwujia" in Chinese and "Siberian ginseng" in the Siberian Taiga region, is the herb used in traditional medicinal systems in China and Russia, which has been applied to the treatment of various nervous and cerebrovascular diseases, such as depression, mental fatigue, and transient global cerebral ischemia. The previous research works usually tended to focus on the neuroprotective effects of AS, but ignored its additional effects that are not entirely beneficial to the nervous system. Therefore, to discover the potential intervention targets of AS and evaluate their roles in the nervous system are the urgent problems. MATERIALS AND METHODS Ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods were integrated to investigate the metabolic profiles of AS-treated rats. The analysis of possible pathways influenced by AS was performed by ingenuity pathway analysis (IPA) with MetPA. RESULTS Treated with AS, 16 modulated metabolites were identified and considered as the potential intervention targets of AS, out of which 3 metabolites had protective effects on the nervous system, whereas 7 metabolites showed the neurotoxicity. CONCLUSION These results may reveal that the effects of AS on nervous system had two sides, and it could not only exert the neuroprotection but also produce some potential neurotoxicity.
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Affiliation(s)
- Shuai-nan Zhang
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
| | - Xu-zhao Li
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
| | - Yu wang
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
| | - Na zhang
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
| | - Zhi-ming Yang
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
| | - Shu-min Liu
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China; Drug Safety Evaluation Center, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China.
| | - Fang Lu
- Chinese Medicine Toxicological Laboratory, Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China.
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Felipo V, Urios A, Giménez-Garzó C, Cauli O, Andrés-Costa MJ, González O, Serra MA, Sánchez-González J, Aliaga R, Giner-Durán R, Belloch V, Montoliu C. Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests. World J Gastroenterol 2014; 20:11815-11825. [PMID: 25206287 PMCID: PMC4155373 DOI: 10.3748/wjg.v20.i33.11815] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 01/23/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy.
METHODS: Blood flow (BF) was analyzed by arterial spin labeling (ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy (MHE). Images were collected using a 3 Tesla MR scanner (Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score (PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins (IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated.
RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere (P = 0.03) and vermis (P = 0.012) and reduced in occipital lobe (P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE (P = 0.02). Bimanual coordination was impaired in patients without MHE (P = 0.05) and much more in patients with MHE (P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE (P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE (P < 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A (NCT-A), B (NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitric oxide (NO) metabolites. BF in vermis cerebellar also correlates with NO metabolites and with 3-nitrotyrosine. IL-18 in plasma correlates with BF in thalamus and occipital lobe.
CONCLUSION: Non invasive BF determination in cerebellum using ASL may detect MHE earlier than the PHES. Altered NO-cGMP pathway seems to be associated to altered BF in cerebellum.
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Sheen JM, Chen YC, Tain YL, Huang LT. Increased circulatory asymmetric dimethylarginine and multiple organ failure: bile duct ligation in rat as a model. Int J Mol Sci 2014; 15:3989-4006. [PMID: 24603538 PMCID: PMC3975379 DOI: 10.3390/ijms15033989] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/04/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages.
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Affiliation(s)
- Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Yu-Chieh Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
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Cauli O, Llansola M, Agustí A, Rodrigo R, Hernández-Rabaza V, Rodrigues TB, López-Larrubia P, Cerdán S, Felipo V. Cerebral oedema is not responsible for motor or cognitive deficits in rats with hepatic encephalopathy. Liver Int 2014; 34:379-87. [PMID: 23869990 DOI: 10.1111/liv.12258] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 06/12/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Low-grade cytotoxic oedema is considered a main contributor to the neurological (motor and cognitive) alterations in patients with hepatic encephalopathy (HE). This assumption is mainly based on studies with cultured astrocytes treated with very large ammonia concentrations or with animal models of acute liver failure with strong HE. However, the possible contribution of cerebral oedema (vasogenic or cytotoxic) to cognitive or motor alterations in chronic mild HE has not been demonstrated. The aim of this work was to assess whether cerebral oedema contributes to cognitive and/or motor alterations in rats with chronic mild HE. METHODS Motor activity and coordination and different types of learning and memory were assessed in rats with porta-caval shunts (PCS). Brain oedema was assessed by gravimetry in cerebellum and cortex and apparent diffusion coefficient (ADC) by magnetic resonance in 16 areas. RESULTS Four weeks after surgery, PCS rats show reduced motor activity and coordination, impaired ability to learn a conditional discrimination task in the Y maze and reduced spatial memory in the Morris water maze. PCS rats did not show increased brain water content at 4 or 10 weeks or changes in ADC at 4 weeks. At 10 weeks, increased ADC in some areas is compatible with vasogenic but not cytotoxic oedema. CONCLUSION Cerebral oedema is not involved in motor and cognitive alterations in rats (and likely in humans) with mild HE. Proper understanding of the mechanisms responsible for the neurological alterations in HE is necessary to design efficient treatments.
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Affiliation(s)
- Omar Cauli
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
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20
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Singh S, Trigun S. Low grade cirrhosis induces cognitive impairment and motor dysfunction in rats: Could be a model for minimal hepatic encephalopathy. Neurosci Lett 2014; 559:136-40. [DOI: 10.1016/j.neulet.2013.11.058] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/27/2013] [Accepted: 11/30/2013] [Indexed: 01/16/2023]
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Bukanova JV, Solntseva EI, Kondratenko RV, Skrebitsky VG. Glycine receptor in hippocampal neurons as a target for action of extracellular cyclic nucleotides. Neurosci Lett 2013; 561:58-63. [PMID: 24373992 DOI: 10.1016/j.neulet.2013.12.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 12/10/2013] [Accepted: 12/17/2013] [Indexed: 11/17/2022]
Abstract
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are well known intracellular second messengers. At present study, we describe the effects of extracellularly applied cAMP and cGMP on glycine-induced chloride currents (I(Gly)) in isolated rat hippocampal pyramidal neurons. 50 or 500 μM glycine was applied for 600 ms with 1 min intervals. cAMP and cGMP were co-applied with glycine. We found that both cAMP and cGMP rapidly, reversibly and in a dose-dependent manner accelerated the I(Gly) desensitization. The effect was more prominent on I(Gly) induced by 500 μM than by 50 μM glycine. Dose-response curves were constructed in the 0.1-100,000 nM range of cAMP and cGMP concentrations. They demonstrate that threshold concentration of both compounds was about 1 nM and maximal effect was manifested at 100 nM. When cAMP and cGMP were added to the recording pipette, their extracellular application caused the effects similar to those obtained with normal intracellular medium. The effects of cyclic nucleotides remained unchanged in the presence of the antagonist of adenosine receptors in extracellular solution, and the agonist of adenosine receptors did not mimic the effect of cyclic nucleotides. The changes in the decay kinetics were equally pronounced at negative and positive membrane potentials. When co-administered 1 nM cAMP and 1 nM cGMP caused a weaker effect than either of the compounds alone which suggests a negative interaction between binding sites for cAMP and cGMP. This work describes a novel mode of action of cyclic nucleotides, namely, the modulation of GlyRs functions from extracellular side.
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Affiliation(s)
- Julia V Bukanova
- Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia
| | - Elena I Solntseva
- Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia.
| | - Rodion V Kondratenko
- Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia
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Chepkova AN, Sergeeva OA, Haas HL. Alterations of corticostriatal plasticity by ammonium and rescue by green tea polyphenols. Arch Biochem Biophys 2013; 536:176-82. [DOI: 10.1016/j.abb.2013.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/31/2013] [Accepted: 02/05/2013] [Indexed: 01/22/2023]
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Llansola M, Montoliu C, Cauli O, Hernández-Rabaza V, Agustí A, Cabrera-Pastor A, Giménez-Garzó C, González-Usano A, Felipo V. Chronic hyperammonemia, glutamatergic neurotransmission and neurological alterations. Metab Brain Dis 2013; 28:151-4. [PMID: 23010935 DOI: 10.1007/s11011-012-9337-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 09/19/2012] [Indexed: 02/01/2023]
Abstract
This mini-review focus on our studies on alterations in glutamatergic neurotransmission and their role in neurological alterations in rat models of chronic hyperammonemia and hepatic encephalopathy (HE). Hyperammonemia impairs the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum, which is responsible for reduced learning ability. We studied the underlying mechanisms and designed treatments to restore the pathway and learning. This was achieved by treatment with: phosphodiesterase 5 inhibitors, cGMP, anti-inflammatories (ibuprofen), p38 inhibitors or GABAA receptor antagonists (bicuculline). Hyperammonemia alters signal transduction associated to metabotropic glutamate receptors (mGluRs). Hypokinesia in hyperammonemia and HE is due to increased extracellular glutamate and mGluR1 activation in substantia nigra; blocking this receptor restores motor activity. The motor responses to mGluRs activation in nucleus accumbens (NAcc) are altered in hyperammonemia and HE, with reduced dopamine and increased glutamate release. This leads to activation of different neuronal circuits and enhanced motor responses. These studies show that altered responses to activation of NMDA receptors and mGluRs play essential roles in cognitive and motor alterations in hyperammonemia and HE and provide new treatments restoring cognitive and motor function.
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Affiliation(s)
- Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Eduardo Primo Yufera, 3. 46012 Valencia, Spain
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Jover-Cobos M, Noiret L, Sharifi Y, Jalan R. Ornithine phenylacetate revisited. Metab Brain Dis 2013; 28:327-31. [PMID: 23456516 DOI: 10.1007/s11011-013-9391-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 02/19/2013] [Indexed: 12/12/2022]
Abstract
In patients with liver failure hyperammonemia is associated with the development of hepatic encephalopathy (HE) and immune impairment. Treatment of hyperammonemia is an unmet clinical need. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. This review describes the mechanism of action of OP and its effect on plasma ammonia levels, brain function and inflammation of OP in both acute and chronic liver failure. Ammonia levels could shown to be reduced for up to 24 h in animal models until 120 h in patients with repeated dosing of the drug. Reduction of plasma ammonia levels is due to the stimulation of ammonia removal in the form of glutamine (through glutamine synthetase), the direct excretion of ammonia in the form phenylacetylglutamine and to a normalisation of glutaminase activity in the gut. Administration of OP is associated with a reduction of brain oedema in rats with chronic bile duct ligation and diminution of intracranial hypertension in a pig model of ALF. Studies to date have indicated that it is safe in humans and trials in overt HE are underway to establish OP as a treatment for this major complication of liver disease.
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Affiliation(s)
- Maria Jover-Cobos
- Liver Failure Group, UCL Institute for Liver and Digestive Health, The Royal Free Hospital, University College London, Pond Street, London NW3 2PF, UK.
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Kawamoto EM, Vasconcelos AR, Degaspari S, Böhmer AE, Scavone C, Marcourakis T. Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system. AGE (DORDRECHT, NETHERLANDS) 2013; 35:331-342. [PMID: 22278206 PMCID: PMC3592952 DOI: 10.1007/s11357-011-9365-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 12/05/2011] [Indexed: 05/31/2023]
Abstract
Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study age-related disorders and new anti-aging therapies.
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Affiliation(s)
- Elisa Mitiko Kawamoto
- />Department of Pharmacology, Institute of Biomedical Science—ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900 São Paulo, Brazil
- />Laboratory of Neurosciences, NIA, NIH, Baltimore, MD USA
| | - Andrea Rodrigues Vasconcelos
- />Department of Pharmacology, Institute of Biomedical Science—ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900 São Paulo, Brazil
| | - Sabrina Degaspari
- />Department of Pharmacology, Institute of Biomedical Science—ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900 São Paulo, Brazil
| | - Ana Elisa Böhmer
- />Department of Pharmacology, Institute of Biomedical Science—ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900 São Paulo, Brazil
| | - Cristoforo Scavone
- />Department of Pharmacology, Institute of Biomedical Science—ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900 São Paulo, Brazil
| | - Tania Marcourakis
- />Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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Brand L, van Zyl J, Minnaar EL, Viljoen F, du Preez JL, Wegener G, Harvey BH. Corticolimbic changes in acetylcholine and cyclic guanosine monophosphate in the Flinders Sensitive Line rat: a genetic model of depression. Acta Neuropsychiatr 2012; 24:215-25. [PMID: 25286814 DOI: 10.1111/j.1601-5215.2011.00622.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Objective: Depression is suggested to involve disturbances in cholinergic as well as glutamatergic pathways, particularly the N-methyl-d-aspartate receptor-mediated release of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The aim of this study was to determine whether the Flinders Sensitive Line (FSL) rat, a genetic model of depression, presents with corticolimbic changes in basal acetylcholine (ACh) levels and NO/cGMP signalling.Methods: Basal levels of nitrogen oxides (NOx) and both basal and l-arginine-stimulated nitric oxide synthase (NOS) formation of l-citrulline were analysed in hippocampus and frontal cortex in FSL and control Flinders resistant line (FRL) rats by fluorometric and electrochemical high-performance liquid chromatography, respectively. In addition, ACh and cGMP levels were analysed by liquid chromatography tandem mass spectrometry and radioimmunoassay, respectively.Results: Significantly elevated frontal cortical but reduced hippocampal ACh levels were observed in FSL versus FRL rats. Basal cGMP levels were significantly reduced in the frontal cortex, but not hippocampus, of FSL rats without changes in NOx and l-citrulline, suggesting that the reduction of cGMP follows through an NOS-independent mechanism.Conclusions: These data confirm a bidirectional change in ACh in the frontal cortex and hippocampus of the FSL rat, as well as provide evidence for a frontal cortical ACh-cGMP interaction in the depressive-like behaviour of the FSL rat.
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Affiliation(s)
- Linda Brand
- Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
| | - Jurgens van Zyl
- Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
| | - Estella L Minnaar
- Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
| | - Francois Viljoen
- Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
| | - Jan L du Preez
- Analytical Technology Laboratory, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
| | - Gregers Wegener
- Centre for Psychiatric Research, University of Aarhus, Denmark
| | - Brian H Harvey
- Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University, Potchefstroom, South Africa
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Arias N, Méndez M, Arias J, Arias JL. Brain metabolism and spatial memory are affected by portal hypertension. Metab Brain Dis 2012; 27:183-91. [PMID: 22314871 DOI: 10.1007/s11011-012-9276-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 01/19/2012] [Indexed: 11/24/2022]
Abstract
Portal hypertension is a major complication of cirrhosis that frequently leads to a neuropsychiatric disorder that affects cognition. The present study was undertaken in order to compare the performance of sham-operated rats (SHAM) and portal hypertension rats (PH) in reference memory tasks in the Morris water maze (MWM). Two groups of animals were used: SHAM group (n=12) was used as a control group and PH group (n=12) by the triple portal vein ligation method was used as an animal model of early evolutive phase of PH. The portal pressure was measured in the splenic parenchyma. Our work shows that spatial learning in the MWM is not impaired in PH group although this group showed a one-day delay in the task acquisition compared to the SHAM group. We assessed the brain metabolic activity of the animals by means of cytochrome c-oxidase (COx) histochemistry. Significant changes were found in the CA3, dentate gyrus, basolateral, medial, lateral and central amygdala, showing lower COx activity in the PH group as compared to the SHAM group in all cases. We found no changes in metabolic activity in prefrontal cortex and CA1 area between groups. In fact, different neural networks were shown according to the execution level of the subjects. The early PH evolution induced changes in brain metabolic activity without biggest alterations in spatial memory.
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Affiliation(s)
- Natalia Arias
- Laboratorio de Neurociencias, Departamento de Psicología, Universidad de Oviedo, Asturias, Spain
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Plano SA, Agostino PV, de la Iglesia HO, Golombek DA. cGMP-phosphodiesterase inhibition enhances photic responses and synchronization of the biological circadian clock in rodents. PLoS One 2012; 7:e37121. [PMID: 22590651 PMCID: PMC3349644 DOI: 10.1371/journal.pone.0037121] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 04/13/2012] [Indexed: 12/13/2022] Open
Abstract
The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.
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Affiliation(s)
- Santiago A. Plano
- Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/CONICET, Buenos Aires, Argentina
| | - Patricia V. Agostino
- Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/CONICET, Buenos Aires, Argentina
| | | | - Diego A. Golombek
- Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/CONICET, Buenos Aires, Argentina
- * E-mail:
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G-substrate: the cerebellum and beyond. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 106:381-416. [PMID: 22340725 DOI: 10.1016/b978-0-12-396456-4.00004-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The discovery of nitric oxide (NO) as an activator of soluble guanylate cyclase (sGC) has stimulated extensive research on the NO-sGC-3':5'-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase (PKG) pathway. However, the restricted localization of pathway components and the lack of information on PKG substrates have hindered research seeking to examine the physiological roles of the NO-sGC-cGMP-PKG pathway. An excellent substrate for PKG is the G-substrate, which was originally discovered in the cerebellum. The role of G-substrate in the cerebellum and other brain structures has been revealed in recent years. This review discusses the relationship between the G-substrate and other components of the NO-sGC-cGMP-PKG pathway and describes the characteristics of the G-substrate gene and protein related to diseases. Finally, we discuss the physiological role of G-substrate in the cerebellum, where it regulates cerebellum-dependent long-term memory, and its role in the ventral tegmental area and retina, where it acts as an effective neuroprotectant.
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Balasubramaniyan V, Wright G, Sharma V, Davies NA, Sharifi Y, Habtesion A, Mookerjee RP, Jalan R. Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 2012; 302:G145-52. [PMID: 21903766 DOI: 10.1152/ajpgi.00097.2011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ammonia is central in the pathogenesis of hepatic encephalopathy, which is associated with dysfunction of the nitric oxide (NO) signaling pathway. Ornithine phenylacetate (OP) reduces hyperammonemia and brain water in cirrhotic animals. This study aimed to determine whether endothelial NO synthase activity is altered in the brain of cirrhotic animals, whether this is associated with changes in the endogenous inhibitor, asymmetric-dimethylarginine (ADMA) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH-1), and whether these abnormalities are restored by ammonia reduction using OP. Sprague-Dawley rats were studied 4-wk after bile duct ligation (BDL) (n = 16) or sham operation (n = 8) and treated with placebo or OP (0.6 g/kg). Arterial ammonia, brain water, TNF-α, plasma, and brain ADMA were measured using standard techniques. NOS activity was measured radiometrically, and protein expression for NOS enzymes, ADMA, DDAH-1, 4-hydroxynonenol ((4)HNE), and NADPH oxidase (NOX)-1 were measured by Western blotting. BDL significantly increased arterial ammonia (P < 0.0001), brain water (P < 0.05), and brain TNF-α (P < 0.01). These were reduced significantly by OP treatment. The estimated eNOS component of constitutive NOS activity was significantly lower (P < 0.05) in BDL rat, and this was significantly attenuated in OP-treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham (P < 0.01) and restored toward normal following treatment with OP. Brain (4)HNE and NOX-1 protein expression were significantly increased in BDL rat brain, which were significantly decreased following OP administration. We show a marked abnormality of NO regulation in cirrhotic rat brains, which can be restored by reduction in ammonia concentration using OP.
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Zielińska M, Ruszkiewicz J, Hilgier W, Fręśko I, Albrecht J. Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y+ LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochem Int 2010; 58:190-5. [PMID: 21115085 DOI: 10.1016/j.neuint.2010.11.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 11/17/2010] [Accepted: 11/19/2010] [Indexed: 12/16/2022]
Abstract
The pathogenesis of hepatic encephalopathy (HE) is associated with hyperammonemia (HA) and subsequent exposure of the brain to excess of ammonia. Alterations of the NO/cGMP pathway and increased glutamine (Gln) content are collectively responsible for many HE symptoms, but how the two events influence each other is not clear. Previously we had shown that Gln administered intracerebrally inhibited the NO/cGMP pathway in control rats and even more so in rats with HA, and we speculated that this effect is due to inhibition by Gln of arginine (Arg) transport (Hilgier et al., 2009). In this study we demonstrate that a 3-day HA in the ammonium acetate model increases the expression in the brain of y(+)LAT2, the heteromeric transporter which preferentially stimulates Arg efflux from the cells in exchange for Gln. The expression of the basic amino acid transporter CAT1, transporting Arg but not Gln remained unaffected by HA. Multiple parameters of Arg or Gln uptake and/or efflux and their mutual dependence were altered in the cerebral cortical slices obtained from HA rats, in a manner indicating enhanced y(+)LAT2-mediated transport. HA elevated Gln content and decreased cGMP content as measured both in the cerebral cortical tissue and microdialysates. Intracortical administration of 6-diazo-5-oxo-L-norleucine (DON), which inhibits Gln fluxes between different cells of the CNS, attenuated the HA-induced decrease of cGMP in the microdialysates of HA rats, but not of control rats. The results suggest that, reduced delivery of Arg due to enhanced y(+)LAT2-mediated exchange of extracellular Gln for intracellular Arg may contribute to the decrease of NO/cGMP pathway activity evoked in the brain by HA.
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Affiliation(s)
- Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106 Warsaw, Poland.
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McPhail MJW, Bajaj JS, Thomas HC, Taylor-Robinson SD. Pathogenesis and diagnosis of hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 2010; 4:365-78. [PMID: 20528123 DOI: 10.1586/egh.10.32] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatic encephalopathy (HE) is a common and potentially devastating neuropsychiatric complication of acute liver failure and cirrhosis. Even in its mildest form, minimal HE (MHE), the syndrome significantly impacts daily living and heralds progression to overt HE. There is maturity in the scientific understanding of the cellular processes that lead to functional and structural abnormalities in astrocytes. Hyperammonemia and subsequent cell swelling is a key pathophysiological abnormality, but this aspect alone is insufficient to fully explain the complex neurotransmitter abnormalities that may be observable using sophisticated imaging techniques. Inflammatory cytokines, reactive oxygen species activation and the role of neurosteroids on neurotransmitter binding sites are emerging pathological lines of inquiry that have yielded important new information on the processes underlying HE and offer promise of future therapeutic targets. Overt HE remains a clinical diagnosis and the neurophysiological and imaging modalities used in research studies have not transferred successfully to the clinical situation. MHE is best characterized by psychometric evaluation, but these tests can be lengthy to perform and require specific expertise to interpret. Simpler computer-based tests are now available and perhaps offer an opportunity to screen, diagnose and monitor MHE in a clinical scenario, although large-scale studies comparing the different techniques have not been undertaken. There is a discrepancy between the depth of understanding of the pathophysiology of HE and the translation of this understanding to a simple, easily understood diagnostic and longitudinal marker of disease. This is a present area of focus for the management of HE.
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Affiliation(s)
- Mark J W McPhail
- Hepatology Section, Department of Medicine, 10th Floor QEQM Wing, St Mary's Hospital Campus, Imperial College London, South Wharf Street, London W2 1NY, UK
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