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Valdez LB, Zaobornyj T, Bandez MJ, López-Cepero JM, Boveris A, Navarro A. Complex I syndrome in striatum and frontal cortex in a rat model of Parkinson disease. Free Radic Biol Med 2019; 135:274-282. [PMID: 30862545 DOI: 10.1016/j.freeradbiomed.2019.03.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/27/2019] [Accepted: 03/05/2019] [Indexed: 12/21/2022]
Abstract
Mitochondrial dysfunction named complex I syndrome was observed in striatum mitochondria of rotenone treated rats (2 mg rotenone/kg, i. p., for 30 or 60 days) in an animal model of Parkinson disease. After 60 days of rotenone treatment, the animals showed: (a) 6-fold increased bradykinesia and 60% decreased locomotor activity; (b) 35-34% decreases in striatum O2 uptake and in state 3 mitochondrial respiration with malate-glutamate as substrate; (c) 43-57% diminished striatum complex I activity with 60-71% decreased striatum mitochondrial NOS activity, determined both as biochemical activity and as functional activity (by the NO inhibition of active respiration); (d) 34-40% increased rates of mitochondrial O2•- and H2O2 productions and 36-46% increased contents of the products of phospholipid peroxidation and of protein oxidation; and (e) 24% decreased striatum mitochondrial content, likely associated to decreased NO-dependent mitochondrial biogenesis. Intermediate values were observed after 30 days of rotenone treatment. Frontal cortex tissue and mitochondria showed similar but less marked changes. Rotenone-treated rats showed mitochondrial complex I syndrome associated with cellular oxidative stress in the dopaminergic brain areas of striatum and frontal cortex, a fact that describes the high sensitivity of mitochondrial complex I to inactivation by oxidative reactions.
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Affiliation(s)
- Laura B Valdez
- University of Buenos Aires, School of Pharmacy and Biochemistry, Physical Chemistry Division, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), Buenos Aires, Argentina.
| | - Tamara Zaobornyj
- University of Buenos Aires, School of Pharmacy and Biochemistry, Physical Chemistry Division, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), Buenos Aires, Argentina
| | - Manuel J Bandez
- University of Cadiz, School of Medicine, Department of Biochemistry and Molecular Biology, Cadiz, Spain
| | - José María López-Cepero
- University of Cadiz, School of Medicine, Department of Cell Biology and Histology, Cadiz, Spain
| | - Alberto Boveris
- University of Buenos Aires, School of Pharmacy and Biochemistry, Physical Chemistry Division, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), Buenos Aires, Argentina
| | - Ana Navarro
- University of Cadiz, School of Medicine, Department of Biochemistry and Molecular Biology, Cadiz, Spain
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Stebbings KA, Choi HW, Ravindra A, Llano DA. The impact of aging, hearing loss, and body weight on mouse hippocampal redox state, measured in brain slices using fluorescence imaging. Neurobiol Aging 2016; 42:101-9. [PMID: 27143426 DOI: 10.1016/j.neurobiolaging.2016.03.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/18/2016] [Accepted: 03/05/2016] [Indexed: 01/21/2023]
Abstract
The relationships between oxidative stress in the hippocampus and other aging-related changes such as hearing loss, cortical thinning, or changes in body weight are not yet known. We measured the redox ratio in a number of neural structures in brain slices taken from young and aged mice. Hearing thresholds, body weight, and cortical thickness were also measured. We found striking aging-related increases in the redox ratio that were isolated to the stratum pyramidale, while such changes were not observed in thalamus or cortex. These changes were driven primarily by changes in flavin adenine dinucleotide, not nicotinamide adenine dinucleotide hydride. Multiple regression analysis suggested that neither hearing threshold nor cortical thickness independently contributed to this change in hippocampal redox ratio. However, body weight did independently contribute to predicted changes in hippocampal redox ratio. These data suggest that aging-related changes in hippocampal redox ratio are not a general reflection of overall brain oxidative state but are highly localized, while still being related to at least one marker of late aging, weight loss at the end of life.
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Affiliation(s)
- Kevin A Stebbings
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Hyun W Choi
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Aditya Ravindra
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Daniel Adolfo Llano
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
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Tallis S, Caltana LR, Souto PA, Delfante AE, Lago NR, Brusco A, Perazzo JC. Changes in CNS cells in hyperammonemic portal hypertensive rats. J Neurochem 2014; 128:431-444. [PMID: 24382264 DOI: 10.1111/jnc.12458] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 09/14/2013] [Accepted: 09/16/2013] [Indexed: 01/06/2023]
Abstract
Rats with pre-hepatic portal hypertension because of partial portal vein ligation develop minimal hepatic encephalopathy (MHE) with hyperammonemia, impaired blood-brain barrier, mild brain edema, and severe mitochondrial changes in the hippocampus. The aim of this study was to evaluate changes of different neural cells in the cerebral cortex and the hippocampus. Animals were divided into two groups, MHE and sham. Astrocytes were studied by immunostaining with glial fibrillary acidic protein and S100β protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1α (HIF-1α) and its downstream proteins, P-glycoprotein (P-gp) and erythropoietin receptor (Epo-R), were also evaluated. Astrocytes were increased in area and number only in the hippocampus, while S100β increased in both brain areas in MHE animals. Microtubule associated protein-2 and NF-200 immunoreactivities (-ir) were significantly reduced in both areas. Hippocampal Nestin-ir was increased in MHE animals. These cellular changes were similar to those described in ischemic conditions, thus HIF-1α, P-gp, and Epo-R were also evaluated. A high expression of HIF-1α in cortical neurons was observed in the MHE group. It is likely that this hypoxia-like state is triggered via ammonia occupying the binding domain of HIF-1α and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.
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Affiliation(s)
- Silvina Tallis
- Laboratory of Hepatic Encephalopathy and Portal Hypertension, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina; Laboratory of Experimental Pathology, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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Hu LS, George J, Wang JH. Current concepts on the role of nitric oxide in portal hypertension. World J Gastroenterol 2013; 19:1707-1717. [PMID: 23555159 PMCID: PMC3607747 DOI: 10.3748/wjg.v19.i11.1707] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 09/13/2012] [Accepted: 12/06/2012] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis. Portal pressure can be increased by a rise in portal blood flow, an increase in vascular resistance, or the combination. In cirrhosis, the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow. Although much of this increase is a mechanical consequence of architectural disturbances, there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis. Many vasoactive substances contribute to the development of PHT. Among these, nitric oxide (NO) is the key mediator that paradoxically regulates the sinusoidal (intra-hepatic) and systemic/splanchnic circulations. NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation. NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation. NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.
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Alterations of motor performance and brain cortex mitochondrial function during ethanol hangover. Alcohol 2012; 46:473-9. [PMID: 22608205 DOI: 10.1016/j.alcohol.2011.09.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/13/2011] [Accepted: 09/16/2011] [Indexed: 10/28/2022]
Abstract
Ethanol has been known to affect various behavioral parameters in experimental animals, even several hours after ethanol (EtOH) is absent from blood circulation, in the period known as hangover. The aim of this study was to assess the effects of acute ethanol hangover on motor performance in association with the brain cortex energetic metabolism. Evaluation of motor performance and brain cortex mitochondrial function during alcohol hangover was performed in mice 6 hours after a high ethanol dose (hangover onset). Animals were injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Ethanol hangover group showed a bad motor performance compared with control animals (p < .05). Oxygen uptake in brain cortex mitochondria from hangover animals showed a 34% decrease in the respiratory control rate as compared with the control group. Mitochondrial complex activities were decreased being the complex I-III the less affected by the hangover condition; complex II-III was markedly decreased by ethanol hangover showing 50% less activity than controls. Complex IV was 42% decreased as compared with control animals. Hydrogen peroxide production was 51% increased in brain cortex mitochondria from the hangover group, as compared with the control animals. Quantification of the mitochondrial transmembrane potential indicated that ethanol injected animals presented 17% less ability to maintain the polarized condition as compared with controls. These results indicate that a clear decrease in proton motive force occurs in brain cortex mitochondria during hangover conditions. We can conclude that a decreased motor performance observed in the hangover group of animals could be associated with brain cortex mitochondrial dysfunction and the resulting impairment of its energetic metabolism.
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Perazzo JC, Tallis S, Delfante A, Souto PA, Lemberg A, Eizayaga FX, Romay S. Hepatic encephalopathy: An approach to its multiple pathophysiological features. World J Hepatol 2012; 4:50-65. [PMID: 22489256 PMCID: PMC3321490 DOI: 10.4254/wjh.v4.i3.50] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Revised: 11/19/2011] [Accepted: 02/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.
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Affiliation(s)
- Juan Carlos Perazzo
- Juan Carlos Perazzo, Silvina Tallis, Amalia Delfante, Pablo Andrés Souto, Abraham Lemberg, Francisco Xavier Eizayaga, Salvador Romay, Laboratory of Portal Hypertension and Hepatic Encephalopathy, Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 950, CP 1113, Buenos Aires, Argentina
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Bustamante J, Lores-Arnaiz S, Tallis S, Roselló DM, Lago N, Lemberg A, Boveris A, Perazzo JC. Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy. Mol Cell Biochem 2011; 354:231-240. [PMID: 21505893 DOI: 10.1007/s11010-011-0822-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Accepted: 02/17/2011] [Indexed: 01/22/2023]
Abstract
In this study, we describe the presence of apoptosis, associated with a mitochondrial dysfunction in the hippocampus of animals in an experimental model defined as minimal hepatic encephalopathy (MHE). This experimental model was studied after 10 days of induced portal vein calibrated stricture, leading to portal hypertension and to a moderate hyperammonemia, without the presence of other evident central nervous system changes. The molecular mechanisms here proposed indicate the presence of apoptotic intrinsic pathways that point to hippocampal mitochondria as an important mediator of apoptosis in this experimental model. In this model of MHE, the presence of DNA fragmentation is documented by 2.3-times increased number of TUNEL-positive cells. These findings together with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane of the MHE animals together with 11% of cytochrome c release indicate the presence of apoptosis in this experimental model. A detailed analysis of the hippocampal mitochondrial physiology was performed after mitochondrial isolation. The determination of the respiratory rate in the presence of malate plus glutamate and ADP showed a 45% decrease in respiratory control in MHE animals as compared with the sham group. A marked decrease of cytochrome oxidase (complex IV of the electron transport chain) was also observed, showing 46% less activity in hippocampal mitochondria from MHE animals. In addition, mitochondria from these animals showed less ability to maintain membrane potential (ΔΨ (m)) which was 13% lower than the sham group. Light scattering experiments showed that mitochondria from MHE animals were more sensitive to swell in the presence of increased calcium concentrations as compared with the sham group. In addition, in vitro studies performed in mitochondria from sham animals showed that mitochondrial permeability transition (MPT) could be a mitochondrial mediator of the apoptotic signaling in the presence of NH(4) (+) and calcium.
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Affiliation(s)
- J Bustamante
- Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956, C1113AAD Buenos Aires, Argentina.
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Abstract
BACKGROUND Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat. AIM We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis. METHODS One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-α) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes. RESULTS The significant increase of fractalkine in mesenteric lymph nodes (P<0.05) and its receptor (CX3CR1) in the small bowel (P<0.05) and hippocampus (P<0.01), associated with the increased expression of SDF1-α in the hippocampus (P<0.01) and the cerebellum (P<0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis. CONCLUSION The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines.
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Navarro A, Bandez MJ, Lopez-Cepero JM, Gómez C, Boveris A. High doses of vitamin E improve mitochondrial dysfunction in rat hippocampus and frontal cortex upon aging. Am J Physiol Regul Integr Comp Physiol 2010; 300:R827-34. [PMID: 21106913 DOI: 10.1152/ajpregu.00525.2010] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Rat aging from 4 to 12 mo was accompanied by hippocampus and frontal cortex mitochondrial dysfunction, with decreases of 23 to 53% in tissue and mitochondrial respiration and in the activities of complexes I and IV and of mitochondrial nitric oxide synthase (mtNOS) (P < 0.02). In aged rats, the two brain areas showed mitochondria with higher content (35-78%) of oxidation products of phospholipids and proteins and with higher (59-95%) rates of O(2)(-) and H(2)O(2) production (P < 0.02). Dietary supplementation with vitamin E (2.0 or 5.0 g/kg of food) from 9 to 12 mo of rat age, restored in a dose-dependent manner, the decreases in tissue and mitochondrial respiration (to 90-96%) and complexes I and IV and mtNOS activities (to 86-88%) of the values of 4-mo-old rats (P < 0.02). Vitamin E prevented, by 73-80%, the increases in oxidation products, and by 62-68%, the increases in O(2)(-) and H(2)O(2) production (P < 0.05). High resolution histochemistry of cytochrome oxidase in the hippocampal CA1 region showed higher staining in vitamin E-treated rats than in control animals. Aging decreased (19%) hippocampus mitochondrial mass, an effect that was restored by vitamin E. High doses of vitamin E seem to sustain mitochondrial biogenesis in synaptic areas.
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Affiliation(s)
- Ana Navarro
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Cádiz, Cádiz, Spain
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Mitochondrial function and nitric oxide production in hippocampus and cerebral cortex of rats exposed to enriched environment. Brain Res 2010; 1319:44-53. [DOI: 10.1016/j.brainres.2010.01.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Revised: 01/04/2010] [Accepted: 01/07/2010] [Indexed: 11/20/2022]
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Begega A, Méndez M, Rubio S, Santín LJ, Aller MA, Arias J, Arias JL. Portal hypertension in 18-month-old rats: memory deficits and brain metabolic activity. Physiol Behav 2010; 100:135-42. [PMID: 20184905 DOI: 10.1016/j.physbeh.2010.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 02/09/2010] [Accepted: 02/15/2010] [Indexed: 11/16/2022]
Abstract
Portal hypertension is a major complication of cirrhosis that frequently leads to a neuropsychiatric disorder that affects cognition. We compared the performance of 18-month-old prehepatic portal hypertensive rats (PH) and 18-month-old normal rats (CO) in spatial short-term and reference memory tasks in the Morris water maze and in active avoidance task. The PH group showed worse spatial short-term memory than the CO group. Also, the PH group tended to perform worse than the CO group in the reference memory task, but it presented a correct acquisition of the active avoidance task. We assessed the brain metabolic activity of the animals by means of cytochrome c-oxidase (COx) histochemistry. We found that the PH group developed prefrontal dysfunction characterized by increased COx activity in this region compared to the CO group. Similar results were found in the medial mammillary nucleus and dentate gyrus, whereas the CA1 area, bed nucleus of the stria terminalis, and supramammillary nucleus showed lower COx activity in the PH group as compared to the CO group. We conclude that the 18-month-old portal hypertensive rats present spatial memory impairment without alteration of implicit learning. This deficit could be related to the alteration of the metabolic activity of the brain regions involved in the processing of spatial memories.
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Affiliation(s)
- Azucena Begega
- Laboratorio de Neurociencias, Departamento de Psicología, Universidad de Oviedo, Plaza Feijoo s/n, 33003 Oviedo, Spain
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Acosta GB, Fernández MA, Roselló DM, Tomaro ML, Balestrasse K, Lemberg A. Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats. World J Gastroenterol 2009; 15:2893-9. [PMID: 19533812 PMCID: PMC2699008 DOI: 10.3748/wjg.15.2893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [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
AIM: To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension.
METHODS: Male Wistar rats were divided into sham-operated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas.
RESULTS: We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, significantly and persistent increase in this excitatory neurotransmitter activity.
CONCLUSION: The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modifies the normal function in some brain regions.
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Roselló DM, Balestrasse K, Coll C, Coll S, Tallis S, Gurni A, Tomaro ML, Lemberg A, Perazzo JC. Oxidative stress and hippocampus in a low-grade hepatic encephalopathy model: protective effects of curcumin. Hepatol Res 2008; 38:1148-1153. [PMID: 19000058 DOI: 10.1111/j.1872-034x.2008.00377.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM The present study was performed on prehepatic portal hypertensive rats, a model of low-grade hepatic encephalopathy, designed to evaluate whether oxidative stress was a possible pathway implicated in hippocampal damage and if so, the effect of an anti-oxidant to prevent it. METHODS Prehepatic portal hypertension was induced by a regulated portal vein stricture. Oxidative stress was investigated by assessing related biochemical parameters in rat hippocampus. The effect of the anti-oxidant curcumin, administered in a single i.p. dose of 100 mg/kg on the seventh, ninth and eleventh days after surgery, was evaluated. RESULTS Oxidative stress in the rat hippocampal area was documented. Curcumin significantly decreased tissue malondialdehyde levels and significantly increased glutathione peroxidase, catalase and superoxide dismutase activities in the hippocampal tissue of portal hypertensive rats. CONCLUSION Oxidative stress was found to be implicated in the hippocampal damage and curcumin protected against this oxidative stress in low-grade hepatic encephalopathic rats. These protective effects may be attributed to its anti-oxidant properties.
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Affiliation(s)
- Diego Martín Roselló
- Laboratory of Portal Hypertension, University of Buenos Aires, Buenos Aires, Argentina
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Navarro A, López-Cepero JM, Bández MJ, Sánchez-Pino MJ, Gómez C, Cadenas E, Boveris A. Hippocampal mitochondrial dysfunction in rat aging. Am J Physiol Regul Integr Comp Physiol 2007; 294:R501-9. [PMID: 18077512 DOI: 10.1152/ajpregu.00492.2007] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hippocampus mitochondrial dysfunction with impaired electron transfer and increased oxidative damage was observed upon rat aging. Hippocampal mitochondria of aged (12 mo) and senescent (20 mo) rats showed, compared with young (4 mo) rats, marked decreases in the rate of state 3 respiration with NAD-dependent substrates (32-51%) and in the activities of mitochondrial complexes I (57-73%) and IV (33-54%). The activity of mitochondrial nitric oxide synthase was also decreased, 53-66%, with age. These losses in enzymatic activity were more marked in the hippocampus than in brain cortex or in whole brain. The histochemical assay of mitochondrial complex IV in the hippocampus showed decreased staining upon aging. Oxidative damage, determined as the mitochondrial content of thiobarbituric-acid reactive substances (TBARS) and protein carbonyls, increased in aged and senescent hippocampus (66-74% in TBARS and 48-96% in carbonyls). A significant statistical correlation was observed between mitochondrial oxidative damage and enzymatic activity. Mitochondrial dysfunction with shortage of energy supply is considered a likely cause of dysfunction in aged hippocampus.
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Affiliation(s)
- Ana Navarro
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Plaza Fragela 9, 11003-Cádiz, Spain.
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Scorticati C, Perazzo JC, Rettori V, McCann SM, De Laurentiis A. Role of ammonia and nitric oxide in the decrease in plasma prolactin levels in prehepatic portal hypertensive male rats. Neuroimmunomodulation 2006; 13:152-159. [PMID: 17119344 DOI: 10.1159/000097260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 09/19/2006] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVES Since very little is known about neuroendocrine changes that occur in portal-systemic hepatic encephalopathy, we studied plasma prolactin (PRL) levels and the involvement of hyperammonemia, nitric oxide (NO) and dopaminergic and adrenergic systems in the control of this hormone secretion in a male rat model of prehepatic portal hypertension (PH). METHODS We conducted in vivo studies to determine plasma ammonia and PRL levels. Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), epinephrine and norepinephrine content in medial basal hypothalamus (MBH) and anterior pituitary (AP) were measured. In addition, NO synthase (NOS) activity and protein expression were evaluated in APs. In in vitro studies, the APs from intact rats were incubated with different doses of ammonia and PRL secretion was determined. In ex vivo studies, the APs from normal and PH rats were incubated in the presence of ammonia and/or a NOS inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME) and PRL secretion was determined. RESULTS PH rats had a significant increase in plasma ammonia levels (p < 0.001) and a decrease in plasma PRL levels (p < 0.05). Neither DA nor DOPAC content or DOPAC/DA ratios were modified in both MBH and APs; however, we observed a significant increase in norepinephrine content in both MBH and AP (p < 0.001 and p < 0.05, respectively) and a significant increase in epinephrine in APs (p < 0.001). Moreover, PH produced an increase in NOS activity (p < 0.01) and NOS protein expression (p < 0.0001) in APs. The ammonia (100 microM) significantly reduced PRL secretion from APs in vitro (p < 0.05). The presence of L-NAME, an inhibitor of NOS, abrogated the inhibitory effect of ammonia on PRL secretion from APs from control and PH rats. CONCLUSIONS We found that plasma PRL levels were decreased in PH rats probably due to the high ammonia levels. The central noradrenergic system could also mediate this decrease. Also, the increase in NOS activity and/or content in AP induced NO production that directly inhibited PRL secretion from the AP, without the participation of the dopaminergic system.
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Affiliation(s)
- Camila Scorticati
- Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Medicina, Buenos Aires, Argentina
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Gonzales S, Perez MJ, Perazzo JC, Tomaro ML. Antioxidant role of heme oxygenase-1 in prehepatic portal hypertensive rats. World J Gastroenterol 2006; 12:4149-4155. [PMID: 16830363 PMCID: PMC4087362 DOI: 10.3748/wjg.v12.i26.4149] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2006] [Revised: 02/10/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the effect of bilirubin on the oxidative liver status and the activity and expression of heme oxygenase-1 (HO-1) in rat liver injury induced by prehepatic portal hypertension. METHODS Wistar male rats, weighing 200-250 g, were divided at random into two groups: one group with prehepatic portal hypertension (PH) induced by regulated prehepatic portal vein ligation (PPVL) and the other group corresponded to sham operated rats. Portal pressure, oxidative stress parameters, antioxidant enzymes, HO-1 activity and expression and hepatic sinusoidal vasodilatation were measured. RESULTS In PPVL rats oxidative stress was evidenced by a marked increase in thiobarbituric acid reactive substances (TBARS) content and a decrease in reduced glutathione (GSH) levels. The activities of liver antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were also diminished while activity and expression of HO-1 were enhanced. Administration of bilirubin (5 mumol/kg body weight) 24 h before the end of the experiment entirely prevented all these effects. Pretreatment with Sn-protoporphyrin IX (Sn-PPIX) (100 mug/kg body weight, i.p.), a potent inhibitor of HO, completely abolished the oxidative stress and provoked a slight decrease in liver GSH levels as well as an increase in lipid peroxidation. Besides, carbon monoxide, another heme catabolic product, induced a significant increase in sinusoidal hepatic areas in PPVL group. Pretreatment of PPVL rats with Sn-PPIX totally prevented this effect. CONCLUSION These results suggest a beneficial role of HO-1 overexpression in prehepatic portal hypertensive rats.
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Affiliation(s)
- Soledad Gonzales
- School of Pharmacy and Biochemistry, University of Buenos Aires 1113, Ciudad Autonoma de Buenos Aires, Republica Argentina
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