Hippocampal mitochondrial dysfunction with decreased mtNOS activity in prehepatic portal hypertensive rats

Lores‐Arnaiz, Silvia; Perazzo, Juan Carlos; Prestifilippo, Juan Pablo; Lago, Néstor; D’Amico, Gabriela; Czerniczyniec, Analía; Bustamante, Juanita; Boveris, Alberto; Lemberg, A

doi:10.1016/j.neuint.2005.05.006

Cited by 26 publications

(31 citation statements)

References 30 publications

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“…This lack of information is because of the unavailability of an effective isolation procedure for rat hippocampal mitochondria, a situation that was overcame by a recent report (28). In the present study, we describe the gradual impairment of mitochondrial function in rat hippocampus during aging compared with less marked mitochondrial dysfunctions observed in brain cortex and whole brain.…”

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confidence: 55%

Hippocampal mitochondrial dysfunction in rat aging

Navarro¹,

López-Cepero²,

Bández³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Navarro A, Ló pez-Cepero JM, Bá ndez MJ, Sá nchez-Pino M-J, Gó mez C, Cadenas E, Boveris A. Hippocampal mitochondrial dysfunction in rat aging. Am J Physiol Regul Integr Comp Physiol 294: R501-R509, 2008. First published December 12, 2007 doi:10.1152/ajpregu.00492.2007.-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. mitochondrial nitric oxide synthase; reduced nicotinamide adenide dinucleotide dehydrogenase; cytochrome oxidase; oxidative damage MAMMALIAN AGING is characterized by a gradual and continuous loss, starting at full adulthood, of the quality of physiological functions and responses. The losses are more marked in the functions that depend on the integrated response of the central nervous system (19) than in the functions of the renal or cardiovascular systems. Mitochondria were brought to attention in mammalian aging biology because of the central role of mitochondria in producing biochemical energy (ATP) to meet cellular requirements in aerobic cells and to the decline of basal metabolic rate and of physical performance that are characteristic of aging (32).The free radical theory of aging, based on the pioneer works of Gerschman et al. (18) and Harman (20), considers that aging is caused by the continuous inactivation of biologically essential macromolecules and subcellular structures due to chemical modifications produced by reactions mediated by oxygen free radicals. When the free radical theory of aging is focused in mitochondria, it emerges as the mitochondrial theory of aging (6,21,32,47). Mitochondria are considered likely pacemakers of tissue aging because of their continuous production of superoxide radical (O 2•Ϫ ) and of nitric oxide (NO) and to the mitochondrial sensitivity to free radical-mediated oxidative damage (32).Aged mammalian brain shows a decreased capacity to produce ATP by oxidative phosphorylation, and it is considered that this decreased capacity for energy production ...

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confidence: 55%

Hippocampal mitochondrial dysfunction in rat aging

Navarro¹,

López-Cepero²,

Bández³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Furthermore, the accumulation of ventricular lactate indicates severe energy failure in the brain due to mitochondrial dysfunction and acute hypoxia during stroke��like episodes. Translational defects of the mito�� chondrial respiratory chain subunits and pathological alterations in the microvasculature and in BBB compo�� nents have been documented in patients with MELA�, thus supporting the notion that BBB permeability may be increased due to mitochondrial respiratory failure in the cortical microvasculature [157] , as it has also been demonstrated in MHE [57] . In MELA�, severe defects of respiratory chain complexes in immortalized endothelial cells and astrocytes as well as in primary astrocytes har�� boring the m.3243A �� G mutation were associated [158,159] .…”

Section: Sharing Pathways: Mitochondrial Encephalopathy Lactic Acidomentioning

confidence: 53%

“…Maybe we could see a little further with a little help from some experimen�� tal data. In a model of MHE [57] that displays moderate hyperammonemia and portal hypertension, it was clearly demonstrated that BBB has morphofunctional changes. Transmission electron microscopy revealed tight junction disruption in BBB capillaries in the hippocampal area, with mild edema of astrocytes and EC�.…”

Section: Blood Brain Barrier Brain Barrier Brain Barriermentioning

confidence: 99%

“…Significant amounts of glutamine have been shown to be metabo�� lized in astrocytes. Thus, the generation of mitochondrial ammonia may reach high levels, inducing the mitochon�� drial potential membrane, reactive oxygen species (RO�), with the potential consequence of morpho��functional oxidative damage of the mitochondria [57,58] and its respira�� tory chain [58] .…”

Section: Glutaminementioning

confidence: 99%

“…�hat means that in an experimental MHE, increased permeability and angio�� genesis in the hippocampal area was seen. Furthermore, energy failing, pathological changes in the endothelial mitochondria and decreased nitric oxide synthase (NO�) activity were documented [57] . Jensen et al [88] suggest that BBB leakage induce microglial reactions.…”

Section: Blood Brain Barrier Brain Barrier Brain Barriermentioning

confidence: 99%

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Hepatic encephalopathy: An approach to its multiple pathophysiological features

Perazzo¹,

Tallis²,

Delfante³

et al. 2012

WJH

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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 ex-HE is rapidly ex-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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