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Vicente Felipo - One of the best experts on this subject based on the ideXlab platform.
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A multi-omic study for uncovering molecular mechanisms associated with Hyperammonemia-induced cerebellar function impairment in rats
Cell Biology and Toxicology, 2021Co-Authors: Sonia Tarazona, Marta Llansola, Héctor Carmona, Ana Conesa, Vicente FelipoAbstract:Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE). Hyperammonemia (HA) and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE. The cerebellum is one of the main cerebral regions affected in MHE. Rats with chronic HA show some motor and cognitive alterations reproducing neurological impairment in cirrhotic patients with MHE. Neuroinflammation and altered neurotransmission and signal transduction in the cerebellum from hyperammonemic (HA) rats are associated with motor and cognitive dysfunction, but underlying mechanisms are not completely known. The aim of this work was to use a multi-omic approach to study molecular alterations in the cerebellum from hyperammonemic rats to uncover new molecular mechanisms associated with Hyperammonemia-induced cerebellar function impairment. We analyzed metabolomic, transcriptomic, and proteomic data from the same cerebellums from control and HA rats and performed a multi-omic integrative analysis of signaling pathway enrichment with the PaintOmics tool. The histaminergic system, corticotropin-releasing hormone, cyclic GMP-protein kinase G pathway, and intercellular communication in the cerebellar immune system were some of the most relevant enriched pathways in HA rats. In summary, this is a good approach to find altered pathways, which helps to describe the molecular mechanisms involved in the alteration of brain function in rats with chronic HA and to propose possible therapeutic targets to improve MHE symptoms.
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Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors
Frontiers Media S.A., 2019Co-Authors: Michele Malaguarnera, Marta Llansola, Tiziano Balzano, Belén Gómez-giménez, Carles Antúnez-muñoz, Núria Martínez-alarcón, Rahebeh Mahdinia, Vicente FelipoAbstract:Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In Hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline
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Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus by enhancing activation of the IL-1 receptor: underlying mechanisms
Journal of Neuroinflammation, 2018Co-Authors: Lucas Taoro-gonzalez, Yaiza M. Arenas, Andrea Cabrera-pastor, Vicente FelipoAbstract:Background Hyperammonemic rats reproduce the cognitive alterations of patients with hepatic encephalopathy, including altered spatial memory, attributed to altered membrane expression of AMPA receptor subunits in hippocampus. Neuroinflammation mediates these cognitive alterations. We hypothesized that Hyperammonemia-induced increase in IL-1β in hippocampus would be responsible for the altered GluA1 and GluA2 membrane expression. The aims of this work were to (1) assess if increased IL-1β levels and activation of its receptor are responsible for the changes in GluA1 and/or GluA2 membrane expression in Hyperammonemia and (2) identify the mechanisms by which activation of IL-1 receptor leads to altered membrane expression of GluA1 and GluA2. Methods We analyzed in hippocampal slices from control and hyperammonemic rat membrane expression of AMPA receptors using the BS3 cross-linker and phosphorylation of the GluA1 and GluA2 subunits using phosphor-specific antibodies. The IL-1 receptor was blocked with IL-Ra, and the signal transduction pathways involved in modulation of membrane expression of GluA1 and GluA2 were analyzed using inhibitors of key steps. Results Hyperammonemia reduces GluA1 and increases GluA2 membrane expression and reduces phosphorylation of GluA1 at Ser831 and of GluA2 at Ser880. Hyperammonemia increases IL-1β, enhancing activation of IL-1 receptor. This leads to activation of Src. The changes in membrane expression of GluA1 and GluA2 are reversed by blocking the IL-1 receptor with IL-1Ra or by inhibiting Src with PP2. After Src activation, the pathways for GluA2 and GluA1 diverge. Src increases phosphorylation of GluN2B at Tyr14721 and membrane expression of GluN2B in hyperammonemic rats, leading to activation of MAP kinase p38, which binds to and reduces phosphorylation at Thr560 and activity of PKCζ, resulting in reduced phosphorylation at Ser880 and enhanced membrane expression of GluA2. Increased Src activity in hyperammonemic rats also activates PKCδ which enhances phosphorylation of GluN2B at Ser1303, reducing membrane expression of CaMKII and phosphorylation at Ser831 and membrane expression of GluA1. Conclusions This work identifies two pathways by which neuroinflammation alters glutamatergic neurotransmission in hippocampus. The steps of the pathways identified could be targets to normalize neurotransmission in Hyperammonemia and other pathologies associated with increased IL-1β by acting, for example, on p38 or PKCδ. Graphical abstract IL-1β alters membrane expression of GluA1 and GluA2 AMPA receptor subunits by two difrerent mechanisms in the hippocampus of hyperammonemic rats.
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Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus by enhancing activation of the IL-1 receptor: underlying mechanisms.
Journal of neuroinflammation, 2018Co-Authors: Lucas Taoro-gonzalez, Yaiza M. Arenas, Andrea Cabrera-pastor, Vicente FelipoAbstract:Hyperammonemic rats reproduce the cognitive alterations of patients with hepatic encephalopathy, including altered spatial memory, attributed to altered membrane expression of AMPA receptor subunits in hippocampus. Neuroinflammation mediates these cognitive alterations. We hypothesized that Hyperammonemia-induced increase in IL-1β in hippocampus would be responsible for the altered GluA1 and GluA2 membrane expression. The aims of this work were to (1) assess if increased IL-1β levels and activation of its receptor are responsible for the changes in GluA1 and/or GluA2 membrane expression in Hyperammonemia and (2) identify the mechanisms by which activation of IL-1 receptor leads to altered membrane expression of GluA1 and GluA2. We analyzed in hippocampal slices from control and hyperammonemic rat membrane expression of AMPA receptors using the BS3 cross-linker and phosphorylation of the GluA1 and GluA2 subunits using phosphor-specific antibodies. The IL-1 receptor was blocked with IL-Ra, and the signal transduction pathways involved in modulation of membrane expression of GluA1 and GluA2 were analyzed using inhibitors of key steps. Hyperammonemia reduces GluA1 and increases GluA2 membrane expression and reduces phosphorylation of GluA1 at Ser831 and of GluA2 at Ser880. Hyperammonemia increases IL-1β, enhancing activation of IL-1 receptor. This leads to activation of Src. The changes in membrane expression of GluA1 and GluA2 are reversed by blocking the IL-1 receptor with IL-1Ra or by inhibiting Src with PP2. After Src activation, the pathways for GluA2 and GluA1 diverge. Src increases phosphorylation of GluN2B at Tyr14721 and membrane expression of GluN2B in hyperammonemic rats, leading to activation of MAP kinase p38, which binds to and reduces phosphorylation at Thr560 and activity of PKCζ, resulting in reduced phosphorylation at Ser880 and enhanced membrane expression of GluA2. Increased Src activity in hyperammonemic rats also activates PKCδ which enhances phosphorylation of GluN2B at Ser1303, reducing membrane expression of CaMKII and phosphorylation at Ser831 and membrane expression of GluA1. This work identifies two pathways by which neuroinflammation alters glutamatergic neurotransmission in hippocampus. The steps of the pathways identified could be targets to normalize neurotransmission in Hyperammonemia and other pathologies associated with increased IL-1β by acting, for example, on p38 or PKCδ. IL-1β alters membrane expression of GluA1 and GluA2 AMPA receptor subunits by two difrerent mechanisms in the hippocampus of hyperammonemic rats.
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neuroinflammation increases gabaergic tone and impairs cognitive and motor function in Hyperammonemia by increasing gat 3 membrane expression reversal by sulforaphane by promoting m2 polarization of microglia
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Tiziano Balzano, Lucas Taorogonzalez, Alba Gonzalezusano, Vicente FelipoAbstract:Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in Hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.
Marta Llansola - One of the best experts on this subject based on the ideXlab platform.
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A multi-omic study for uncovering molecular mechanisms associated with Hyperammonemia-induced cerebellar function impairment in rats
Cell Biology and Toxicology, 2021Co-Authors: Sonia Tarazona, Marta Llansola, Héctor Carmona, Ana Conesa, Vicente FelipoAbstract:Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE). Hyperammonemia (HA) and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE. The cerebellum is one of the main cerebral regions affected in MHE. Rats with chronic HA show some motor and cognitive alterations reproducing neurological impairment in cirrhotic patients with MHE. Neuroinflammation and altered neurotransmission and signal transduction in the cerebellum from hyperammonemic (HA) rats are associated with motor and cognitive dysfunction, but underlying mechanisms are not completely known. The aim of this work was to use a multi-omic approach to study molecular alterations in the cerebellum from hyperammonemic rats to uncover new molecular mechanisms associated with Hyperammonemia-induced cerebellar function impairment. We analyzed metabolomic, transcriptomic, and proteomic data from the same cerebellums from control and HA rats and performed a multi-omic integrative analysis of signaling pathway enrichment with the PaintOmics tool. The histaminergic system, corticotropin-releasing hormone, cyclic GMP-protein kinase G pathway, and intercellular communication in the cerebellar immune system were some of the most relevant enriched pathways in HA rats. In summary, this is a good approach to find altered pathways, which helps to describe the molecular mechanisms involved in the alteration of brain function in rats with chronic HA and to propose possible therapeutic targets to improve MHE symptoms.
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Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors
Frontiers Media S.A., 2019Co-Authors: Michele Malaguarnera, Marta Llansola, Tiziano Balzano, Belén Gómez-giménez, Carles Antúnez-muñoz, Núria Martínez-alarcón, Rahebeh Mahdinia, Vicente FelipoAbstract:Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In Hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline
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neuroinflammation increases gabaergic tone and impairs cognitive and motor function in Hyperammonemia by increasing gat 3 membrane expression reversal by sulforaphane by promoting m2 polarization of microglia
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Tiziano Balzano, Lucas Taorogonzalez, Alba Gonzalezusano, Vicente FelipoAbstract:Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in Hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.
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Hyperammonemia induces glial activation neuroinflammation and alters neurotransmitter receptors in hippocampus impairing spatial learning reversal by sulforaphane
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Michele Malaguarnera, Lucas Taorogonzalez, Vicente FelipoAbstract:Background Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic Hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether Hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement.
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impaired release of corticosterone from adrenals contributes to impairment of circadian rhythms of activity in hyperammonemic rats
Archives of Biochemistry and Biophysics, 2013Co-Authors: Marta Llansola, Hanan Ahabrach, Mohammed Errami, Andrea Cabrerapastor, Kaoutar Addaoudi, Vicente FelipoAbstract:Abstract Patients with liver cirrhosis may present impaired sleep-wake and circadian rhythms, relative adrenal insufficiency and altered hypothalamus–pituitary–adrenal gland (HPA) axis. The underlying mechanisms remain unclear. Circadian rhythms are modulated by corticosteroids which secretion is regulated by HPA axis. Hyperammonemia alters circadian rhythms of activity and corticosterone in rats. The aims were: (1) assessing whether corticosterone alterations are responsible for altered circadian rhythm in Hyperammonemia: (2) to shed light on the mechanism by which corticosterone circadian rhythm is altered in Hyperammonemia. The effects of daily corticosterone injection at ZT10 on circadian rhythms of activity, plasma corticosterone, adreno-corticotropic hormone (ACTH) and hypothalamic corticotropic releasing hormone (CRH) were assessed in control and hyperammonemic rats. ACTH-induced corticosterone release was analyzed in cultured adrenal cells. Corticosterone injection restores the corticosterone peak in hyperammonemic rats and their activity and circadian rhythm. Plasma ACTH and CRH in hypothalamus are increased in hyperammonemic rats. Corticosterone injection normalizes ACTH. Chronic Hyperammonemia impairs adrenal function, reduces corticosterone content and ACTH-induced corticosterone release in adrenals, leading to reduced feedback modulation of HPA axis by corticosterone which contributes to impair circadian rhythms of activity. Impaired circadian rhythms and motor activity may be corrected in Hyperammonemia and hepatic encephalopathy by corticosterone treatment.
Seymour Packman - One of the best experts on this subject based on the ideXlab platform.
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Brain MR Imaging in Acute Hyperammonemic Encephalopathy Arising from Late-Onset Ornithine Transcarbamylase Deficiency
2015Co-Authors: Jun-ichi Takanashi, Dana Kostiner, James A. Barkovich, Sabrina F. Cheng, John C. Baker, Seymour PackmanAbstract:Summary: The brain MR imaging characteristics of three patients with acute hyperammonemic encephalopathy re-sulting from late-onset ornithine transcarbomylase defi-ciency are presented. MR images revealed injury to the cortex, especially the cingulate gyrus and insular cortex, with sparing of the perirolandic and occipital cortices. These findings presumably reflect the distribution of brain injury from hypoperfusion secondary to Hyperammonemia. Knowledge of the MR findings may help expedite diagnosis and treatment and prevent chronic impairment. Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of metabolism of the urea cycle, with an incidence of one case per 14,000 live births (1). OTCD is an X-linked disorder charac-terized by signs and symptoms of encephalopathy
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acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male
Hepatology International, 2008Co-Authors: Ophir D Klein, Dana Kostiner, Kara Weisiger, Ellen Moffatt, Neal I Lindeman, Stephen I Goodman, Mendel Tuchman, Seymour PackmanAbstract:Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle defect. While hemizygous males typically present with hyperammonemic coma in infancy, reports of rare late-onset presentations exist, with poor outcomes in males up to 58 years old. Relatives with mutations identical to affected patients often remain asymptomatic, and it is likely that environmental and genetic factors influence disease penetrance and expression. Here, we present our investigation of a patient with late-onset presentation, and we emphasize the potential role of environmental and genetic factors on disease expression. The patient was a previously healthy 62-year-old man who developed mental slowing, refractory seizures, and coma over an 8-day period. Interestingly, the patient had recently used home gardening fertilizers and pesticides. Evaluations for drug and alcohol use, infections, and liver disease were negative. Despite aggressive therapy, blood NH3 concentration peaked at 2,050 μM and the patient died from cerebral edema and cerebellar herniation. Analysis of the OTC gene showed a Pro-225-Thr (P225T) change in exon 7, a mutation that has been previously implicated in OTC deficiency. This case illustrates that OTC deficiency can cause acute, severe Hyperammonemia in a previously healthy adult and that the P225T mutation can be associated with late-onset OTC deficiency. We speculate that exposure to organic chemicals might have contributed to the onset of symptoms in this patient. This case also emphasizes that persistent Hyperammonemia may cause irreversible neurologic damage and that after the diagnosis of Hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle disorders and other causes of hyperammonemic encephalopathy.
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brain mr imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders
American Journal of Neuroradiology, 2003Co-Authors: Jun-ichi Takanashi, James A. Barkovich, Sabrina F. Cheng, Kara Weisiger, Mendel Tuchman, Carol O Zlatunich, Christine Mudge, Philip J Rosenthal, Seymour PackmanAbstract:We present brain MR images in three patients with neonatal-onset hyperammonemic encephalopathy resulting from urea-cycle disorders (two sisters with deficiency of the carbamyl phosphate synthetase I reaction step and one boy with an ornithine transcarbamylase deficiency). MR imaging revealed almost identical findings of injury to the bilateral lentiform nuclei and the deep sulci of the insular and perirolandic regions; to our knowledge, this pattern has not been previously reported. We hypothesize that these lesions presumably reflect the distribution of brain injury due to hypoperfusion secondary to Hyperammonemia and hyperglutaminemia in the neonatal period.
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brain mr imaging in acute hyperammonemic encephalopathy arising from late onset ornithine transcarbamylase deficiency
American Journal of Neuroradiology, 2003Co-Authors: Jun-ichi Takanashi, Dana Kostiner, James A. Barkovich, Sabrina F. Cheng, John C. Baker, Seymour PackmanAbstract:The brain MR imaging characteristics of three patients with acute hyperammonemic encephalopathy resulting from late-onset ornithine transcarbomylase deficiency are presented. MR images revealed injury to the cortex, especially the cingulate gyrus and insular cortex, with sparing of the perirolandic and occipital cortices. These findings presumably reflect the distribution of brain injury from hypoperfusion secondary to Hyperammonemia. Knowledge of the MR findings may help expedite diagnosis and treatment and prevent chronic impairment.
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Hyperammonemia in urea cycle disorders: Role of the nephrologist
American Journal of Kidney Diseases, 2001Co-Authors: Robert Mathias, Dana Kostiner, Seymour PackmanAbstract:Hyperammonemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by irritability, somnolence, vomiting, seizures, and coma. Although the majority of these patients present in the newborn period, they may also present in childhood, adolescence, and adulthood with failure to thrive, persistent vomiting, developmental delay, or behavioral changes. Persistent Hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. After the diagnosis of Hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy. In a patient with a presumed inherited metabolic disorder, the aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Initiation of dialysis in the encephalopathic patient with Hyperammonemia is indicated if the ammonia blood level is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltration and peritoneal dialysis are also effective modalities for reducing blood ammonia levels. An improved understanding of the metabolism of ammonia and neurological consequences of Hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patient population.
Ana Agusti - One of the best experts on this subject based on the ideXlab platform.
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neuroinflammation increases gabaergic tone and impairs cognitive and motor function in Hyperammonemia by increasing gat 3 membrane expression reversal by sulforaphane by promoting m2 polarization of microglia
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Tiziano Balzano, Lucas Taorogonzalez, Alba Gonzalezusano, Vicente FelipoAbstract:Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in Hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.
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Hyperammonemia induces glial activation neuroinflammation and alters neurotransmitter receptors in hippocampus impairing spatial learning reversal by sulforaphane
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Michele Malaguarnera, Lucas Taorogonzalez, Vicente FelipoAbstract:Background Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic Hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether Hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement.
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pregnenolone sulfate restores the glutamate nitric oxide cgmp pathway and extracellular gaba in cerebellum and learning and motor coordination in hyperammonemic rats
ACS Chemical Neuroscience, 2014Co-Authors: Alba Gonzalezusano, Ana Agusti, Omar Cauli, Vicente FelipoAbstract:Around 40% of cirrhotic patients show minimal hepatic encephalopathy (MHE), with mild cognitive impairment which reduces their quality of life and life span. Treatment of MHE is unsatisfactory, and there are no specific treatments for the neurological alterations in MHE. Hyperammonemia is the main contributor to neurological alterations in MHE. New agents acting on molecular targets involved in brain mechanisms leading to neurological alterations are needed to treat MHE. Chronic Hyperammonemia impairs learning of a Y-maze task by impairing the glutamate-nitric-oxide (NO)-cGMP pathway in cerebellum, in part by enhancing GABAA receptor activation, which also induces motor in-coordination. Acute pregnenolone sulfate (PregS) restores the glutamate-NO-cGMP pathway in hyperammonemic rats. This work aimed to assess whether chronic treatment of hyperammonemic rats with PregS restores (1) motor coordination; (2) extracellular GABA in cerebellum; (3) learning of the Y-maze task; (4) the glutamate-NO-cGMP pathway in cerebellum. Chronic intracerebral administration of PregS normalizes motor coordination likely due to extracellular GABA reduction. PregS restores learning ability by restoring the glutamate-NO-cGMP pathway, likely due to both enhanced NMDA receptor activation and reduced GABAA receptor activation. Similar treatments would improve cognitive and motor alterations in patients with MHE.
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Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy
Gastroenterology, 2010Co-Authors: Regina Rodrigo, Omar Cauli, Ulises Gomezpinedo, Ana Agusti, Vicente Hernandezrabaza, Jose Manuel Garciaverdugo, Vicente FelipoAbstract:Background & Aims Hyperammonemia and inflammation cooperate to induce neurological alterations in hepatic encephalopathy. Recent studies in animal models suggest that chronic Hyperammonemia and neuroinflammation impair learning ability by the same mechanism. Chronic Hyperammonemia might induce inflammatory factors in the brain that impair cognitive function. We sought to determine whether Hyperammonemia itself induces neuroinflammation, whether ammonia-induced neuroinflammation mediates cognitive impairment, and whether neuroinflammation also occurs in rats with bile duct ligation (BDL rats)—a model of chronic liver injury that results in Hyperammonemia and hepatic encephalopathy. Methods Chronic moderate Hyperammonemia was induced by feeding male Wistar rats an ammonium-containing diet or performing BDL. Rats that received a standard diet or a sham operation were used as controls. Neuroinflammation was assessed by measuring activation of microglia and inflammatory factors. Brain samples were collected from hyperammonemic and BDL rats; microglial activation was determined by immunohistochemistry and quantification of inflammatory markers (ie, inducible nitric oxide synthase, interleukin-1β, and prostaglandin E2). Learning ability and motor activity were assessed in hyperammonemic and BDL rats given ibuprofen as an anti-inflammatory agent. Results Chronic moderate Hyperammonemia or BDL activated the microglia, especially in cerebellum; increased inducible nitric oxide synthase, interleukin-1β, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls. Ibuprofen reduced microglial activation and restored cognitive and motor functions in the hyperammonemic and BDL rats. Conclusions Chronic Hyperammonemia is sufficient to induce microglial activation and neuroinflammation; these contribute to the cognitive and motor alterations that occur during hepatic encephalopathy.
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Hyperammonemia increases gabaergic tone in the cerebellum but decreases it in the rat cortex
Gastroenterology, 2009Co-Authors: Omar Cauli, Ana Agusti, Mohammad Taghi Mansouri, Vicente FelipoAbstract:Background & Aims GABAA receptors modulate the function of the glutamate-nitric oxide-guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, which is reduced in cerebellum in hyperammonemic rats. It has been proposed that Hyperammonemia-induced increases in γ-aminobutyric acid "(GABAergic) tone" contribute to the pathogenesis of hepatic encephalopathy (HE), although this has not been assessed in vivo in animal models. We studied whether chronic Hyperammonemia in rats increases GABAergic tone in the cerebellum and/or cerebral cortex and whether this increase contributes to cognitive impairment. Methods We blocked GABA A receptors of rats with bicuculline and analyzed the function of this pathway in cerebellum and effects on learning ability. Results Hyperammonemia increased GABAergic tone in cerebellum but decreased it in the cerebral cortex of rats. Increased GABAergic tone in the cerebellum of rats with Hyperammonemia could have been caused by increases in extracellular GABA; tetrahydrodeoxy-corticosterone (a neurosteroid that enhances GABA A receptor activation); or amounts of the α1, α6, and γ2 subunits of GABA A receptors. The decrease in GABAergic tone observed in the cortex could have resulted from the reduced amount of GABA A receptors δ and γ2 subunits or increased levels of pregnanolone (5-fold), which selectively reduces activation of GABA A receptors that contain α4 subunits (widely expressed in cortex but not in cerebellum). Treatment with bicuculline normalized GABAergic tone and restored the increase in cGMP that was induced by activation of N-methyl -d-aspartate receptors and learning ability in hyperammonemic rats. Conclusions Increased GABAergic tone in the cerebellum contributes to cognitive impairment in hyperammonemic rats.
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neuroinflammation increases gabaergic tone and impairs cognitive and motor function in Hyperammonemia by increasing gat 3 membrane expression reversal by sulforaphane by promoting m2 polarization of microglia
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Tiziano Balzano, Lucas Taorogonzalez, Alba Gonzalezusano, Vicente FelipoAbstract:Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in Hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.
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Hyperammonemia induces glial activation neuroinflammation and alters neurotransmitter receptors in hippocampus impairing spatial learning reversal by sulforaphane
Journal of Neuroinflammation, 2016Co-Authors: Vicente Hernandezrabaza, Marta Llansola, Andrea Cabrerapastor, Ana Agusti, Michele Malaguarnera, Lucas Taorogonzalez, Vicente FelipoAbstract:Background Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic Hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether Hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement.
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Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy
Gastroenterology, 2010Co-Authors: Regina Rodrigo, Omar Cauli, Ulises Gomezpinedo, Ana Agusti, Vicente Hernandezrabaza, Jose Manuel Garciaverdugo, Vicente FelipoAbstract:Background & Aims Hyperammonemia and inflammation cooperate to induce neurological alterations in hepatic encephalopathy. Recent studies in animal models suggest that chronic Hyperammonemia and neuroinflammation impair learning ability by the same mechanism. Chronic Hyperammonemia might induce inflammatory factors in the brain that impair cognitive function. We sought to determine whether Hyperammonemia itself induces neuroinflammation, whether ammonia-induced neuroinflammation mediates cognitive impairment, and whether neuroinflammation also occurs in rats with bile duct ligation (BDL rats)—a model of chronic liver injury that results in Hyperammonemia and hepatic encephalopathy. Methods Chronic moderate Hyperammonemia was induced by feeding male Wistar rats an ammonium-containing diet or performing BDL. Rats that received a standard diet or a sham operation were used as controls. Neuroinflammation was assessed by measuring activation of microglia and inflammatory factors. Brain samples were collected from hyperammonemic and BDL rats; microglial activation was determined by immunohistochemistry and quantification of inflammatory markers (ie, inducible nitric oxide synthase, interleukin-1β, and prostaglandin E2). Learning ability and motor activity were assessed in hyperammonemic and BDL rats given ibuprofen as an anti-inflammatory agent. Results Chronic moderate Hyperammonemia or BDL activated the microglia, especially in cerebellum; increased inducible nitric oxide synthase, interleukin-1β, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls. Ibuprofen reduced microglial activation and restored cognitive and motor functions in the hyperammonemic and BDL rats. Conclusions Chronic Hyperammonemia is sufficient to induce microglial activation and neuroinflammation; these contribute to the cognitive and motor alterations that occur during hepatic encephalopathy.