Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice

Amaral, Alexandre Umpierrez; Seminotti, Bianca; Silva, Janaína Camacho da; Oliveira, Francine Hehn de; Ribeiro, Rafael Teixeira; Vargas, Carmen Regla; Leipnitz, Guilhian; Santamarı́a, Abel; Souza, Diogo O.; Wajner, Moaçir

doi:10.1007/s12640-017-9848-0

Cited by 6 publications

(4 citation statements)

References 64 publications

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“…Otherwise, QA provoked extensive vacuolation and edema in Gcdh‐/‐ mice striatum. A further study showed that QA enhanced CD3 staining and the number of YNO2 positive cells in these animals, implying T lymphocyte infiltration and nitrosative stress, respectively (Amaral et al, 2018). Synergistic toxic effects of QA and GA in neuronal cultures, co‐cultures and mixed cultures from WT rat cerebral cortex and striatum has been also recently described, strengthening a synergistic role of QA and GA in GA I neurodegeneration (Pierozan et al, 2018; Kotlar et al, 2019).…”

Section: Oxidative Stress and Neuroinflammation In Gcdh−/− Micementioning

confidence: 94%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3‐hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh−/−) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood‐brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

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Section: Oxidative Stress and Neuroinflammation In Gcdh−/− Micementioning

confidence: 94%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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“…After the administration, the syringe was left in place for an additional 30‐s period and then slowly withdrawn. The dose of QA used was based on previous studies (Amaral et al., 2018; Seminotti et al., 2016). According to the treatment and the diet received, the animals were divided into six final groups as follows: Gcdh +/+ ‐Lys‐V group, Gcdh +/+ ‐Lys‐QA group, Gcdh −/− ‐Lys‐V group, Gcdh −/− ‐Lys‐QA group, Gcdh −/− ‐N‐V group; and Gcdh −/− ‐N‐QA group.…”

Section: Methodsmentioning

confidence: 99%

Increased susceptibility to quinolinic acid‐induced seizures and long‐term changes in brain oscillations in an animal model of glutaric acidemia type I

Caus

Pasquetti

Seminotti

et al. 2021

J of Neuroscience Research

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Glutaric acidemia type I (GA‐I) is an inborn error of metabolism of lysine, hydroxylysine, and tryptophan, caused by glutaryl‐CoA‐dehydrogenase (GCDH) deficiency, characterized by the buildup of toxic organic acids predominantly in the brain. After acute catabolic states, patients usually develop striatal degeneration, but the mechanisms behind this damage are still unknown. Quinolinic acid (QA), a metabolite of the kynurenine pathway, increases especially during infections/inflammatory processes, and could act synergically with organic acids, contributing to the neurological features of GA‐I. The aim of this study was to investigate whether QA increases seizure susceptibility and modifies brain oscillation patterns in an animal model of GA‐I, the Gcdh−/− mice taking high‐lysine diet (Gcdh−/−‐Lys). Therefore, the characteristics of QA‐induced seizures and changes in brain oscillatory patterns were evaluated by video‐electroencephalography (EEG) analysis recorded in Gcdh−/−‐Lys, Gcdh+/+‐Lys, and Gcdh−/−‐N (normal diet) animals. We found that the number of seizures per animal was similar for all groups receiving QA, Gcdh−/−‐Lys‐QA, Gcdh+/+‐Lys‐QA, and Gcdh−/−‐N‐QA. However, severe seizures were observed in the majority of Gcdh−/−‐Lys‐QA mice (82%), and only in 25% of Gcdh+/+‐Lys‐QA and 44% of Gcdh−/−‐N‐QA mice. All Gcdh−/−‐Lys animals developed spontaneous recurrent seizures (SRS), but Gcdh−/−‐Lys‐QA animals had increased number of SRS, higher mortality rate, and significant predominance of lower frequency oscillations on EEG. Our results suggest that QA plays an important role in the neurological features of GA‐I, as Gcdh−/−‐Lys mice exhibit increased susceptibility to intrastriatal QA‐induced seizures and long‐term changes in brain oscillations.

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“…Since QA cannot cross the blood-brain barrier (BBB), it is usually administered in the striatum. QA causes striatal neurodegeneration by excitotoxicity in rats [ 68 ], mice [ 69 ], and primates [ 70 ], like in human HD [ 71 ], and although it does not affect interneurons, it induces astrogliosis [ 72 ] and motor and cognitive symptoms [ 73 ] similar to those of HD.…”

Section: Hd Rodent Modelsmentioning

confidence: 99%

“…Non-genetic models reproduce increased GFAP expression in the striatum. Intrastriatal administration of QA induces astrogliosis in the striatum of rats [ 68 , 72 ] and mice [ 69 ]. Likewise, the intraperitoneal administration of 3NP induces higher GFAP immunoreactivity in the striatum of rats [ 105 - 109 ] and mice [ 110 , 111 ], although when the 3NP dose is high, it kills neurons and astrocytes so that the lesion zone lacks GFAP staining while the marginal area shows increased GFAP immunoreactivity [ 106 ].…”

Section: Hd Rodent Modelsmentioning

confidence: 99%

Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

Saba

Couselo

Bruno

et al. 2022

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: Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia and astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison with other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.

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Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice

Cited by 6 publications

References 64 publications

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Increased susceptibility to quinolinic acid‐induced seizures and long‐term changes in brain oscillations in an animal model of glutaric acidemia type I

Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

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