PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine

被引：11

作者：

de Assis Lima, Isabel Vieira ^{[1
]}

Campos, Alline Cristina ^{[2
]}

Miranda, Aline Silva ^{[2
]}

Marciano Vieira, Erica Leandro ^{[2
]}

Amaral-Martins, Flavia ^{[1
]}

Vago, Juliana Priscila ^{[3
]}

de Melo Santos, Rebeca Priscila ^{[1
]}

Sousa, Lirlandia Pires ^{[3
]}

Vieira, Luciene Bruno ^{[1
]}

Teixeira, Mauro Martins ^{[4
]}

Fiebich, Bernd L. ^{[6
]}

Dutra Moraes, Marcio Flavio ^{[5
]}

Teixeira, Antonio Lucio ^{[2
]}

Pinheiro de Oliveira, Antonio Carlos ^{[1
]}

机构：

[1] Univ Fed Minas Gerais, Dept Pharmacol, BR-31270901 Belo Horizonte, MG, Brazil

[2] Univ Fed Minas Gerais, Dept Internal Med, BR-31270901 Belo Horizonte, MG, Brazil

[3] Univ Fed Minas Gerais, Dept Clin & Toxicol Anal, BR-31270901 Belo Horizonte, MG, Brazil

[4] Univ Fed Minas Gerais, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil

[5] Univ Fed Minas Gerais, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, Brazil

[6] Univ Freiburg, Sch Med, Dept Psychiat, D-79104 Freiburg, Germany

来源：

EXPERIMENTAL NEUROLOGY | 2015年 / 267卷

关键词：

Phosphatidylinositol; 3-kinase; Seizures; Cytokines; Neurodegeneration; Neurotrophins; Microglia; Glutamate; Pilocarpine; TEMPORAL-LOBE EPILEPSY; PHOSPHOINOSITIDE 3-KINASE GAMMA; BORN GRANULE CELLS; RAT DENTATE GYRUS; STATUS EPILEPTICUS; NMDA RECEPTOR; PHOSPHATIDYLINOSITOL; 3-KINASE; HIPPOCAMPAL NEUROGENESIS; DIFFERENTIAL REGULATION; MICROGLIAL ACTIVATION;

D O I：

10.1016/j.expneurol.2015.02.021

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Phosphatidylinositol 3-kinase (PI3K) is an enzyme involved in different pathophysiological processes, including neurological disorders. However, its role in seizures and postictal outcomes is still not fully understood. We investigated the role of PI3K gamma on seizures, production of neurotrophic and inflammatory mediators, expression of a marker for microglia, neuronal death and hippocampal neurogenesis in mice (WT and PI3K gamma(-/-)) subjected to intrahippocampal microinjection of pilocarpine. PI3K gamma(-/-) mice presented a more severe status epilepticus (SE) than WT mice. In hippocampal synaptosomes, genetic or pharmacological blockade of PI3K gamma enhanced the release of glutamate and the cytosolic calcium concentration induced by KCI. There was an enhanced neuronal death and a decrease in the doublecortin positive cells in the dentate gyrus of PI3K gamma(-/-) animals after the induction of SE. Levels of BDNF were significantly increased in the hippocampus of WT and PI3K gamma(-/-) mice, although in the prefrontal cortex, only PI3K gamma(-/-) animals showed significant increase in the levels of this neurotrophic factor. Pilocarpine increased hippocampal microglial immunolabeling in both groups, albeit in the prelimbic, medial and motor regions of the prefrontal cortex this increase was observed only in PI3K gamma(-/-) mice. Regarding the levels of inflammatory mediators, pilocarpine injection increased interleukin (IL) 6 in the hippocampus of WT and PI3K gamma(-/-) animals and in the prefrontal cortex of PI3K gamma(-/-) animals 24 h after the stimulus. Levels of TNF alpha were enhanced in the hippocampus and prefrontal cortex of only PI3K gamma(-/-) mice at this time point. On the other hand, PI3K gamma(-/-) deletion impaired the increase in IL-10 in the hippocampus induced by pilocarpine. In conclusion, the lack of PI3K gamma revealed a deleterious effect in an animal model of convulsions induced by pilocarpine, suggesting that this enzyme may play a protective role in seizures and pathological outcomes associated with this condition. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：123 / 134

页数：12

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