PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine.
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 PI3Kγ on seizures, production of neurotrophic and inflammatory mediators, expression of a marker for microglia, neuronal death and hippocampal neurogenesis in mice (WT and PI3Kγ(-/-)) subjected to intrahippocampal microinjection of pilocarpine. PI3Kγ(-/-) mice presented a more severe status epilepticus (SE) than WT mice. In hippocampal synaptosomes, genetic or pharmacological blockade of PI3Kγ enhanced the release of glutamate and the cytosolic calcium concentration induced by KCl. There was an enhanced neuronal death and a decrease in the doublecortin positive cells in the dentate gyrus of PI3Kγ(-/-) animals after the induction of SE. Levels of BDNF were significantly increased in the hippocampus of WT and PI3Kγ(-/-) mice, although in the prefrontal cortex, only PI3Kγ(-/-) 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 PI3Kγ(-/-) mice. Regarding the levels of inflammatory mediators, pilocarpine injection increased interleukin (IL) 6 in the hippocampus of WT and PI3Kγ(-/-) animals and in the prefrontal cortex of PI3Kγ(-/-) animals 24h after the stimulus. Levels of TNFα were enhanced in the hippocampus and prefrontal cortex of only PI3Kγ(-/-) mice at this time point. On the other hand, PI3Kγ deletion impaired the increase in IL-10 in the hippocampus induced by pilocarpine. In conclusion, the lack of PI3Kγ 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.
Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Isabel Vieira de Assis
IV
Lima
Department of Internal Medicine, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Alline Cristina
AC
Campos
Department of Internal Medicine, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Aline Silva
AS
Miranda
Department of Internal Medicine, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Érica Leandro Marciano
ÉL
Vieira
Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Flávia
F
Amaral-Martins
Department of Clinical and Toxicological Analysis, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Juliana Priscila
JP
Vago
Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Rebeca Priscila de Melo
RP
Santos
Department of Clinical and Toxicological Analysis, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Lirlândia Pires
LP
Sousa
Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Luciene Bruno
LB
Vieira
Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Mauro Martins
MM
Teixeira
Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, D-79104 Freiburg, Germany.
Bernd L
BL
Fiebich
Department of Biophysics and Physiology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Márcio Flávio Dutra
MF
Moraes
Department of Internal Medicine, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil.
Antonio Lucio
AL
Teixeira
Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901, Belo Horizonte, Brazil. Electronic address: antoniooliveira@icb.ufmg.br.
Antonio Carlos Pinheiro
AC
de Oliveira
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency* / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018721:Muscarinic Agonists / Q000633:toxicity*; D009479:Neuropeptides / Q000378:metabolism; D010862:Pilocarpine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011810:Quinoxalines / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics*; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000627:therapeutic use; D013997:Time Factors
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D018721:Muscarinic Agonists; D009479:Neuropeptides; D011810:Quinoxalines; D045162:Thiazolidinediones; D010862:Pilocarpine; D018698:Glutamic Acid; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D002118:Calcium
Cytokines; Glutamate; Microglia; Neurodegeneration; Neurotrophins; Phosphatidylinositol 3-kinase; Pilocarpine; Seizures