P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice
Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, res...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1179723/full |
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| author | Vinícius Santos Alves Joyce Pereira da Silva Fabiana Cristina Rodrigues Suzana Maria Bernardino Araújo André Luiz Gouvêa Raíssa Leite-Aguiar Stephanie Alexia Cristina Silva Santos Milla Souza Pessoa da Silva Fernanda Silva Ferreira Eduardo Peil Marques Beatriz Amanda Barbosa Rangel dos Passos Tatiana Maron-Gutierrez Eleonora Kurtenbach Robson da Costa Cláudia Pinto Figueiredo Angela T. S. Wyse Robson Coutinho-Silva Luiz Eduardo Baggio Savio |
| author_facet | Vinícius Santos Alves Joyce Pereira da Silva Fabiana Cristina Rodrigues Suzana Maria Bernardino Araújo André Luiz Gouvêa Raíssa Leite-Aguiar Stephanie Alexia Cristina Silva Santos Milla Souza Pessoa da Silva Fernanda Silva Ferreira Eduardo Peil Marques Beatriz Amanda Barbosa Rangel dos Passos Tatiana Maron-Gutierrez Eleonora Kurtenbach Robson da Costa Cláudia Pinto Figueiredo Angela T. S. Wyse Robson Coutinho-Silva Luiz Eduardo Baggio Savio |
| author_sort | Vinícius Santos Alves |
| collection | DOAJ |
| description | Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice.Methods: Sepsis was induced in wild-type (WT), P2X7−/−, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated.Results: Initially, we observed that both WT and P2X7−/− sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba−1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7−/− sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10).Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target. |
| first_indexed | 2024-04-09T17:01:40Z |
| format | Article |
| id | doaj.art-404e1516ba5445f7a2f38678c8143349 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-09T17:01:40Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-404e1516ba5445f7a2f38678c81433492023-04-21T04:40:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-04-011410.3389/fphar.2023.11797231179723P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving miceVinícius Santos Alves0Joyce Pereira da Silva1Fabiana Cristina Rodrigues2Suzana Maria Bernardino Araújo3André Luiz Gouvêa4Raíssa Leite-Aguiar5Stephanie Alexia Cristina Silva Santos6Milla Souza Pessoa da Silva7Fernanda Silva Ferreira8Eduardo Peil Marques9Beatriz Amanda Barbosa Rangel dos Passos10Tatiana Maron-Gutierrez11Eleonora Kurtenbach12Robson da Costa13Cláudia Pinto Figueiredo14Angela T. S. Wyse15Robson Coutinho-Silva16Luiz Eduardo Baggio Savio17Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilFaculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilLaboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilLaboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, BrazilLaboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilFaculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilFaculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilIntroduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice.Methods: Sepsis was induced in wild-type (WT), P2X7−/−, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated.Results: Initially, we observed that both WT and P2X7−/− sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba−1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7−/− sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10).Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.https://www.frontiersin.org/articles/10.3389/fphar.2023.1179723/fullsepsis-associated encephalopathyP2X7 receptorcognitive impairmentneuroinflammationBrilliant Blue Gacetylcholinesterase |
| spellingShingle | Vinícius Santos Alves Joyce Pereira da Silva Fabiana Cristina Rodrigues Suzana Maria Bernardino Araújo André Luiz Gouvêa Raíssa Leite-Aguiar Stephanie Alexia Cristina Silva Santos Milla Souza Pessoa da Silva Fernanda Silva Ferreira Eduardo Peil Marques Beatriz Amanda Barbosa Rangel dos Passos Tatiana Maron-Gutierrez Eleonora Kurtenbach Robson da Costa Cláudia Pinto Figueiredo Angela T. S. Wyse Robson Coutinho-Silva Luiz Eduardo Baggio Savio P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice Frontiers in Pharmacology sepsis-associated encephalopathy P2X7 receptor cognitive impairment neuroinflammation Brilliant Blue G acetylcholinesterase |
| title | P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice |
| title_full | P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice |
| title_fullStr | P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice |
| title_full_unstemmed | P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice |
| title_short | P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice |
| title_sort | p2x7 receptor contributes to long term neuroinflammation and cognitive impairment in sepsis surviving mice |
| topic | sepsis-associated encephalopathy P2X7 receptor cognitive impairment neuroinflammation Brilliant Blue G acetylcholinesterase |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1179723/full |
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