Participação do receptor P2x7 nos efeitos de longo prazo da inflamação sistêmica neonatal: estresse oxidativo hipocampal, alteração da nocicepção e ansiedade
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Data
2018-03-29
Autores
Silva, Clivandir Severino da [UNIFESP]
Orientadores
Mello, Luiz Eugenio Araujo de Moraes [UNIFESP]
Tipo
Dissertação de mestrado
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Objetivos: Avaliar os efeitos da inflamação sistêmica no período neonatal
sobre a taxa de mortalidade, a massa corporal, o comportamento associado à
ansiedade, a nocicepção e o estresse oxidativo no giro denteado do hipocampo em
longo prazo e se o bloqueio do receptor P2X7 (P2X7R) com Brilliant Blue G (BBG)
modula os efeitos da inflamação sobre essas variáveis. Metodologia: Filhotes de
ratos da cepa Wistar norvegicus (machos e fêmeas) foram distribuídos nos
grupos experimentais NAIVE, salina (SAL)+SAL, SAL+lipopolissacarídeo (LPS) e
BBG+LPS. As soluções foram injetadas via intraperitoneal no primeiro, terceiro,
quinto e sétimo dia pós-natal (DPN). A massa corporal foi analisada no DPN1,
DPN10, DPN21, DPN45 e DPN89. No DPN80, DPN82 e DPN84 foram realizados
respectivamente os testes do labirinto em cruz elevado, da placa quente e de
retirada da cauda. Os animais foram perfundidos no DPN89 e os encéfalos
extraídos. Os encéfalos foram cortados em fatias coronais e algumas, contendo o
hipocampo, coradas com etidina. Resultados: Os animais expostos à inflamação
sistêmica neonatal (grupo SAL+LPS) apresentaram aumento da taxa de mortalidade
nas primeiras semanas de vida, atraso transitório no ganho de massa corporal e
aumento da concentração de ânion superóxido no giro denteado do hipocampo na
fase adulta quando comparados com os animais dos grupos controles (grupos
NAIVE e SAL+SAL) e o bloqueio do P2X7R (grupo BBG+LPS) reduziu a taxa de
mortalidade e a concentração de ânion superóxido. A exposição à inflamação não
induziu comportamento associado à ansiedade e alteração da nocicepção em longo
prazo. Conclusão: A ativação do P2X7R durante o processo inflamatório sistêmico
no período neonatal colabora para desencadear eventos fisiopatológicos que podem
culminar com a morte dos neonatos e, caso ela não ocorra, promove estresse
oxidativo na idade adulta no giro denteado do hipocampo, por induzir aumento da
produção de ânion superóxido. Portanto, o bloqueio da ativação do P2X7R, usando
BBG, pode ser uma estratégia para reduzir a taxa mortalidade decorrente de complicações da inflamação sistêmica neonatal e prevenir alterações no tecido nervoso associadas ao estresse oxidativo.
Aims: To evaluate the effects of systemic inflammation in the neonatal period on mortality, body weight, anxiety behavior pain sensitivity and oxidative stress production in the hippocampus dentate gyrus during adulthood, and analyze whether P2X7 receptor (P2X7R) blockade with Brilliant Blue G (BBG) modulates the inflammatory effects on these variables. Methods: Wistar norvegicus (male and female) rat pups were allocated in the experimental groups NAIVE, saline (SAL)+SAL, SAL+lipopolysaccharide (LPS) and BBG+LPS. The solutions were injected intraperitoneally on the first, third, fifth and seventh postnatal day (PND). The body weight was measured on PND1, PND10, PND21, PND45 and PND89. The elevated plus maze, hot plate and tail withdrawal test were performed on PND80, PND82 and PND84 respectively. The animals were perfused on PND89, their brains extracted and cut into coronal slices. Segments those containing the hippocampus were stained with etidine. Results: Animals exposed to systemic neonatal inflammation (SAL+LPS group) presented higher mortality, transient delay in body weight gain and higher production of anion superoxide in the dentate gyrus of hippocampus during adulthood when compared to both control groups (NAIVE and SAL+SAL groups). In addition, it was observed a decrease in mortality and anion superoxide concentration in the P2X7R blockade group (BBG+LPS group). No significant differences were found regarding anxiety behavior and pain sensitivity between the study groups. Conclusion: P2X7R activation throughout exposure to systemic inflammatory processes in the neonatal period triggers pathophysiology events that can lead to death. Surviving animals presents increase in oxidative stress production in the hippocampus dentate gyrus during adulthood. Thus, blocking P2X7R activation with BBG during the inflammatory process could promote an antioxidant effect and, thereby is presented here as a promising strategy to prevent neurological and/or psychiatric disorders and disorders associated with oxidative stress.
Aims: To evaluate the effects of systemic inflammation in the neonatal period on mortality, body weight, anxiety behavior pain sensitivity and oxidative stress production in the hippocampus dentate gyrus during adulthood, and analyze whether P2X7 receptor (P2X7R) blockade with Brilliant Blue G (BBG) modulates the inflammatory effects on these variables. Methods: Wistar norvegicus (male and female) rat pups were allocated in the experimental groups NAIVE, saline (SAL)+SAL, SAL+lipopolysaccharide (LPS) and BBG+LPS. The solutions were injected intraperitoneally on the first, third, fifth and seventh postnatal day (PND). The body weight was measured on PND1, PND10, PND21, PND45 and PND89. The elevated plus maze, hot plate and tail withdrawal test were performed on PND80, PND82 and PND84 respectively. The animals were perfused on PND89, their brains extracted and cut into coronal slices. Segments those containing the hippocampus were stained with etidine. Results: Animals exposed to systemic neonatal inflammation (SAL+LPS group) presented higher mortality, transient delay in body weight gain and higher production of anion superoxide in the dentate gyrus of hippocampus during adulthood when compared to both control groups (NAIVE and SAL+SAL groups). In addition, it was observed a decrease in mortality and anion superoxide concentration in the P2X7R blockade group (BBG+LPS group). No significant differences were found regarding anxiety behavior and pain sensitivity between the study groups. Conclusion: P2X7R activation throughout exposure to systemic inflammatory processes in the neonatal period triggers pathophysiology events that can lead to death. Surviving animals presents increase in oxidative stress production in the hippocampus dentate gyrus during adulthood. Thus, blocking P2X7R activation with BBG during the inflammatory process could promote an antioxidant effect and, thereby is presented here as a promising strategy to prevent neurological and/or psychiatric disorders and disorders associated with oxidative stress.
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Citação
SILVA, Clivandir Severino da. Participação do receptor P2x7 nos efeitos de longo prazo da inflamação sistêmica neonatal: estresse oxidativo hipocampal, alteração da nocicepção e ansiedade. 2018. 121 f. Dissertação (Mestrado em Neurologia e Neurociências) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2018.