Efeitos do tratamento com a galantamina na prole de genitores submetidos a sobrecarga de frutose: papel do reflexo colinérgico anti-inflamatório
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2024-06-27
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Tese de doutorado
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Objetivo: Investigamos os efeitos neuroimunes, cardiometabólicos e autonômicos do tratamento com a galantamina (GAL) na prole de genitores de ratos submetidos ao consumo crônico de frutose, bem como a participação do reflexo colinérgico anti-inflamatório, por meio da desnervação dos nervos esplênico e colinérgicos, nessa condição. Métodos: Foram utilizados ratos Wistar (genitores) que foram submetidos à sobrecarga de frutose na água de beber (10%) ou ao consumo de água por 60 dias. Em seguida, os genitores foram alocados em caixas para propiciar o acasalamento. A sobrecarga de frutose para as fêmeas foi mantida até o final da lactação. Aos 21 dias de vida (final da lactação) a prole dos genitores (n=40), foi separada em 4 grupos (5 machos e 5 fêmeas por grupo): controle (C), frutose (F), frutose tratado com GAL (GAL) e frutose desnervado tratado com a GAL (D+GAL) (5mg/Kg/ v.o.). Tais grupos, receberam ração padrão e água ad libitum, e foram avaliados e comparados após 30 dias (4 semanas) do desmame quanto a parâmetros metabólicos, hemodinâmicos, neuroimunes (autonômicos e inflamatórios) e de estresse oxidativo. Resultados: O grupo F apresentou redução da constante de decaimento da glicose plasmática (KITT) e aumento da pressão arterial média (PAM) e da frequência cardíaca (FC) (vs. C). Já o grupo GAL teve redução do KITT e da PAM (vs. F e D+GAL) e FC (vs. F). O grupo D+GAL apresentou aumento do KITT, PAM e FC (vs. C). Na modulação autonômica, o grupo F teve redução da variância do intervalo de pulso (Var-IP) e da banda de alta frequência normalizado (HF-IP (nu)), e aumento da banda de baixa frequência normalizado (LF-IP (nu)) e do balanço simpato vagal (LF/HF) cardíacos (vs. C). Os grupos GAL e D+GAL apresentaram aumento do RMSSD, da banda de alta frequência normalizada (HF-IP (nu)) e diminuição do LF-IP (nu) e do LF/HF (vs. F). O grupo F teve aumento (vs. C) na variância e na banda de baixa frequência da pressão arterial sistólica (LF-PAS), enquanto o grupo GAL apresentou diminuição nesses índices. Já o grupo D+GAL manteve o aumento da variância da PAS e do LF-PAS (vs. C). Na sensibilidade do barorreflexo o grupo F apresentou diminuição das respostas bradicárdica e taquicárdica (vs. C). O grupo GAL apresentou aumento das respostas bradicárdica (vs. F) e taquicárdica (vs. F e D+ GAL) . No baço somente os grupos F e D+GAL apresentaram aumento de TNF- α (vs.xC). No entanto, no coração o grupo F teve aumento de TNF-α e da NADPH oxidase e redução da FRAP e da atividade da CAT (vs. C), o que não foi observado nos grupos GAL e D+GAL. Não houve diferença entre os grupos para dano oxidativo avaliado por lipoperoxidação e oxidação de proteínas no coração e no baço. Conclusão: A prole de ratos submetidos ao consumo exacerbado de frutose apresentou, antes da maturação sexual, disfunções cardiometabólicas acompanhadas de alterações neuroimunes e desbalanço de marcadores pró e antioxidantes. A tratamento com GAL atenuou essas alterações, demonstrando papel fundamental da disfunção autonômica. A desnervação esplênica, apesar de não alterar os benefícios cardíacos, impediu a modulação da inflamação no baço, da disautonomia vascular e da pressão arterial induzidas pela GAL, sugerindo participação do reflexo colinérgico inflamatório nesta condição.
Objective: We investigated the neuroimmune, cardiometabolic and autonomic effects of galantamine (GAL) treatment in the offspring of rats subjected to chronic fructose consumption, as well as the participation of the anti-inflammatory cholinergic reflex, through denervation of the splenic and cholinergic nerves, in this condition. Methods: Wistar rats (parents) were subjected to fructose overload in their drinking water (10%) or water consumption for 60 days. The parents were then placed in boxes to encourage mating. Fructose overload for the females was maintained until the end of lactation. At 21 days old (end of lactation), the offspring of the parents (n=40) were divided into 4 groups (5 males and 5 females per group): control (C), fructose (F), fructose treated with GAL (GAL) and denervated fructose treated with GAL (D+GAL) (5mg/Kg/ v.o.). These groups received standard feed and water ad libitum and were assessed and compared 30 days (4 weeks) after weaning for metabolic, hemodynamic, neuroimmune (autonomic and inflammatory) and oxidative stress parameters. Results: The F group showed a reduction in the plasma glucose decay constant (KITT) and an increase in mean arterial pressure (MAP) and heart rate (HR) (vs. C). The GAL group had a reduction in Kitt and MAP (vs. F and D+GAL) and HR (vs. F). The D+GAL group had an increase in KITT, MAP and HR (vs. C). Regarding autonomic modulation, the F group had a reduction in pulse interval variance (Var-IP) and normalized high frequency band (HF-IP (nu)), and an increase in normalized low frequency band (LF-IP (nu)) and cardiac sympathovagal balance (LF/HF) (vs. C). The GAL and D+GAL groups showed an increase in RMSSD, normalized high frequency band (HF-IP (nu)) and a decrease in LF-IP (nu) and LF/HF (vs. F). The F group showed an increase (vs. C) in the variance and low-frequency band of systolic blood pressure (LF-PAS), while the GAL group showed a decrease in these indices. The D+GAL group maintained the increase in SBP variance and LF-PAS (vs. C). Regarding the baroreflex sensitivity, the F group showed a decrease in bradycardic and tachycardic responses (vs. C). The GAL group showed an increase in bradycardic (vs. F) and tachycardic responses (vs. F and D+ GAL). In the spleen, the only F and D+GAL groups showed an increase in TNF-α (vs. C). However, in the heart the F group showed an increase in TNF-α and NADPH oxidase and a reduction in FRAP and CAT activity (vs. C), which was not observed in the GAL and D+GAL groups. There was no difference between the groups in terms of oxidative damage assessed by lipoperoxidation and protein oxidation in the heart and spleen. Conclusion: The offspring of rats subjected to exacerbated fructose consumption showed cardiometabolic dysfunctions before sexual maturation, accompanied by neuroimmune alterations and an imbalance of pro- and antioxidant markers. Treatment with GAL attenuated these alterations, demonstrating the fundamental role of autonomic dysfunction. Although splenic denervation did not alter the cardiac benefits, it did prevent the modulation of inflammation in the spleen, vascular dysautonomia and blood pressure induced by GAL, suggesting the involvement of the inflammatory cholinergic reflex in this condition.
Objective: We investigated the neuroimmune, cardiometabolic and autonomic effects of galantamine (GAL) treatment in the offspring of rats subjected to chronic fructose consumption, as well as the participation of the anti-inflammatory cholinergic reflex, through denervation of the splenic and cholinergic nerves, in this condition. Methods: Wistar rats (parents) were subjected to fructose overload in their drinking water (10%) or water consumption for 60 days. The parents were then placed in boxes to encourage mating. Fructose overload for the females was maintained until the end of lactation. At 21 days old (end of lactation), the offspring of the parents (n=40) were divided into 4 groups (5 males and 5 females per group): control (C), fructose (F), fructose treated with GAL (GAL) and denervated fructose treated with GAL (D+GAL) (5mg/Kg/ v.o.). These groups received standard feed and water ad libitum and were assessed and compared 30 days (4 weeks) after weaning for metabolic, hemodynamic, neuroimmune (autonomic and inflammatory) and oxidative stress parameters. Results: The F group showed a reduction in the plasma glucose decay constant (KITT) and an increase in mean arterial pressure (MAP) and heart rate (HR) (vs. C). The GAL group had a reduction in Kitt and MAP (vs. F and D+GAL) and HR (vs. F). The D+GAL group had an increase in KITT, MAP and HR (vs. C). Regarding autonomic modulation, the F group had a reduction in pulse interval variance (Var-IP) and normalized high frequency band (HF-IP (nu)), and an increase in normalized low frequency band (LF-IP (nu)) and cardiac sympathovagal balance (LF/HF) (vs. C). The GAL and D+GAL groups showed an increase in RMSSD, normalized high frequency band (HF-IP (nu)) and a decrease in LF-IP (nu) and LF/HF (vs. F). The F group showed an increase (vs. C) in the variance and low-frequency band of systolic blood pressure (LF-PAS), while the GAL group showed a decrease in these indices. The D+GAL group maintained the increase in SBP variance and LF-PAS (vs. C). Regarding the baroreflex sensitivity, the F group showed a decrease in bradycardic and tachycardic responses (vs. C). The GAL group showed an increase in bradycardic (vs. F) and tachycardic responses (vs. F and D+ GAL). In the spleen, the only F and D+GAL groups showed an increase in TNF-α (vs. C). However, in the heart the F group showed an increase in TNF-α and NADPH oxidase and a reduction in FRAP and CAT activity (vs. C), which was not observed in the GAL and D+GAL groups. There was no difference between the groups in terms of oxidative damage assessed by lipoperoxidation and protein oxidation in the heart and spleen. Conclusion: The offspring of rats subjected to exacerbated fructose consumption showed cardiometabolic dysfunctions before sexual maturation, accompanied by neuroimmune alterations and an imbalance of pro- and antioxidant markers. Treatment with GAL attenuated these alterations, demonstrating the fundamental role of autonomic dysfunction. Although splenic denervation did not alter the cardiac benefits, it did prevent the modulation of inflammation in the spleen, vascular dysautonomia and blood pressure induced by GAL, suggesting the involvement of the inflammatory cholinergic reflex in this condition.
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MIRANDA, Victor Hugo Martins de. Efeitos do tratamento com a galantamina na prole de genitores submetidos a sobrecarga de frutose: papel do reflexo colinérgico anti-inflamatório. 2024. 115 f. Tese (Doutorado em Medicina Translacional) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2024.