Investigação de parâmetros reprodutivos em ratos machos expostos ao psicoestimulante Lisdexanfetamina do período juvenil a peripuberdade
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Data
2023-02-28
Autores
Stein, Julia [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
O transtorno de déficit de atenção e hiperatividade (TDAH) é um distúrbio do neurodesenvolvimento comum em crianças e adolescentes, com maior incidência de diagnósticos no sexo masculino. Desatenção, hiperatividade e impulsividade em níveis acima do esperado são os principais sintomas do TDAH, afetando negativamente a vida diária dos pacientes. O tratamento adequado é essencial e baseia-se numa estratégia multimodal, com intervenções cognitivo-comportamentais e tratamento farmacológico, geralmente com medicações estimulantes. Um dos principais medicamentos utilizado é o Dimesilato de Lisdexanfetamina (LDX), uma formulação de liberação prolongada, pois é uma pró-droga da dextroanfetamina, hidrolisada no interior dos eritrócitos. Sua ação é mediada pelo aumento dos níveis de catecolaminas, principalmente dopamina e noradrenalina, nas fendas sinápticas. Como os neurotransmissores influenciam o controle hormonal e atuam diretamente nas gônadas, a LDX poderia interferir no desempenho reprodutivo. O período juvenil e a peripuberdade são janelas críticas do desenvolvimento, mais susceptíveis ao efeito de substâncias exógenas. Assim, o objetivo deste estudo foi avaliar os efeitos da exposição ao LDX do período juvenil até a peripuberdade sobre os parâmetros de toxicidade sistêmica e reprodutiva de ratos machos. Ratos Wistar machos (23 dias de idade) foram divididos em um grupo controle (água deionizada) e três grupos expostos a LDX em doses terapêuticas (convertidas para dose animais): 5,2; 8,6 e 12,1 mg/kg/dia. O tratamento ocorreu do dia pós natal 23 (DPN) ao 53, via gavage. Durante o tratamento, foram avaliados sinais clínicos de toxicidade, peso corporal, ingestão de água e ração, comportamento social de brincar e estabelecimento da puberdade. No dia pós-natal (PND) 54, metade dos animais foi morta para peso dos órgãos, análise hematológica e bioquímica, histologia testicular e estresse oxidativo do testículo. Na vida adulta (PND 90), os animais foram avaliados quanto ao comportamento sexual masculino e parâmetros de fertilidade. No DPN 120, os animais foram mortos para registro do peso dos órgãos, parâmetros hematológicos e espermáticos, contratilidade do ducto deferente, histologia testicular e estresse oxidativo do testículo. Observou-se redução no consumo diário de ração e água durante o período de tratamento. Na avaliação do comportamento social de brincar, os animais apresentaram redução nos comportamentos sociais totais. Nenhum grupo experimental teve o dia da separação prepucial alterado em relação ao controle, mas o peso dos animais do grupo de maior dose foi reduzido neste dia. No DPN 54, vários parâmetros foram alterados, principalmente relacionados à toxicidade sistêmica: redução do ganho de peso corporal, aumento do peso relativo do fígado, baço e glândula seminal, redução da contagem de eritrócitos e leucócitos, redução dos níveis de proteínas totais e alterações em parâmetros oxidativos. Na idade adulta, o comportamento sexual masculino e a fertilidade não foram alterados. Já no DPN 120, houve aumento de espermatozoides do tipo C (imóvel), diminuição da contagem nos testículos e epidídimos, alterações histológicas nas células de Leydig e nos túbulos seminíferos e alteração dos parâmetros oxidativos. Com base nos dados apresentados, o LDX foi capaz de induzir distúrbios nos parâmetros toxicológicos sistêmicos (principalmente durante o tratamento) e na função reprodutiva (principalmente na vida adulta), indicando que o uso deste medicamento deve considerar esses aspectos
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, with a higher incidence of diagnoses in male sex. Inattention, hyperactivity and impulsivity in levels above expected are the main symptoms in ADHD, negatively affecting patients’ daily life. Proper treatment is essential and it is based on a multimodal strategy, with cognitive-behavioral interventions and pharmacological treatment, usually with stimulants medications. One of the main drugs is Lisdexamfetamine Dimesylate (LDX), an extended-release formulation since it is a prodrug of dextroamphetamine, hydrolyzed inside erythrocytes. Its action is mediated by increased levels of catecholamines, mainly dopamine and noradrenaline, in synaptic clefts. Neurotransmitters influence hormonal control and act directly in gonads, so LDX could interfere in reproductive performance. Juvenile and peripubertal period are critical windows of development, more susceptible to the effect of exogenous substances. The aim was to evaluate the effects of exposure to Lisdexamfetamine during the juvenile to peripubertal period on parameters of systemic and reproductive toxicity of male rats. Male Wistar rats (23 days old) were divided into a control group (deionized water) and three groups exposed to LDX in therapeutic doses (converted to animal doses): 5.2; 8.6 and 12.1 mg/kg/day. The treatment occurred from post-natal day 23 (PND) to 53, by gavage. During the treatment, clinical signs of toxicity, body weight, water, and food intake, play behavior and puberty onset were evaluated. On postnatal day (PND) 54, half of the animals were killed for organ weight, hematological and biochemical analysis, testis histology and oxidative stress of the testis. In adult life (PND 90), the animals were evaluated in relation to male sexual behavior and fertility parameters. On PND 120, the animals were killed to record organ weight, hematological parameters, sperm parameters, contractile of vas deferens, testis histology and oxidative stress. There was a reduction in the daily food and water consumption during the treatment period. On play behavior evaluation, the animals presented a reduction in total social behaviors. No experimental group had the day of preputial separation altered compared to control, but the weight of the animals in the highest dose group were reduced on this day. At PND 54, several parameters were altered, mainly related to systemic toxicity: reduction in body weight gain, increase in the relative weight of the liver, the spleen and the seminal gland, reduction in the erythrocyte and leukocyte count, reduced total protein levels and a disturbance in oxidative parameters. At adulthood, the male sexual behavior and fertility were not altered. But at PND 120, there was an increase in type C sperm (immobile), reduced sperm count in testis and epididymis, histological alterations in Leydig cells and seminiferous tubules, and oxidative parameters altered. Based on the data presented, LDX was able to induce disturbances in systemic toxicological parameters (mainly during treatment) and in reproductive function (mainly in adult life), indicating that the use of this medication should consider these aspects.
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, with a higher incidence of diagnoses in male sex. Inattention, hyperactivity and impulsivity in levels above expected are the main symptoms in ADHD, negatively affecting patients’ daily life. Proper treatment is essential and it is based on a multimodal strategy, with cognitive-behavioral interventions and pharmacological treatment, usually with stimulants medications. One of the main drugs is Lisdexamfetamine Dimesylate (LDX), an extended-release formulation since it is a prodrug of dextroamphetamine, hydrolyzed inside erythrocytes. Its action is mediated by increased levels of catecholamines, mainly dopamine and noradrenaline, in synaptic clefts. Neurotransmitters influence hormonal control and act directly in gonads, so LDX could interfere in reproductive performance. Juvenile and peripubertal period are critical windows of development, more susceptible to the effect of exogenous substances. The aim was to evaluate the effects of exposure to Lisdexamfetamine during the juvenile to peripubertal period on parameters of systemic and reproductive toxicity of male rats. Male Wistar rats (23 days old) were divided into a control group (deionized water) and three groups exposed to LDX in therapeutic doses (converted to animal doses): 5.2; 8.6 and 12.1 mg/kg/day. The treatment occurred from post-natal day 23 (PND) to 53, by gavage. During the treatment, clinical signs of toxicity, body weight, water, and food intake, play behavior and puberty onset were evaluated. On postnatal day (PND) 54, half of the animals were killed for organ weight, hematological and biochemical analysis, testis histology and oxidative stress of the testis. In adult life (PND 90), the animals were evaluated in relation to male sexual behavior and fertility parameters. On PND 120, the animals were killed to record organ weight, hematological parameters, sperm parameters, contractile of vas deferens, testis histology and oxidative stress. There was a reduction in the daily food and water consumption during the treatment period. On play behavior evaluation, the animals presented a reduction in total social behaviors. No experimental group had the day of preputial separation altered compared to control, but the weight of the animals in the highest dose group were reduced on this day. At PND 54, several parameters were altered, mainly related to systemic toxicity: reduction in body weight gain, increase in the relative weight of the liver, the spleen and the seminal gland, reduction in the erythrocyte and leukocyte count, reduced total protein levels and a disturbance in oxidative parameters. At adulthood, the male sexual behavior and fertility were not altered. But at PND 120, there was an increase in type C sperm (immobile), reduced sperm count in testis and epididymis, histological alterations in Leydig cells and seminiferous tubules, and oxidative parameters altered. Based on the data presented, LDX was able to induce disturbances in systemic toxicological parameters (mainly during treatment) and in reproductive function (mainly in adult life), indicating that the use of this medication should consider these aspects.
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Palavras-chave
Lisdexanfetamina, Psicoestimulantes, Toxicidade sistêmica, Hepatotoxicidade, Toxicidade reprodutiva, Reprodução