Glucose Homeostasis Is Not Affected in a Murine Model of Parkinson’s Disease Induced by 6-OHDA

There is a mutual relationship between metabolic and neurodegenerative diseases. However, the causal relationship in this crosstalk is unclear and whether Parkinson’s disease (PD) causes a posterior impact on metabolism remains unknown. Considering that, this study aimed to evaluate the appearance of possible changes in metabolic homeostasis due to 6-hydroxydopamine (6-OHDA) administration, a neurotoxin that damage dopaminergic neurons leading to motor impairments that resemble the ones observed in PD. For this, male Wistar rats received bilateral 6-OHDA administration in the dorsolateral striatum, and the motor and metabolic outcomes were assessed at 7, 21, or 35 days post-surgical procedure. Dexamethasone, a diabetogenic glucocorticoid (GC), was intraperitoneally administered in the last 6 days to challenge the metabolism and reveal possible metabolic vulnerabilities caused by 6-OHDA. Controls received only vehicles. The 6-OHDA-treated rats displayed a significant decrease in locomotor activity, exploratory behavior, and motor coordination 7 and 35 days after neurotoxin administration. These motor impairments paralleled with no significant alteration in body mass, food intake, glucose tolerance, insulin sensitivity, and biochemical parameters (plasma insulin, triacylglycerol, and total cholesterol levels) until the end of the experimental protocol on days 35–38 post-6-OHDA administration. Moreover, hepatic glycogen and fat content, as well as the endocrine pancreas mass, were not altered in rats treated with 6-OHDA at the day of euthanasia (38th day after neurotoxin administration). None of the diabetogenic effects caused by dexamethasone were exacerbated in rats previously treated with 6-OHDA. Thus, we conclude that bilateral 6-OHDA administration in the striatum causes motor deficits in rats with no impact on glucose and lipid homeostasis and does not exacerbate the adverse effects caused by excess GC. These observations indicate that neurodegeneration of dopaminergic circuits in the 6-OHDA rats does not affect the metabolic outcomes

O tratamento de ratas com olanzapina resulta em exacerbação leve das alterações promovidas pela dexametasona na homeostase lipídica, mas não glicêmica

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2022.A náusea e o vômito estão entre os efeitos adversos da quimioterapia. Na tentativa de atenuar a êmese, são utilizados os coquetéis antieméticos, que contém o glicocorticoide (GC) dexametasona e outros agentes, como a olanzapina, podendo ser combinado com um terceiro fármaco como o aprepitanto. Quando administrados isoladamente, para outros fins terapêuticos, a dexametasona e a olanzapina podem causar efeitos adversos sobre o metabolismo da glicose e dos lipídios, mas os efeitos da administração conjunta são desconhecidos. Para responder essa questão tratamos ratas adultas por 5 dias consecutivos com dexametasona (1 mg/kg/dia, ip) e olanzapina (10 mg/kg/dia, og) e ao final do tratamento avaliamos parâmetros funcionais, bioquímicos e morfológicos. Nossos resultados mostraram que o tratamento com dexametasona reduziu a massa corpórea, a ingesta alimentar, causou intolerância a glicose, resistência à insulina, hiperinsulinemia de jejum, intolerância à lipídeos, maior acúmulo de glicogênio e gordura no fígado, hipertriacilgliceridemia e aumento da massa endócrina do pâncreas. Essas alterações não foram exacerbadas pelo tratamento concomitante com a olanzapina. O tratamento simultâneo com ambos os fármacos causou maior letargia, aumento da concentração de colesterol total e da liberação de VLDL hepático. Concluímos que o tratamento com olanzapina concomitante ao tratamento com dexametasona não exacerba nenhum parâmetro do metabolismo glicêmico, mas leva à um distúrbio na homeostase lipídica, caracterizado por maiores valores de colesterol plasmático e maior liberação de triacilglicerol hepático. Nossos dados corroboram a adição da olanzapina no coquetel antiemético considerando a baixa incidência de efeitos adversos pelo período e dosagem analisados em fêmeas na espécie murina.Abstract: Nausea and vomiting are among the adverse effects of chemotherapy. In an attempt to attenuate emesis, antiemetic cocktails are used, which contain the glucocorticoid (GC) dexamethasone and other agents, such as olanzapine, which can be combined with third drug-like aprepitant. When administered alone for other therapeutic purposes, dexamethasone and olanzapine may cause adverse effects on glucose and lipid metabolism, but the effects of concomitant administration are unknown. To explore this interaction, we treated adult female rats for 5 consecutive days with dexamethasone (1 mg/kg/day, ip) and olanzapine (10 mg/kg/day, og) and at the end of the treatment, we evaluated functional, biochemical and morphological parameters. Our results showed that dexamethasone treatment reduced body mass and food intake, caused glucose intolerance, insulin resistance, fasting hyperinsulinemia, lipid intolerance, increased hepatic glycogen, and triacylglycerol content, plasma triacylglycerol values, and endocrine mass of the pancreas. These changes were not exacerbated by concomitant treatment with olanzapine. Simultaneous treatment with both drugs enhanced lethargy, increased plasma cholesterol total values, and increased hepatic VLDL release. We conclude that h olanzapine treatment did not exacerbate any effect GC on glucose metabolism. However, it worsened lipid homeostasis, characterized by higher values of plasmatic cholesterol and hepatic triglyceride release. Our data corroborate the addition of olanzapine in the cocktail considering a low failure of adverse effects by the period and the analysis of females in the murine species

Preconception exposure to malathion and glucose homeostasis in rats: Effects on dams during pregnancy and post-term periods, and on their progeny

Understanding the individual and global impact of pesticides on human physiology and the different stages of life is still a challenge in environmental health. We analyzed here whether administration of the organophosphate insecticide malathion before pregnancy could affect glucose homeostasis during pregnancy and, in addition, generate possible later consequences in mothers and offspring. For this, adult Wistar rats were allocated into two groups and were treated daily (intragastric) with malathion (14 or 140 mg/kg, body mass (bm)) for 21–25 days. Corn oil was used as vehicle in the Control group. Subgroups were defined based on the absence (nulliparous) or presence (pregnant) of a copulatory plug. Pregnant rats were followed by an additional period of 2 months after the term (post-term), without continuing malathion treatment. Fetuses and adult offspring of males and females were also evaluated. We ran an additional experimental design with rats exposed to malathion before pregnancy at a dose of 0.1 mg/kg bm. Malathion exposure resulted in glucose intolerance in the mothers during pregnancy and post-term period, regardless of the exposure dose. This was accompanied by increased visceral adipose tissue mass, dyslipidemia, unchanged pancreatic β-cell mass, and varying insulin responses to glucose in vivo. The number of total newborns and birthweight was not affected by malathion exposure. Adult offspring from both sexes also became glucose-intolerant, regardless of the pesticide dose their dams were exposed to. This alteration could be associated with changes at the epigenomic level, as reduced hepatic mRNA content of DNA methylases and demethylases was found. We demonstrated that periconceptional exposure to malathion with doses aiming to mimic from work environment to indirect contamination predisposes progenitors and offspring rats to glucose intolerance. Thus, we conclude that subchronic exposure to malathion is a risk factor for gestational diabetes and prediabetes later in life.We are indebted with the staff from the LIDoC and LAMEB. This research was partially granted by the National Council for Scientific and Technological Development (CNPq; grant number 428023/2018–5). In addition, some reagents and materials were acquired by A.R private funding or result from donations from collaborators. This work was submitted as thesis by M.A.B. M.A.B and F.N.S received a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) – Finance Code 001, and P.L.Z received a scholarship from the CNPq. A.R is funded by a CNPq research grant (grant number 304388/2020–3). IQ is funded by a grant of Generalitat Valenciana (PROMETEO/2020/006)