ABSTRACT Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.

Uma forma alterada da proteína prion celular, a PrPSc ou PrPRes, está envolvida na ocorrência das encefalopatias espongiformes transmissíveis. Nós sintetizamos e caracterizamos previamente compostos aromáticos que inibem o acúmulo da proteína prion resistente a proteases (PrPRes) em células infectadas com prion scrapie. Estes compostos pertencem a diferentes classes químicas, incluindo acilhidrazonas, chalconas e oxadiazóis. Alguns dos compostos ativos não apresentaram toxicidade para células de neuroblastoma em cultura e parecem apresentar propriedades de fármacos, uma vez que todos obedecem aos 5 quesitos da regra de Lipinski e apresentam perfil farmacocinético desejável, como predito in silico. Antes de avaliar a eficácia in vivodos compostos aromáticos em camundongos infectados com prion scrapie, é necessário estimar sua segurança em camundongos saudáveis. Neste trabalho nós utilizamos camundongos Suíços para avaliar o perfil de toxicidade aguda dos seis compostos mais promissores, as 2,4,5-trimetoxichalconas (J1, J8, J20 e J35) e os 1,3,4-oxadiazóis (Y13 e Y17). Administração oral em dose única (300 mg/kg) de J1, J8, J20, J35, Y13 e Y17 ou administração repetida via intraperitoneal (10 mg/kg, 3 vezes por semana, por 4 semanas) de J1, J8 e J35, não geraram toxicidade nos camundongos. Nós acreditamos fortemente que as trimetoxichalconas e os oxadiazóis investigados são compostos interessantes para serem futuramente avaliados in vivo contra as doenças causadas por prions.

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.