ß-Cyclodextrins alter the energy metabolism-related enzyme activities in rats.

Although widely used in medicine, separation technology, and other fields, the effects of cyclodextrins on the activities of phosphoryl transfer enzymes have not been previously evaluated. In vivo studies evaluated the function of cyclodextrins as active compounds. Despite the use of cyclodextrins as active compounds, the effects of cyclodextrins on hepatic and renal tissues remain to be fully elucidated. The primary objective of this study was to evaluate the effects of ß- cyclodextrins, methyl-ß-cyclodextrin (M-ß- cyclodextrins), and (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-cyclodextrins) on enzyme activities regulating the maintenance of energy homeostasis in the kidney and liver tissues in relation to toxicity. Serum levels of liver and kidney markers were measured, and oxidative stress parameters were assessed. After 60-day treatments, we observed that the administration of ß-cyclodextrins and M-ß-cyclodextrins inhibited the hepatic activity of pyruvate kinase, an irreversible enzyme within the glycolytic pathway. Additionally, administration of HP-ß-cyclodextrins inhibited creatine kinase activity and increased the total sulfhydryl content in kidneys. Here, we demonstrated for the first time that ß-cyclodextrins, M-ß-cyclodextrins, and HP-ß-cyclodextrins cause bioenergetic dysfunction in renal and hepatic tissues. These findings suggest that understanding the balance between cyclodextrins' efficacy and adverse effects is essential for better accepting their use in medicine.

Advances in Alzheimer's disease's pharmacological treatment.

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Several hypotheses emerged from AD pathophysiological mechanisms. However, no neuronal protective or regenerative drug is available nowadays. Researchers still work in drug development and are finding new molecular targets to treat AD. Therefore, this study aimed to summarize main advances in AD pharmacological therapy. Clinical trials registered in the National Library of Medicine database were selected and analyzed accordingly to molecular targets, therapeutic effects, and safety profile. The most common outcome was the lack of efficacy. Only seven trials concluded that tested drugs were safe and induced any kind of therapeutic improvement. Three works showed therapeutic effects followed by toxicity. In addition to aducanumab recent FDA approval, antibodies against amyloid-ß (Aß) showed no noteworthy results. 5-HT6 antagonists, tau inhibitors and nicotinic agonists' data were discouraging. However, anti-Aß vaccine, BACE inhibitor and anti-neuroinflammation drugs showed promising results.

Lipid-core nanocapsules containing simvastatin improve the cognitive impairment induced by obesity and hypercholesterolemia in adult rats.

The development of cognitive impairment may be related to high levels of plasma cholesterol and obesity. Simvastatin (SV) and lovastatin (LV) are drugs that can potentially be used for the treatment of cognitive deficit. This study aimed to develop and characterize lipid-core nanocapsules (LNC) containing SV (SV-LNC) or LV (LV-LNC), evaluating the effects of SV-LNC in an animal model of cognitive deficit. The formulations SV-LNC and LV-LNC presented a particle average size around 200 nm, a low-polydispersity index, and negative zeta potential. Analysis of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that there is no reaction among LNC components: LV was crystallized in the suspensions, and SV was molecularly dispersed. The encapsulation efficiency of the SV was high (98.9 ± 1.4%), while that of the LV was low (21.5 ± 1.5%).Based on these results, SV-LNC was used in the preclinical studies. Animals fed with a hyperlipidic diet (HD) developed obesity, hypercholesterolemia, and cognitive impairment, which was corroborated by the brain lesions indicated by histological analysis of some of the animals that received the high-fat diet. We observed that free simvastatin (CS3) was able to reduce the enzymatic activity of pyruvate kinase, an important enzyme for brain energy homeostasis, without affecting the memory of the animals that received a standard diet. However, it failed to improve the cognitive damage caused by a diet high in cholesterol and saturated fats. On the other hand, when simvastatin is "camouflaged" in the lipid-core nanocapsules (HNS3), this cognitive impairment improves. Thus, SV-LNC is a promising alternative therapy for the treatment of cognitive impairment.

Creatine nanoliposome reverts the HPA-induced damage in complex II-III activity of the rats' cerebral cortex.

Phenylketonuria (PKU) is a metabolic disorder accumulating phenylalanine (Phe) and its metabolites in plasma and tissues of the patients. Regardless of the mechanisms, which Phe causes brain impairment, are poorly understood, energy deficit may have linked to the neurotoxicity in PKU. It is widely recognized that creatine is involved in maintaining of cerebral energy homeostasis. Because of this, in a previous work, we incorporated it into liposomes and this increased the concentration of creatine in the cerebral cortex. Here, we examined the effect of creatine nanoliposomes on parameters of oxidative stress, enzymes of phosphoryl transfer network, and activities of the mitochondrial respiratory chain complexes (RCC) in the cerebral cortex of young rats chemically induced hyperphenylalaninemia (HPA). HPA was induced with L-phenylalanine (5.2 µmol/g body weight; twice a day; s.c.), and phenylalanine hydroxylase inhibitor, α-methylphenylalanine (2.4 µmol/g body weight; once a day; i.p.), from the 7th to the 19th day of life. HPA reduced the activities of pyruvate kinase, creatine kinase, and complex II + III of RCC in the cerebral cortex. Creatine nanoliposomes prevented the inhibition of the activities of the complexes II + III, caused by HPA, and changes oxidative profile in the cerebral cortex. Considering the importance of the mitochondrial respiratory chain for brain energy production, our results suggesting that these nanoparticles protect against neurotoxicity caused by HPA, and can be viable candidates for treating patients HPA.