Idebenone-Loaded Nanocomposite Microspheres for Nasal Administration-A Perspective in the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease results in neurodegeneration and is characterized by an accumulation of abnormal neuritic lesions and intracellular aggregates of hyperphosphorylated Tau proteins in the cerebrum. That leads to progressive decline in memory, thinking, and learning skills. Oxidative stress has been shown to play a significant role in the pathogenesis of Alzheimer's disease. Antioxidants are identified as part of therapeutic strategy to prevent or reduce the disease. Idebenone is a synthetic analogue of coenzyme Q10 with potent antioxidant properties, originally developed for the treatment of Alzheimer's disease and other cognitive disorders. After oral administration idebenone undergoes excessive first-pass metabolism and has a very low bioavailability of only about 1%. The use of an alternative route of administration such as the nasal and its incorporation into a novel carrier (nanocomposite microspheres) will eliminate the problems associated with reduced absorption, stability, and rapid biotransformation and will increase the opportunity for idebenone to realize its therapeutic potential in Alzheimer's disease. METHODS: Idebenone-loaded nanocomposite microspheres were obtained by spray drying. The structures were characterized using laser diffraction, scanning electron microscopy, high-performance liquid chromatography, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The ability of nanocomposite microspheres to bind human serum albumin was investigated by fluorescence spectroscopy. The mucoadhesive properties of the carrier were also determined. RESULTS: Bioadhesive nanocomposite microparticles with spherical shape, smooth surface, size of 7.37 ± 2.4 µm, and with high production yield, good drug entrapment efficiency, and loading values were obtained. Infrared spectra demonstrated no chemical interactions between idebenone and structure-forming polymers. The ability of particles to bind to human serum albumin depends on their drug loading. CONCLUSIONS: Nanocomposite microspheres were developed as the novel delivery system of idebenone for target nose-to-brain delivery. The obtained carrier may increase the therapeutic potential of idebenone by providing higher concentrations in brain tissue and reducing systemic exposure and side effects.

Emerging Therapeutic Potential of Polyphenols from Geranium sanguineum L. in Viral Infections, Including SARS-CoV-2.

The existing literature supports the anti-inflammatory, antioxidant, and antiviral capacities of the polyphenol extracts derived from Geranium sanguineum L. These extracts exhibit potential in hindering viral replication by inhibiting enzymes like DNA polymerase and reverse transcriptase. The antiviral properties of G. sanguineum L. seem to complement its immunomodulatory effects, contributing to infection resolution. While preclinical studies on G. sanguineum L. suggest its potential effectiveness against COVID-19, there is still a lack of clinical evidence. Therefore, the polyphenols extracted from this herb warrant further investigation as a potential alternative for preventing and treating COVID-19 infections.

Effect of a Ketogenic Diet on Oxidative Posttranslational Protein Modifications and Brain Homogenate Denaturation in the Kindling Model of Epilepsy in Mice.

This study focused on the ketogenic diet (KD) effects on oxidative posttranslational protein modification (PPM) as presumptive factors implicated in epileptogenesis. A 28-day of KD treatment was performed. The corneal kindling model of epileptogenesis was used. Four groups of adult male ICR mice (25-30 g) were randomized in standard rodent chow (SRC) group, KD-treatment group; SRC + kindling group; KD + kindling group (n = 10 each). Advanced oxidation protein products (AOPP) and protein carbonyl contents of brain homogenates together with differential scanning calorimetry (DSC) were evaluated. Two exothermic transitions (Exo1 and Exo2) were explored after deconvolution of the thermograms. Factor analysis was applied. The protective effect of KD in the kindling model was demonstrated with both decreased seizure score and increased seizure latency. KD significantly decreased glucose and increased ketone bodies (KB) in blood. Despite its antiseizure effect, the KD increased the AOPP level and the brain proteome's exothermic transitions, suggestive for qualitative modifications. The ratio of the two exothermic peaks (Exo2/Exo1) of the thermograms from the KD vs. SRC treated group differed more than twice (3.7 vs. 1.6). Kindling introduced the opposite effect, changing this ratio to 2.7 for the KD + kindling group. Kindling significantly increased glucose and KB in the blood whereas decreased the BW under the SRC treatment. Kindling decreased carbonyl proteins in the brain irrespectively of the diet. Further evaluations are needed to assess the nature of correspondence of calorimetric images of the brain homogenates with PPM.

A novel DSC approach for evaluating protectant drugs efficacy against dementia.

Differential scanning calorimetry was applied to evaluate the efficacy of preventive treatments with biologically active compounds of plant origin against neurodegenerative disorder in mice. As we reported recently, large differences exist between the heat capacity profiles of water-soluble brain proteome fractions from healthy animals and from animals with scopolamine-induced dementia: the profiles for healthy animals displayed well expressed exothermic event peaking at 40-45°C, by few degrees above body temperature, but still preceding in temperature the proteome endothermic denaturational transitions; the low-temperature exotherm was completely abolished by the scopolamine treatment. Here we explored this signature difference in the heat capacity profiles to assess the efficacy of preventive treatments with protectant drugs anticipated to slow down or block progression of dementia (myrtenal, ellagic acid, lipoic acid and their combinations, including also ascorbic acid). We found that these neuroprotectants counteract the scopolamine effect and partially or completely preserve the 'healthy' thermogram, and specifically the low-temperature exotherm. These results well correlate with the changes in the cognitive functions of the animals assessed using the Step Through Test for learning and memory. The exothermic event is deemed to be associated with a reversible process of fibrillization and/or aggregation of specific water-soluble brain protein fractions preceding their denaturation. Most importantly, the results demonstrate that the effect of scopolamine and its prevention by protectant substances are clearly displayed in the heat capacity profiles of the brain proteome, thus identifying DSC as a powerful method in drug testing and discovery.