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Introduction: This study aimed to prepare cholesterol and stearic acid-based solid lipid nanoparticles of gabapentin (GAB-SLNs) for protection against streptozotocin (STZ)-induced retinal injury in rats. Methods: We prepared four preparations of GAB-SLNs using a hot high-shear homogenization ultrasonication process, and the best formulation was selected and tested for biological activity. The retinal injury was brought in male adult albino rats while gabapentin doses continued for 6 weeks. Six groups of rats were assigned as the vehicle, diabetic, diabetic + gabapentin (10–20 mg/kg), and diabetic + GAB-SLNs (10–20 mg/kg). GAB-SLN#2 was selected as the optimized formulation with high entrapment efficacy (EE%, 98.64% ± 1.97%), small particle size (185.65 ± 2.41 nm), high negative Zeta potential (−32.18 ± 0.98 mV), low polydispersity index (0.28 ± 0.02), and elevated drug release (99.27% ± 3.48%). The TEM image of GAB-SLN#2 revealed a smooth surface with a spherical shape. Results: GAB-SLNs provided greater protection against retinal injury than free gabapentin as indicated by the histopathology data which demonstrated more organization of retinal layers and less degeneration in ganglion cell layer in rats treated with GAB-SLN#2. Further, GAB-SLN#2 reduced the inflammatory proteins (IL-6/JAK2/STAT3) and vascular endothelial growth factor (VEGF). Conclusion: The preparation of GAB-SLNs enhanced the physical properties of gabapentin and improved its biological activity as a neuroprotectant. Further studies are warranted to validate this technique for the use of oral gabapentin in other neurological disorders. [ABSTRACT FROM AUTHOR]

Background/Objectives: One of the most abundant and growing neurodevelopmental disorders in recent decades is attention deficit hyperactivity disorder (ADHD). Many trials have been performed on using drugs for the improvement of ADHD signs. This study aimed to detect the possible interaction of naringin with Wnt/β-catenin signaling and its putative anti-inflammatory and protective effects in the mouse ADHD model based on bioinformatic, behavioral, and molecular investigations. Furthermore, molecular docking was applied to investigate possible interactions with the GSK-3β and HSP90 proteins. Methods: Male Swiss albino mice were divided into four groups, a normal control group, monosodium glutamate (SGL) control, SGL + naringin 50 mg/kg, and SGL + naringin 100 mg/kg. The psychomotor activity of the mice was assessed using the self-grooming test, rope crawling test, and attentional set-shifting task (ASST). In addition, biochemical analyses were performed using brain samples. Results: The results of the SGL group showed prolonged grooming time (2.47-folds), a lower percentage of mice with successful crawling on the rope (only 16.6%), and a higher number of trials for compound discrimination testing in the ASST (12.83 ± 2.04 trials versus 5.5 ± 1.88 trials in the normal group). Treatment with naringin (50 or 100 mg per kg) produced significant shortening in the grooming time (31% and 27% reductions), as well as a higher percentage of mice succeeding in crawling with the rope (50% and 83%, respectively). Moreover, the ELISA assays indicated decreased dopamine levels (0.36-fold) and increased TNF-α (2.85-fold) in the SGL control group compared to the normal mice, but an improvement in dopamine level was observed in the naringin (50 or 100 mg per kg)-treated groups (1.58-fold and 1.97-fold). Similarly, the PCR test showed significant declines in the expression of the Wnt (0.36), and β-catenin (0.33) genes, but increased caspase-3 (3.54-fold) and BAX (5.36-fold) genes in the SGL group; all these parameters were improved in the naringin 50 or 100 mg/kg groups. Furthermore, molecular docking indicated possible inhibition for HSP90 and GSK-3β. Conclusions: Overall, we can conclude that naringin is a promising agent for alleviating ADHD symptoms, and further investigations are required to elucidate its mechanism of action. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) manifests as poor attention, hyperactivity, as well as impulsive behaviors. Hesperetin (HSP) is a citrus flavanone with strong antioxidant and anti-inflammatory activities. The present study aimed to test hesperetin efficacy in alleviating experimental ADHD in mice and its influence on hippocampal neuron integrity and sirtuin 1 (SIRT1) signaling. An in silico study was performed to test the related proteins. Groups of mice were assigned as control, ADHD model, ADHD/HSP (25 mg/kg), and ADHD/HSP (50 mg/kg). ADHD was induced by feeding with monosodium glutamate (0.4 g/kg, for 8 weeks) and assessed by measuring the motor and attentive behaviors (open filed test, Y-maze test, and marble burying test), histopathological examination of the whole brain tissues, and estimation of inflammatory markers. The in-silico results indicated the putative effects of hesperetin on ADHD by allowing the integration and analysis of large-scale genomic, transcriptomic, and proteomic data. The in vivo results showed that ADHD model mice displayed motor hyperactivity and poor attention in the behavioral tasks and shrank neurons at various hippocampal regions. Further, there was a decline in the mRNA expression and protein levels for SIRT1, the erythroid 2-related factor-2 (Nrf2), kelch like ECH associated protein 1 (Keap1) and hemeoxygenase-1 (OH-1) proteins. Treatment with HSP normalized the motor and attentive behaviors, prevented hippocampal neuron shrinkage, and upregulated SIRT1/Nrf2/Keap1/OH-1 proteins. Taken together, HSP mainly acts by its antioxidant potential. However, therapeutic interventions with hesperetin or a hesperetin-rich diet can be suggested as a complementary treatment in ADHD patients but cannot be suggested as an ADHD treatment per se as it is a heterogeneous and complex disease. [ABSTRACT FROM AUTHOR]

Targeting peroxisome proliferator-activated receptor-gamma (PPAR-[gamma]) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-[gamma] modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-[gamma] receptor ligand with agonistic posttranscriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg x [kg.sup.- 1] x day-1) or NTZ (200 mg x [kg.sup.-1] x [day.sup.-1]) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-[gamma] protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6- phosphate dehydrogenase enzymes and PPAR-[gamma] protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-[gamma] receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored. Key words: high-fat diet/streptozotocin-induced diabetes, insulin resistance, nitazoxanide, peroxisome proliferator activated receptor-gamma, pioglitazone. Le recepteur gamma active par les proliferateurs de peroxysomes (PPAR-[gamma] pour peroxisome << proliferator- activated receptor-gamma >>) est une cible homologuee pour contrer la resistance a l'insuline (RI) dans le diabete de type 2 (DT2). Les modulateurs du PPAR-[gamma] permettent d'obtenir des ameliorations sur le plan des effets indesirables et de la sensibilisation a l'insuline lies aux thiazolidinediones classiques. On propose d'utiliser la nitazoxanide (NTZ), dotee d'une activite posttranscriptionnelle agoniste, comme ligand des PPAR-[gamma]. Dans les presents travaux, nous avons compare l'activite antidiabetique de la NTZ a celle de la pioglitazone (PIO) dans un modele de DT2 engendre par un regime alimentaire a teneur elevee en matieres grasses et la streptozotocine chez le rat. Chez des rats Wistar males adultes diabetiques, nous avons administre par voie orale de la PIO (2,7 mg x [kg.sup.-1] x [jour.sup.-1]) ou de la NTZ (200 mg-[kg.sup.-1]-jour-1) pendant 14, 21 et 28 jours. Nous avons mesure le poids corporel, la glycemie a jeun, la RI, le profil lipidique et les fonctions renale et hepatique des rats. Nous avons evalue le metabolisme hepatique du glucose, les taux d'expression proteique du PPAR-[gamma], ainsi que l'histopathologie du foie, du pancreas, des muscles et des reins. La NTZ permettait d'obtenir des effets marques et proportionnels a la duree d'euglycemie, de sensibilisation a l'insuline et de preservation des fonctions renale et hepatique. Avec la NTZ et la PIO, nous avons observe respectivement une augmentation des concentrations hepatiques des enzymes glucose-6-phosphatase et glucose-6-phosphate deshydrogenase, ainsi que de l'expression proteique du PPAR-[gamma]. On pourrait considerer la NTZ comme constituant une strategie therapeutique orale contre le DT2. Nous recommandons d'etudier plus avant l'activation moleculaire de sous-types du PPAR-[gamma] par la NTZ de maniere systematique. Il conviendrait aussi d'etudier l'utilisation simultanee de NTZ avec d'autres antidiabetiques homologues. [Traduit par la Redaction] Mots-cles : diabete engendre par un regime alimentaire a teneur elevee en matieres grasses et la streptozotocine, resistance a l'insuline, nitazoxanide, recepteur gamma active par les proliferateurs de peroxysomes, pioglitazone., Introduction Insulin resistance (IR) is a disease where cellular failure to insulin responses (Kubota et al. 2017; Sam et al. 2017) and obesity are the main contributors of diabetes mellitus [...]