Exploring the link between pyrethroids exposure and dopaminergic degeneration through morphometric, immunofluorescence, and in-silico approaches: the therapeutic role of chitosan-encapsulated curcumin nanoparticles.

Introduction: The synthetic pyrethroid derivative fenpropathrin (FNE), a commonly used insecticide, has been associated with various toxic effects in mammals, particularly neurotoxicity. The study addressed the hallmarks of the pathophysiology of Parkinson's disease upon oral exposure to fenpropathrin (FNE), mainly the alteration of dopaminergic markers, oxidative stress, and molecular docking in rat models. In addition, the protective effect of curcumin-encapsulated chitosan nanoparticles (CRM-Chs-NPs) was also assessed. Methods: In a 60-day trial, 40 male Sprague Dawley rats were divided into 4 groups: Control, CRM-Chs-NPs (curcumin-encapsulated chitosan nanoparticles), FNE (15 mg/kg bw), and FNE + CRM-Chs-NPs. Results: FNE exposure induced reactive oxygen species generation, ATP production disruption, activation of inflammatory and apoptotic pathways, mitochondrial function and dynamics impairment, neurotransmitter level perturbation, and mitophagy promotion in rat brains. Molecular docking analysis revealed that FNE interacts with key binding sites of dopamine synthesis and transport proteins. On the other hand, CRM-Chs-NPs mitigated FNE's toxic effects by enhancing mitochondrial dynamics, antioxidant activity, and ATP production and promoting anti-inflammatory and antiapoptotic responses. Conclusion: In summary, FNE appears to induce dopaminergic degeneration through various mechanisms, and CRM-Chs-NPs emerged as a potential therapeutic intervention for protecting the nervous tissue microenvironment.

Formulation and Preparation of Losartan-Potassium-Loaded Controlled-Release Matrices Using Ethocel Grade 10 to Establish a Correlation between In Vitro and In Vivo Results.

In the current study, matrices of losartan potassium were formulated with two different polymers (Ethocel 10 premium and Ethocel 10FP premium), along with a filler and a lubricant, at different drug-to-polymer w/w ratios (10:3, 10:4, and 10:5). The matrices were tested by the direct compression method, and their hardness, diameter, thickness, friability, weight variation, content uniformity, and in vitro dissolution tests were assessed to determine 24-h drug release rates. The matrices with Ethocel 10 FP at a 10:4 ratio exhibited pseudo-zero-order kinetics (n-value of 0.986), while the dissolution data of the test matrices and reference tablets did not match. The new test-optimized matrices were also tested in rabbits, and their pharmacokinetic parameters were investigated: half-life (11.78 ± 0.018 h), Tmax (2.105 ± 1.131 h), Cmax (205.98 ± 0.321 µg/mL), AUCo (5931.10 ± 1.232 µg·h/mL), AUCo-inf (7348.46 ± 0.234 µg·h/mL), MRTo-48h (17.34 ± 0.184 h), and Cl (0.002 ± 0.134 mL/min). A correlation value of 0.985 between the in vitro and in vivo results observed for the test-optimized matrices was observed, indicating a level-A correlation between the percentage of the drug released in vitro and the percentage of the drug absorbed in vivo. The matrices might improve patient compliance with once-a-day dosing and therapeutic outcomes.