rosmarinic-acid and Huntington-Disease

The objective of the present study was to investigate the potential use of solid lipid nanoparticles (SLNs) as a drug delivery system to enhance the brain-targeting efficiency of rosmarinic acid (RA) following intranasal (i.n.) administration.. The RA-loaded SLNs was prepared by the hot homogenization technique, in which glycerol monostearate (GMS) as lipid, tween 80 and soya lecithin were used as surfactant along with hydrogenated soya phosphatidyl choline (HSPC) as a stabilizer, and were characterized for particle size, zeta potential (ZP), in vitro study. Nasal delivery of the developed formulation followed by the study of behavioral (locomotor, narrow beam, body weight) and biochemical parameters (glutathione, lipid peroxidation, catalase and nitrite) in wistar rat was carried out.. Optimized RA-loaded SLNs using tween 80 (SLNPRT) have the mean size of (149.2 ± 3.2 nm), ZP (-38.27 mV) entrapment efficiency (61.9 ± 2.2%). 3-NP-treated rat significantly increased behavioral alterations, oxidative damage as compared with the control group. SLNPRT treatment significantly improved behavioral abnormalities and attenuated the oxidative stress in 3NP-treated rats. However, the nasal delivery of SLNPRT produced significant therapeutic action as compared to intravenous application. In the organ distribution study, brain drug concentration was found to be 5.69 µg, in pharmacokinetic study Cmax, tmax, t1/2, AUC values were found to be 0.284 µg/ml, 1.5 h, 3.17 h, and 1.505 µg/ml/h, respectively.. The encouraging results confirmed the developed optimized RA-loaded SLNs formulation following the non-invasive nose-to-brain drug delivery that is a promising therapeutic approach for the effective management in Huntington disease.

Topics: Administration, Intranasal; Animals; Antioxidants; Area Under Curve; Behavior, Animal; Brain; Chemistry, Pharmaceutical; Cinnamates; Depsides; Drug Delivery Systems; Excipients; Half-Life; Huntington Disease; Lipids; Male; Nanoparticles; Oxidative Stress; Particle Size; Rats; Rats, Wistar; Rosmarinic Acid; Surface-Active Agents; Tissue Distribution

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Caspase 3; Caspase Inhibitors; Cinnamates; Curcumin; Depsides; Humans; Huntington Disease; Ligands; Molecular Docking Simulation; Neurodegenerative Diseases; Parkinson Disease; Rosmarinic Acid