Clavulanic Acid: A Novel Potential Agent in Prevention and Treatment of Scopolamine-Induced Alzheimer's Disease.

Background and Aim: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multifaced disorder with a greater genetic contribution. The contribution of many genes such as BDNF, Sirtuin 6, and Seladin 1 has been reported in the pathogenesis of AD. Current therapies include acetylcholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists, which are only temporarily beneficial. Therefore, it seems that more studies should be conducted to determine the exact mechanisms of drugs to deal with the diseases' multifactorial features that we face. Methods: In this study, 42 adult rats were randomly divided into 7 groups and received drugs intraperitoneally and orally according to the protocol as follows: scopolamine group, clavulanic acid group, memantine group, scopolamine + memantine group, clavulanic acid pre- and post-treatment, and normal saline group. The Morris water maze method was performed to evaluate the spatial memory of animals, and the terminal deoxynucleotidyl transferase dUTP nick end labeling assay and real-time polymerase chain reaction were performed to study neuronal cell apoptosis and gene expression, respectively. Results: Significant differences were observed in the spatial memory of rats that received clavulanic acid prophylactically compared to the Alzheimer's model on the day of the test. Moreover, the results obtained during the training showed that both memantine and clavulanic acid improved spatial memory by increasing the time of rats present in the platform position and by reducing the swimming time in the scopolamine-induced Alzheimer's group. Besides, rats that received clavulanic acid and memantine had a greater percentage of healthy cells in comparison with the scopolamine-induced Alzheimer's group; however, the results were more significant for clavulanic acid. Furthermore, the expressions of BDNF, Seladin 1, and Sirtuin 6 as neuroprotective target genes were modified after clavulanic acid and memantine administrations; similarly, the results obtained from clavulanic acid were more significant. Conclusion: The results show that the administration of clavulanic acid before and after the use of scopolamine can reduce the percentage of apoptotic cells in the hippocampus and also improve the parameters related to learning and spatial memory; however, its effect in the prophylactic state was stronger. The results obtained from memantine revealed that it has neuroprotective potency against AD; however, clavulanic acid had a greater effect. Also, with increased expression of the neuroprotective genes, clavulanic acid could be considered as an option in the upcoming preclinical and clinical research about Alzheimer's disease.

Polysorbate-coated mesoporous silica nanoparticles as an efficient carrier for improved rivastigmine brain delivery.

Targeted delivery of neurological therapeutic to the brain has been attracting more and more attention to the treatment of central nervous system (CNS) diseases. Nonetheless, the main obstacle in this road map is the existence of a blood-brain barrier (BBB) which limits the penetration efficiency of most CNS drugs into the brain parenchyma. This present investigation describes a facile synthetic strategy to prepare a highly biocompatible calcium-doped mesoporous silica nanoparticles (MSNs) functionalized by polysorbate-80 (PS) as targeting ligand to deliver rivastigmine (RV) into the brain via crossing the BBB. The developed nanosystem was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), Zeta potential, and N2-adsorption-desorption analysis. In vitro hemolysis studies were carried out to confirm the biocompatibility of the nanocarriers. Our in vivo studies in an animal model of rats showed that the RV-loaded nanosystem was able to enhance the brain-to-plasma concentration ratio, brain uptake clearance, and plasma elimination half-life of the drug compared to the free one drug following intravenous (IV) administration. The results revealed that functionalization of MSNs by PS is crucial to deliver RV into the brain, suggesting PS-functionalized MSNs could be an effective carrier to deliver RV to the brain while overcoming BBB.

Engineered Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as New Generations of Blood-Brain Barrier Transmitters.

The blood-brain barrier (BBB) is considered as the most challenging barrier in brain drug delivery. Indeed, there is a definite link between the BBB integrity defects and central nervous systems (CNS) disorders, such as neurodegenerative diseases and brain cancers, increasing concerns in the contemporary era because of the inability of most therapeutic approaches. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have already been identified as having several advantages in facilitating the transportation of hydrophilic and hydrophobic agents across the BBB. This review first explains BBB functions and its challenges in brain drug delivery, followed by a brief description of nanoparticle-based drug delivery for brain diseases. A detailed presentation of recent progressions in optimizing SLNs and NLCs for controlled release drug delivery, gene therapy, targeted drug delivery, and diagnosis of neurodegenerative diseases and brain cancers is approached. Finally, the problems, challenges, and future perspectives in optimizing these carriers for potential clinical application were described briefly.

Preparation, Optimization, and Evaluation of Methoxy Poly(ethylene glycol)-co-Poly(ε-caprolactone) Nanoparticles Loaded by Rivastigmine for Brain Delivery.

The objective of this study was to formulate and investigate the neuropharmacokinetics and pharmacodynamics of rivastigmine (Riv) loaded methoxy poly(ethylene glycol)-co-poly(ε-caprolactone) (MPEG-PCL) nanoparticles (Riv-NPs) in rats after IV administration. The MPEG-PCL was synthesized via ring-opening polymerization of ε-caprolactone by MPEG and used to prepare Riv-NPs by the nanoprecipitation method. Response surface D-optimal design was applied to optimize Riv-NPs drug delivery system. The optimized formulation showed a particle size (PS) of 98.5 ± 2.1 nm, drug loading (DL) of 19.2 ± 1.1%, and sustained release behavior of the drug. Moreover, the optimized Riv-NPs were characterized by AFM and DSC analyses. A simple and sensitive HPLC-DAD method for bioanalysis was developed and successfully applied to the pharmacokinetic study. The neuropharmacokinetic study in rats indicated that the integration plot was linear, and the brain uptake clearance of the drug-loaded in MPEG-PCL NPs was significantly higher than the free drug. Furthermore, results of pharmacodynamic studies using the Morris water maze test demonstrated faster regain of memory loss with Riv-NPs when compared to the free drug solution. The results revealed that the mentioned biodegradable nanoparticle holds promise as a suitable drug carrier for brain drug delivery.