Bacosides Encapsulated in Lactoferrin Conjugated PEG-PLA-PCL-OH Based Polymersomes Act as Epigenetic Modulator in Chemically Induced Amnesia.

The present study demonstrates the epigenetic mechanisms underlying the effect of Bacoside rich extract of Bacopa monniera-a nootropic herb, on scopolamine treated amnesic mice conferred via chromatin modifying enzymes. The focus of the work was to elucidate the modulation of the chromatin modifying enzymes: DNMT1, DNMT3a, DNMT3b, HDAC2, HDAC5 and CPB in scopolamine induced amnesic mice after treatment with bacoside rich extract of Bacopa monniera (BA) and BA encapsulated in lactoferrin conjugated PEG-PLA-PCL-OH based polymersomes (BAN). We observed remarkable difference between the results obtained after the treatment with BA and BAN. Interestingly BAN was found to be more efficient in downregulating DNA methylation and histone chain deacetylation. Scopolamine treatment showed up-regulation of DNMT1 expression in qRT-PCR by 3.14-fold as compared to the control, which was considerably decreased by 1.5-fold after treatment with BA and remarkably decreased 0.11-fold by BAN treatment. Scopolamine treatment up-regulated the expression of DNMT3a by 1.6-fold while for DNMT3b by 3.13-fold. In DNMT3a and DNMT3b the fold change decreased to 0.64 and 0.76 after BA treatment, whereas the BAN treatment further down-regulated to 0.32- and 0.63-fold, respectively. Similarly scopolamine up-regulated HDAC2 and HDAC5 by 3.12 fold and 3.64-fold, respectively. BA treatment reversed the changes by reducing HDAC2 mRNA to 0.89-fold and HDAC5 mRNA 0.83-fold. BAN further reduced expression of HDAC2 further to 0.39-fold and HDAC5 to 0.31-fold. On the other hand scopolamine down-regulated CBP mRNA expression by 0.28-fold and increased by 1.09 after BA treatment. BAN significantly increased the CPB expression by 1.65-fold as compared to BA treatment. These findings were consolidated by DNMT and HDAC enzyme activity assay, methylation in the promoter region of the memory related genes: ARC and BDNF and Dot blot assay for DNA methylation. The percent activity increase of DNMT and HDAC after scopolamine administration was 375.74 and 240.90 respectively. After treatment with BA the downfall in percent activity was observed as 167.99 in DMNT and 130.57 in HDAC. BAN treatment further decreased the percent enzyme activity of DNMT and HDAC significantly by 30.0 and 61.81 respectively. The potency of BAN in reversing the epigenetic changes of scopolamine induced amnesic mouse brain, can be attributed to the brain specific delivery of BA through polymersomes which are able to cross the blood brain barrier (BBB) via receptor mediated endocytosis.

Lactoferrin-conjugated pH and redox-sensitive polymersomes based on PEG-S-S-PLA-PCL-OH boost delivery of bacosides to the brain.

In the present study, engineered lactoferrin (Lf)-conjugated pH and redox-sensitive polymersomes derived from the triblock copolymer polyethylene glycol-S-S-polylactic acid-polycaprolactone (PEG-S-S-PLA-PCL-OH) have been used to deliver bacosides to the brain. Bacosides are classified as triterpenoid saponins and are used in Indian Ayurveda for reversal of amnesia; however, no study has extensively demonstrated their efficacy as a nano-formulation in an animal model. The polymer was synthesized by ring opening polymerization of lactide and ε-caprolactone. The nanoparticles obtained by nanoprecipitation showed a core-shell morphology, with an average size of 110 nm, by transmission electron microscopy (TEM). The colloidal stability, hemocompatibility and cytocompatibility of the polymersomes proved their biocompatibility. pH and disulfide linkages in the polymeric chain accelerated the disintegration of the polymersomes at pH 6.6 and at pH 6.6 with glutathione (GSH) in comparison to pH 7.4, supporting their degradation behavior. Supermagnetic iron oxide nanoparticles (SPIONs, 74.99 µg mg-1 polymer) encapsulated into the polymersomes demonstrated their uptake in a mouse model by MRI. Furthermore, bacosides encapsulated in the polymersomes (10% loading) showed significant memory loss reversal in chemically induced amnesic mice, supported by the gene expression profiles of Arc, BDNF and CREB as well as by histopathology.

The Molecular Links of Re-Emerging Therapy: A Review of Evidence of Brahmi (Bacopa monniera).

The convolution associated with memory is being resolved with advancement in neuroscience. According to the concurrent assumptions, synaptic plasticity forms one of the basis of memory formation, stabilization and strengthening. In Alzheimer's disease (AD), which is generally characterized by memory dysfunction, connections amongst the cells in the brain are attenuated or lost leading to degeneration of neural networks. Numerous attempts have been made to find new therapies for memory dysfunction with increasing attention and investments being laid on herbal drugs. Many herbal plants and extracts have already documented beneficial results when tested for antiamnesic effects. Brahmi (Bacopa monniera) is one such common herbal drug, which is employed for a long time in the Indian and Chinese medical system in order to treat several disorders. Previous research has shown that Brahmi exerts many pharmacological effects including memory boosting capacity in the treatment of Alzheimer's disease and Schizophrenia, exhibiting antiparkinsonian, antistroke, and anticonvulsant potentials. The present review discusses the chemical constituents of Brahmi along with in vitro and in vivo studies based on the pharmacological effects exerted by it. The efficacy of Brahmi in treating various disorders has evoked sufficient research in recent years and now it is a time to launch multiple clinical trials.

Targeted drug delivery to central nervous system (CNS) for the treatment of neurodegenerative disorders: trends and advances.

The treatment of brain diseases has been a major challenge since a long time. Although there are several potent drugs, which are highly therapeutic yet their efficiency is marred due to the presence of the Blood Brain Barrier (BBB). The BBB, which is present at the capillary level regulates and monitors the entry of all small and large molecules entering into the brain. Although this barrier is of immense importance to the brain in terms of safety, it becomes a hindrance when it comes to therapy because the drug molecules are unable to reach the brain. Various biomaterial-based strategies are being developed to overcome the BBB and deliver the drug into the brain. These include polymeric nanoparticles, liposomes, solid-lipid nanoparticles (SLNPs), nanogels, implants, etc. This review provides an overview on CNS disorders, BBB, and various delivery strategies available for biologists engaged in translational neuroscience, to target CNS.