Oral Delivery of a Nanocrystal Formulation of Schisantherin A with Improved Bioavailability and Brain Delivery for the Treatment of Parkinson’s Disease

Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aiming to improve its solubility and pharmacokinetic profile and thus provide a potential therapeutic agent for the treatment of Parkinson’s disease (PD). The rod-shaped SA-NC had a particle size of ∼160 nm with 33.3% drug loading, and the nanocrystals exhibited a fast dissolution rate <i>in vitro</i>. The intact drug nanocrystals could be internalized into Madin-Darby canine kidney (MDCK) cells, which were followed by rapid intracellular release, and most of the drug was transported to the basolateral side in its soluble form. Following oral administration of the SA-NC or an SA suspension, the accumulated concentration of the SA-NC in the plasma and brain was considerably higher than that observed for the SA suspension, but the drug targeting efficiency was similar. The SA-NC significantly reversed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neuronal loss and locomotion deficiency in zebrafish, as well as the 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced damage of neuronal cell culture model. Further Western blot analysis demonstrated that the stronger neuroprotective effect of SA-NC may be partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. Taken together, these data provide solid evidence that the nanocrystal formulation has the potential to improve the bioavailability and brain concentration of this Biopharmaceutics Classification System (BCS) class II compound, SA, for the treatment of PD

A review of the literature: antibiotic usage and its relevance to the infection in periodontal flaps

<p><b>Objective:</b> This study aimed to investigate the systemic antibiotic usage in the perioperative period of periodontal flaps and its relevance to the infection after surgeries through reviewing the papers of the last decade.</p> <p><b>Materials and methods:</b> A search was conducted for the studies of randomized clinical trials between 2005 and 2014 that reported periodontal flaps in chronic periodontitis patients. Data were extracted and the rate of the systemic antibiotic use, the infection rate after surgeries and the number needed to treat (NNT) to prevent one infected case were calculated. The impact of antibiotic use and materials used in surgeries on the infection was evaluated.</p> <p><b>Results:</b> Eighty-three trials were included. Antibiotics were used in 73.7% of the patients and 75.4% of the flaps. Infection occurred in only five flaps where enamel matrix proteins (EMD) or EMD + bone grafts were used in intrabony defects. Only 0.170% of the surgeries got infected in total. When all kinds of surgeries were included for analysis, the infection rate was 0.073% for the surgeries using antibiotics, which was lower than the infection rate 0.693% for the surgeries not using antibiotics (<i>p</i> < .05). The infection rate was very low in general. NNT was 203 when all the surgeries were included for analysis. Therefore, the difference of the infection rates between using antibiotics and not might lack clinical significance.</p> <p><b>Conclusions:</b> Considering the very low incidence of the infection and the disadvantages of the systemic antibiotic use, we suggest not using systemic antibiotics in the perioperative period of periodontal flaps to prevent infection.</p

Small-Sized mPEG–PLGA Nanoparticles of Schisantherin A with Sustained Release for Enhanced Brain Uptake and Anti-Parkinsonian Activity

Schisantherin A (SA) is a promising anti-Parkinsonism natural product. However, its poor water solubility and rapid serum clearance impose significant barriers to delivery of SA to the brain. This work aimed to develop SA in a nanoparticle formulation that extended SA circulation in the bloodstream and consequently an increased brain uptake and thus to be potentially efficacious for the treatment of Parkinson’s disease (PD). Spherical SA nanoparticles with a mean particle size of 70 nm were prepared by encapsulating SA into methoxy poly­(ethylene glycol)-<i>block</i>-poly­(d,l)-lactic-<i>co</i>-glycolic acid (mPEG–PLGA) nanoparticles (SA-NPs) with an encapsulation efficiency of ∼91% and drug loading of ∼28%. The in vitro release of the SA-NPs lasted for 48 h with a sustained-release pattern. Using the Madin–Darby canine kidney (MDCK) cell model, the results showed that first intact nanoparticles carrying hydrophobic dyes were internalized into cells, then the dyes were slowly released within the cells, and last both nanoparticles and free dyes were externalized to the basolateral side of the cell monolayer. Fluorescence resonance energy transfer (FRET) imaging in zebrafish suggested that nanoparticles were gradually dissociated in vivo with time, and nanoparticles maintained intact in the intestine and brain at 2 h post-treatment. When SA-NPs were orally administrated to rats, much higher <i>C</i>_max and <i>AUC</i>_<i>0‑t</i> were observed in the plasma than those of the SA suspension. Furthermore, brain delivery of SA was much more effective with SA-NPs than with SA suspension. In addition, the SA-NPs exerted strong neuroprotective effects in zebrafish and cell culture models of PD. The protective effect was partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. In summary, this study provides evidence that small-sized mPEG–PLGA nanoparticles may improve cross-barrier transportation, oral bioavailability, brain uptake, and bioactivity of this Biopharmaceutics Classification System (BCS) Class II compound, SA

Pinostrobin Exerts Neuroprotective Actions in Neurotoxin-Induced Parkinson’s Disease Models through Nrf2 Induction

The aim of the present study was to assess the neuroprotective effects of pinostrobin (PSB), a dietary bioflavonoid, and its underlying mechanisms in neurotoxin-induced Parkinson’s disease (PD) models. First, PSB could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons and improve behavior deficiency in zebrafish, supporting its potential neuroprotective actions in vivo. Next, PSB could decreased apoptosis and death in the 1-methyl-4-phenylpyridinium (MPP⁺)-intoxicated SH-SY5Y cells, evidenced by MTT, LDH, Annexin V-FITC/PI, and DNA fragmentation assay. PSB also blocked MPP⁺-induced apoptotic cascades, including loss of mitochondrial membrane potential, activation of caspase 3, and reduced ratio of Bcl-2/Bax. In addition, PSB suppressed MPP⁺-induced oxidative stress but increased antioxidant enzymes, evidenced by decrease of reactive oxygen species generation and lipid peroxidation and up-regulation of GSH-Px, SOD, CAT, GSH/GSSG, and NAD/NADH. Further investigations showed that PSB significantly enhanced Nrf2 expression and nuclear accumulation, improved ARE promoter activity and up-regulated expression of HO-1 and GCLC. Furthermore, Nrf2 knockdown via specific Nrf2 siRNA abolished PSB-induced antioxidative and antiapoptotic effects against MPP⁺ insults. Interestingly, we then found that PSB promoted phosphorylation of PI3K/AKT and ERK, and pharmacological inhibition of PI3K/AKT or ERK signaling diminished PSB-induced Nrf2/ARE activation and protective actions. In summary, PSB confers neuroprotection against MPTP/MPP⁺-induced neurotoxicity in PD models. Promoting activation of Nrf2/ARE signaling contributes to PSB-mediated antioxidative and neuroprotective actions, which, in part, is mediated by PI3K/AKT and ERK

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<p>In response to the microenvironment, microglia may polarize into either an M1 pro-inflammatory phenotype, exacerbating neurotoxicity, or an M2 anti-inflammatory phenotype, conferring neuroprotection. Betulinic acid (BA) is a naturally pentacyclic triterpenoid with considerable anti-inflammatory properties. Here, we aim to investigate the potential effects of BA on microglial phenotype polarization and to reveal the underlying mechanisms of action. First, we confirmed that BA promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Then, we demonstrated that the effect of BA on microglial polarization was dependent on AMP-activated protein kinase (AMPK) activation, as evidenced by the fact that both AMPK inhibitor compound C and AMPK siRNA abolished the M2 polarization promoted by BA. Moreover, we found that calmodulin-dependent protein kinase kinase β (CaMKKβ), but not liver kinase B1, was the upstream kinase required for BA-mediated AMPK activation and microglial M2 polarization, via the use of both the CaMKKβ inhibitor STO-609 and CaMKKβ siRNA. Finally, BA enhanced AMPK phosphorylation and promoted M2 microglial polarization in the cerebral cortex of LPS-injected mice brains, which was attenuated by pre-administration of the AMPK inhibitor. This study demonstrated that BA promoted M2 polarization of microglia, thus conferring anti-neuroinflammatory effects via CaMKKβ-dependent AMPK activation.</p