Novel multiple agents loaded PLGA nanoparticles for brain delivery via inner ear administration: in vitro and in vivo evaluation.

The aim of this study was to develop novel multiple agents loaded poly (D,L-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) and evaluate their potential for brain delivery via inner ear administration. PLGA NPs loaded with salvianolic acid B (Sal B), tanshinone IIA (TS IIA) and panax notoginsenoside (PNS) were prepared by double emulsion/solvent evaporation method. It was observed that optimized NPs displayed satisfactory encapsulation efficiency and desired sustained-release characteristics. NPs following intratympanic administration (IT) in guinea pigs greatly improved drug distribution within the inner ear, cerebrospinal fluid (CSF) and brain tissues compared with intravenous administration (IV). Pharmacodynamic studies demonstrated that NPs following IT markedly inhibited oxidizing reactions and protected the brain from cerebral ischemia reperfusion (I/R) injury by upregulating superoxide dismutase (SOD) activity both in serum and brain tissues, simultaneously significantly reducing the levels of malondialdehyde (MDA) and nitric oxide synthase (NOS). Moreover intratympanic delivery did not cause injury of cochlear function by preliminary study on the toxicity. These findings suggested that PLGA NPs-based delivery system via inner ear administration was a promising candidate to brain delivery for the treatment of brain diseases.

Pharmacokinetics and dopamine/acetylcholine releasing effects of ginsenoside Re in hippocampus and mPFC of freely moving rats.

AIM: To investigate the pharmacokinetics and dopamine/acetylcholine-releasing effects of ginsenoside Re (Re) in brain regions related to learning and memory, and to clarify the neurochemical mechanisms underlying its anti-dementia activity. METHODS: Microdialysis was conducted on awake, freely moving adult male SD rats with dialysis probes implanted into the hippocampus, medial prefrontal cortex (mPFC) or the third ventricle. The concentrations of Re, dopamine (DA) and acetylcholine (ACh) in dialysates were determined using LC-MS/MS. RESULTS: Subcutaneous administration of a single dose of Re (12.5, 25 or 50 mg/kg) rapidly distributed to the cerebrospinal fluid and exhibited linear pharmacokinetics. The peak concentration (C(max)) occurred at 60 min for all doses. Re was not detectable after 240 min in the dialysates for the low dose of 12.5 mg/kg. At the same time, Re dose-dependently increased extracellular levels of DA and ACh in the hippocampus and mPFC, and more prominent effects were observed in the hippocampus. CONCLUSION: The combined study of the pharmacokinetics and pharmacodynamics of Re demonstrate that increase of extracellular levels of DA and ACh, particularly in the hippocampus, may contribute, at least in part, to the anti-dementia activity of Re.

[In vivo distribution and pharmacokinetics of multiple effective components contained in Panax notoginseng saponins after intratympanic administration].

OBJECTIVE: To investigate in vivo distribution and pharmacokinetics of ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1 ) and sanchinoside R1 (R1) after intratympanic administration (IT) or intravenous administration (IV) of Panax notoginseng saponions (PNS) solution, and provide a novel route for delivering traditional Chinese medicine (TCM) to the brain. METHOD: The guinea pigs were employed as experimental animal. Perilymph (PL), cerebrospinal fluid (CSF), brain tissue and plasma were collected periodically after IT and IV of PNS solution. The concentrations of Rb1, Rg1 and R1 were measured by high performance liquid chromatography (HPLC), and statistic program DAS was applied to the calculation of pharmacokinetic parameters. The self-defined weighting coefficients based on area under curve (AUC) of each component were created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters were then calculated from non-compartmental model analysis. RESULT: Rb1, Rg1 and R1 diffused through the round window membrane into PL of the inner ear, and then transported to the brain after IT of PNS solution. However, the pharmacokinetic parameters showed significant differences between the three components. Based on the self-defined AUC weighting coefficients integration approach, the holistic pharmacokinetic profiles of PNS were obtained, from which the integrated pharmacokinetic parameters were calculated. The C(max) in CSF and brain tissues following IT were respectively 1.5 and 0.4-fold higher than those following IV. After IT, the AUC in CSF and brain tissues increased by 0.5 and 1.2 times compared with IV. Furthermore, the C(max) and AUC in plasma following IT were respectively 45.9% and 33.1% lower than those following IV. CONCLUSION: This novel intra-cochlear administration might serve as a potential and promising alternative to TCM delivery with enhanced brain-targeted efficiency.