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Enhanced Neuroprotection of Acetyl-11-Keto-β-Boswellic Acid (AKBA)-Loaded O-Carboxymethyl Chitosan Nanoparticles Through Antioxidant and Anti-Inflammatory Pathways

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Abstract

Acetyl-11-keto-β-boswellic acid (AKBA), a main active constituent from Boswellia serrata resin, is a novel candidate for therapy of cerebral ischemia-reperfusion (I/R) injury. Nevertheless, its poor solubility in aqueous solvent, bioavailability, and rapid clearance limit its curative efficacy. To enhance its potency, in our study, AKBA-loaded o-carboxymethyl chitosan nanoparticle (AKBA-NP) delivery system was synthesized. The transmission electron microscopy and transmission electron microscope images of AKBA-NPs suggested that particle size was 132 ± 18 nm, and particles were spherical in shape with smooth morphology. In pharmacokinetics study, AKBA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life compared with AKBA. The tissue distribution study confirmed that AKBA-NPs had a better brain delivery efficacy in comparison with AKBA. The results from our pharmacodynamic studies showed that AKBA-NPs possess better neuroprotection compared with AKBA in primary neurons with oxygen-glucose deprivation (OGD) model and in animals with middle cerebral artery occlusion (MCAO) model. Additionally, AKBA-NPs modulate antioxidant and anti-inflammatory pathways more effectively than AKBA by increasing nuclear erythroid 2-related factor 2 and heme oxygenase-1 expression, and by decreasing nuclear factor-kappa B and 5-lipoxygenase expression. Collectively, our results suggest that AKBA-NPs serve as a potent delivery vehicle for AKBA in cerebral ischemic therapy.

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Abbreviations

AKBA:

Acetyl-11-keto-β-boswellic acid

AKBA-NPs:

AKBA-loaded o-carboxymethyl chitosan nanoparticles

EPR:

Enhanced permeability and retention

GPx:

Glutathione peroxidase

IL-1β:

Interleukin-1β

I/R:

Ischemia-reperfusion

HO-1:

Heme oxygenase-1

5-LOX:

5-Lipoxygenase

MCAO:

Middle cerebral artery occlusion

MDA:

Malondialdehyde

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

Nrf2:

Nuclear factor erythroid-2-related factor 2

NF-κB:

Nuclear factor kappa-beta

O-CMC:

O-Carboxymethyl chitosan

OGD:

Oxygen and glucose deprivation

SD:

Standard deviation

SEM:

Scanning electron microscope

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor-α

TTC:

2,3,5-Triphenyltetrazolium chloride

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick-end labeling

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Acknowledgments

This research was financially supported by the Key Technologies for New Drug Innovation and Development of China (Nos. 2011ZXJ09202-13 and 2012BAK25B00) and the National Natural Science Foundation of China (Nos. 81373947 and 81201985).

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    Authors and Affiliations

    1. Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

      Yi Ding, Liang Li, Yikai Zhang, Jie Ge, Ying Song, Yuwen Li & Aidong Wen

    2. Department of Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi’an, 710032, China

      Youbei Qiao

    3. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, 710032, China

      Min Wang & Huinan Zhang

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    Correspondence to Yuwen Li or Aidong Wen.

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    Yi Ding and Youbei Qiao contributed equally to this work.

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    Ding, Y., Qiao, Y., Wang, M. et al. Enhanced Neuroprotection of Acetyl-11-Keto-β-Boswellic Acid (AKBA)-Loaded O-Carboxymethyl Chitosan Nanoparticles Through Antioxidant and Anti-Inflammatory Pathways. Mol Neurobiol 53, 3842–3853 (2016). https://doi.org/10.1007/s12035-015-9333-9

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