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Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects

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Abstract

Vascular dementia (VaD) has a serious impact on the patients’ quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood–brain barrier (BBB) permeability remain challenges. This research introduced a PEG–PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG–PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1β and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG–PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.

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Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Abbreviations

AD:

Alzheimer’s disease

BBB:

Blood brain barrier

BCCAO:

Bilateral common carotid artery occlusion

BDNF:

Brain-derived neurotrophic factor

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CCH:

Chronic cerebral hypoperfusion

CREB:

cAMP-response element binding protein

CSF:

Cerebrospinal fluid

DLS:

Dynamic light scattering

DMF:

N,N-dimethylformamide

EA:

Ethyl acrylate

EF:

Epimedium flavonoid

ELISA:

Enzyme-linked immunosorbent assay

ER:

Endoplasmic reticulum

ERK:

Extracellular regulated protein kinases

FDA:

Food and Drug Administration

Gel:

Hydrogel

HE:

Hematoxylin and eosin

HPLC:

High performance liquid chromatography

Ica:

Icariin

Ica gel:

Ica chitosan hydrogel

Ica ig:

Ica Intragastric administration

Ica NPs and gel:

Ica-PEG–PLGA NPs and chitosan hydrogel hydrogel

Ica NPs group:

Ica-PEG–PLGA NPs

IHC:

immunohistochemistry

IL-1β/IL-1b:

Interleukin 1β

IL6:

Interleukin 6

LTP:

Long-term potentiation

MWM:

Morris water maze

NMDA:

N-methyl d-aspartate

NMDARs:

N-methyl D-aspartate receptors

NPs:

nanoparticles

GluN2B:

A main subunit of the NMDA receptor

NSCs:

Neural stem cells

PBS:

Phosphate buffered saline

PDI:

Polydispersity Index

PEG–PLGA:

Poly(ethyleneglycol)–poly(lactic-co-glycolic acid)

P-gp:

P-glycoprotein

PSD-95:

Post-synaptic density 95

PVA:

Polyvinyl alcohol

RCTs:

Randomized controlled trails

RT-PCR:

Reverse transcription-polymerase chain reaction

SD:

Sprague Dawley

ß-GP:

β-Glycerophosphate

SYP:

Synaptophysin

TB:

Toluidine blue

TEM:

Transmission electron microscopy

TFE:

Epimedium koreanum

TJ:

Tight junction

TNF-α:

Tumor necrosis factor-α

TrkB:

Tropomyosin receptor kinas B

VaD:

Vascular dementia

VCI:

Vascular cognitive impairment

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Acknowledgements

The authors would like to acknowledge financial supports from Science and Technology Department of Jilin Province [Grant Number: 20200201467JC].

Funding

This work was supported in part by Science and Technology Department of Jilin Province [Grant Number: 20200201467JC].

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Authors and Affiliations

  1. College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People’s Republic of China

    Tieshu Li, Shuling Li, Chun Ma, Zhiying Guan & Lihua Yang

  2. School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, People’s Republic of China

    Yin Xiong

  3. Affiliated Hospital of Yangzhou University, Yangzhou University, 88 South Daxue Road, Yangzhou, 225009, People’s Republic of China

    Xinxin Li

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Contributions

Writing (original draft), graphics drawing and editing, tissue sample analysis, project administration, data curation and interpretation, T.L.; conceptualization and methodology, S.L.; writing (review and editing revising the manuscript critically for intellectual content), investigation, and data analysis, Y.X.; animal experimentation, X.L.; writing (manuscript revising), manufacturing, and characterization of binary formulation, C.M. and Z.G.; formulation design, project coordination, and funding acquisition, L.Y.; All authors have read and agreed to the published version of the manuscript.

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Correspondence to Lihua Yang.

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Conflict of interest

The authors declare no conflict of interest.

Ethical Approval and Informed Consent

All animal experiments in this study were conducted in accordance with the protocols of the Laboratory Animal Ethics Committee of the School of Pharmacy, Jilin University (approval Document No.: 20220036). There are currently no alternatives that mimic the nose-to-brain pathway, which is very complex. The experiments in vitro could not fully disclose the delivery efficiency and safety assessment of the formulation in vivo. A total of 120 male Sprague Dawley (SD) rats (12 weeks old) with body weights between 300 to 320 g were housed at a temperature of 22 ± 2℃, a relative humidity of 50 ± 2%, and a 12-h dark light cycle. All the experimental rats took food and drank water as they pleased. In order to minimize rats suffering, the invasive surgeries on rats were performed under anesthesia (intraperitoneal injections with 3% sodium pentobarbital (1.5 mL/kg)). In addition, invasive operations were performed by skilled technicians in order to speed up operations and reduce the size of the surgical area for rats, which maximized the survival rate of rats and reduced the number of rats in the experiments. At the end of the study, the rats were anesthetized by intraperitoneal injection of sodium pentobarbital and then euthanized in a thermostatically controlled dark box filled with 70% CO2. The study has adhered to the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.

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Li, T., Li, S., Xiong, Y. et al. Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects. Neurochem Res (2024). https://doi.org/10.1007/s11064-024-04129-5

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