携载miRNA-124纳米粒子经鼻吸入对缺血性脑卒中模型大鼠的神经保护作用

doi:10.13481/j.1671-587x.20200616

Abstract

Abstract: Objective

To investigate the pharmacodynamic effects of nasal inhalation of microRNA-124（miRNA-124） nanoparticles on the durg distribution in brain tissue， neurological function score， water content in brain tissue and levels of serum inflammatory factors in the ischemic stroke model rats， and to elucidate its neuroprotective effect on the rats with ischemia stroke.

Methods

The target RVG29 was coupled to the poly（ethylene glycol）-poly（lactic-co-glycolic acid）（PEG-PLGA） nanoparticles， the particle size and encapsulation efficiency of the prepared nanoparticles were measured.The PEG-PLGA nanoparticles modified with neurotropic virus-derived peptide RVG29 labeled near-infrared dye 1，1'-dioctadecyl-3，3，3，3-tetramethylindole three-carbon cyanine iodide （DiR）were given to the rats， and the durg biodistribution at different time points after nasal inhalation was measured. The rat model of cerebral ischemia-reperfusion was established by the suture method， and 90 rats were randomly divided into sham operation group， model group， Fasudil group， miRNA-124 nasal inhalation group， PEG-PLGA/miRNA-124 nasal inhalation group， and RVG29-PEG-PLGA/miRNA-124 nasal inhalation group， and there were 6 rats in each group. The neurological function scores and water contents in brain tissue of the rats in various groups were evaluated； the levels of interleukin-4（IL-4）， interleukin-6（IL-6）， tumor necrosis factor-α（TNF-α）， and interleukin-1β （IL-1β）in peripheral serum of the rats in various groups were detected by ELISA method.

Results

The average particle size of RVG29-PEG-PLGA nanoparticles was 204 nm， and the encapsulation efficiency was 28%. The rats in sham operation group had no neurological dysfunction. Compared with sham operation group， the neurological function score， water content in brain tissue， and levels of serum IL-4， IL-6， TNF-α， and IL-1β of the rats in model group were increased （P<0.05）. Compared with model group， the neurological function scores， water contents in brain tissue， and levels of serum IL-4， IL-6， TNF-α， and IL-1β of the rats in Fasudil group， miR-124 nasal inhalation group， PEG-PLGA/miRNA-124 nasal inhalation group， and RVG29-PEG-PLGA/miRNA-124 nasal inhalation group were decreased （P<0.05）. Compared with Fasudil group， the neurological function score， water content in brain tissue， and levels of serum IL-4， IL-6， TNF-α， and IL-1β of the rats in RVG29-PEG-PLGA/miRNA-124 nasal inhalation group were decreased （P<0.05）.

Conclusion

The RVG29-PEG-PLGA nanoparticles have a good ability of nasal inhalation into the brain. Intervention of nanoparticle-carrying miRNA-124 of the rats with ischemic stroke can improve the neurological dysfunction， reduce the cerebral edema and improve the inflammation， and exert the neuroprotection effect.

Key words: nanoparticles, cerebral ischemia-reperfusion, neuroprotection, nasal inhalation, RVG29

CLC Number:

R743.3

Rubin HAO,Haotian WANG,Lihua YANG,Chun MA,Shuling Li,Xinxin LI,Tieshu LI. Neuroprotective effect of nasal inhalation of miRNA-124 nanoparticles on ischemic stroke model rats[J].Journal of Jilin University(Medicine Edition), 2020, 46(6): 1208-1214.

Figures/Tables 4

References 27

1	SUN J， SHI J， HOU J， et al. Electroacupuncture protects rats from ischemic brain injury via coffilin in mice［J］. J Cell Biochem， 2020， 121（1）： 43-48.
2	ZHAI M L， LIU C， LI Y X， et al. Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injury［J］. Aging （Albany NY）， 2019， 11（21）： 9556-9568.
3	BAZRGAR M， KHODABAKHSH P， MOHAGHEGHI F， et al. Brain microRNAs dysregulation： Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer's disease and related tauopathies［J］. Pharmacol Res， 2020， 155： 104729.
4	HOU Q， RUAN H， GILBERT J， et al. MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity［J］. Nat Commun， 2015， 6： 10045.
5	LIU X L， FENG Z T， DU L P， et al. The potential role of MicroRNA-124 in cerebral ischemia injury［J］. Int J Mol Sci， 2019， 21（1）： E120.
6	HAMZEI TAJ S， KHO W， RIOU A， et al. MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia［J］. Biomaterials， 2016， 91： 151-165.
7	HONG W， ZHANG Z H， LIU L P， et al. Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin-sensitive and -resistant Pneumococcal meningitis： formulated with RVG₂₉ and Pluronic^® P85 unimers［J］. Drug Deliv， 2018， 25（1）： 1886-1897.
8	潘峰，郭夏青，沈江宜，等. 大黄素对缺血性脑卒中模型大鼠的神经保护作用及其对ERK1/2信号通路的影响［J］. 吉林大学学报（医学版）， 2019， 45（6）： 1212-1217， 1480.
9	KANAZAWA T， KURANO T， IBARAKI H， et al. Therapeutic effects in a transient middle cerebral artery occlusion rat model by nose-to-brain delivery of anti-TNF-alpha siRNA with cell-penetrating peptide-modified polymer micelles［J］. Pharmaceutics， 2019， 11（9）： E478.
10	DING D， ZHU Q. Recent advances of PLGA micro/nanoparticles for the delivery of biomacromolecular therapeutics［J］. Mater Sci Eng C Mater Biol Appl， 2018， 92： 1041-1060.
11	HOYOS-CEBALLOS G P， RUOZI B， OTTONELLI I， et al. PLGA-PEG-ANG-2 nanoparticles for blood-brain barrier crossing： proof-of-concept study［J］. Pharmaceutics， 2020， 12（1）： E72.
12	CABAN-TOKTAS S， SAHIN A， LULE S， et al. Combination of Paclitaxel and R-flurbiprofen loaded PLGA nanoparticles suppresses glioblastoma growth on systemic administration［J］. Int J Pharm， 2020， 578： 119076.
13	GAN L， LI Z， LV Q， et al. Rabies virus glycoprotein （RVG29）-linked microRNA-124-loaded polymeric nanoparticles inhibit neuroinflammation in a Parkinson’s disease model［J］. Int J Pharm， 2019， 567： 118449.
14	FRÉCHOU M， ZHU X Y， LIERE P， et al. Dose-dependent and long-term cerebroprotective effects of intranasal delivery of progesterone after ischemic stroke in male mice［J］. Neuropharmacology， 2020， 170： 108038.
15	SUKUMAR U K， BOSE R J C， MALHOTRA M， et al. Intranasal delivery of targeted polyfunctional gold-iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide［J］. Biomaterials， 2019， 218： 119342.
16	LANDOWSKI L M， NIEGO B， SUTHERLAND B A， et al. Applications of nanotechnology in the diagnosis and therapy of stroke［J］. Semin Thromb Hemost， 2020， 46（5）： 592-605.
17	CHUNG E P， COTTER J D， PRAKAPENKA A V， et al. Targeting small molecule delivery to the brain and spinal cord via intranasal administration of rabies virus glycoprotein （RVG29）-modified PLGA nanoparticles［J］. Pharmaceutics， 2020， 12（2）： 93.
18	YOU L H， WANG J， LIU T Q， et al. Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in parkinsonian mice［J］. ACS Nano， 2018， 12（5）： 4123-4139.
19	HUA H C， ZHANG X M， MU H J， et al. RVG29-modified docetaxel-loaded nanoparticles for brain-targeted glioma therapy［J］. Int J Pharm， 2018， 543（1/2）： 179-189.
20	HASSANIPOUR M， ZARISFI M， EHSANI V， et al. Whole body hypothermia extends tissue plasminogen activator treatment window in the rat model of embolic stroke［J］. Life Sci， 2020， 256： 117450.
21	LIU Z J， RAN Y Y， QIE S Y， et al. Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through STAT3 pathway［J］. CNS Neurosci Ther， 2019， 25（12）： 1353-1362.
22	DANIEL B， NAGY G， CZIMMERER Z， et al. The nuclear receptor PPARγ controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory［J］. Immunity， 2018， 49（4）： 615-626.
23	FENG H X， HU L H， ZHU H W， et al. Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent［J］. Acta Pharm Sin B， 2020， 10（3）： 434-446.
24	SHAPOURI-MOGHADDAM A， MOHAMMADIAN S， VAZINI H， et al. Macrophage plasticity， polarization， and function in health and disease［J］. J Cell Physiol， 2018，233（9）： 6425-6440.
25	YE Y B， XU Y， LAI Y， et al. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization［J］. J Cell Biochem， 2018， 119（3）： 2951-2963.
26	ANRATHER J， IADECOLA C. Inflammation and stroke： an overview［J］. Neurotherapeutics， 2016， 13（4）： 661-670.
27	ATRI C， GUERFALI F Z， LAOUINI D. Role of human macrophage polarization in inflammation during infectious diseases［J］. Int J Mol Sci， 2018， 19（6）： E1801.

Group	IL-4	IL-6	TNF-α	IL-1β
Sham operation	57.39±6.47	52.85±7.14	30.36±4.80	43.94±4.56
Model	140.57±9.08^*	159.57±5.88^*	79.52±3.47^*	152.36±7.38^*
Fasudil	79.03±5.24^△	84.66±6.46^△	60.63±3.91^△	81.58±6.64^△
miRNA-124 nasal inhalation	115.55±8.50^△	133.99±6.60^△	71.68±2.43^△	100.82±5.88^△
PEG-PLGA/miRNA-124 nasal inhalation	90.29±4.11^△	104.29±10.99^△	65.20±2.80^△	91.47±4.42^△
RVG29-PEG-PLGA/miRNA-124 nasal inhalation	67.66±7.18^△#	72.96±4.26^△#	47.99±3.75^△#	62.75±4.69^△#

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Neuroprotective effect of nasal inhalation of miRNA-124 nanoparticles on ischemic stroke model rats

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