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Research ArticleResearch Article: New Research, Disorders of the Nervous System

Protein Nanoparticles Modified with PDGF-B as a Novel Therapy After Acute Cerebral Infarction

Soh Takagishi, Koichi Arimura, Masaharu Murata, Katsuma Iwaki, Tomohiro Okuda, Keisuke Ido, Ataru Nishimura, Sayoko Narahara, Takahito Kawano and Koji Iihara
eNeuro 30 August 2021, 8 (5) ENEURO.0098-21.2021; DOI: https://doi.org/10.1523/ENEURO.0098-21.2021
Soh Takagishi
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Koichi Arimura
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Masaharu Murata
2Center for Advanced Medical Innovation, Kyushu University, Fukuoka 812-8582, Japan
3Department of Advanced Medical Initiatives, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Katsuma Iwaki
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Tomohiro Okuda
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Keisuke Ido
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Ataru Nishimura
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Sayoko Narahara
2Center for Advanced Medical Innovation, Kyushu University, Fukuoka 812-8582, Japan
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Takahito Kawano
2Center for Advanced Medical Innovation, Kyushu University, Fukuoka 812-8582, Japan
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Koji Iihara
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
4National Cerebral and Cardiovascular Center, Suita, Japan, Osaka 564-8565, Japan
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  • Figure 1.
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    Figure 1.

    Characterization of PDGF-B HSPNP. A, The size of small HSP 16.5 NPs (HSPNPs) and PDGF-B modified HSPNPs (PDGF-B HSPNPs), determined using dynamic light scattering. B, Immunoblot analyses for Akt, phospho-Akt, and β-actin in cultured human brain vascular pericyte cells treated with PBS, HSPNPs, PDGF-BB, and PDGF-B HSPNPs. β-Actin was used as the loading control. d: diameter.

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    Figure 2.

    Dose and time effects of PDGF-B HSPNP accumulation in the infarct area. A, Dose effects of PDGF-B HSPNP accumulation in the infarct area 6 h after administration (2.5, 5, and 10 nmol; n = 3–10). B, Temporal profile of PDGF-B HSPNP accumulation (3, 7, 15 d after administration of PDGF-B HSPNPs; n = 3–10). C, Frozen sections 3 d after PDGF-B HSPNP administration. Left panel, MAP-2 staining to confirm the infarct area. Right panel, Fluorescence microscopy. Scale bars: 200 μm. NPs are widely distributed in the infarct area on day 3.

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    Figure 3.

    Therapeutic effects of administration of PDGF-B HSPNPs. Evaluation of infarct volume with MRI. The infarct volume was calculated using the following formula: infarct volume ratio = (ipsilateral T2 high intensity area)/(contralateral hemisphere × 2). Because of individual differences in cerebral infarct volume, we evaluated the infarct volume before injection of NPs (24 h after MCAO) as a control. A, The infarct volume decreased in the PDGF-B HSPNP group (1.04 μmol/l) compared with the PBS or PDGF-BB protein group. B, MRI on days 3 and 7 after administration of PBS, PDGF-BB, and PDGF-B HSPNPs. C, The infarct volume decreased in the PDGF-B HSPNP group (1.04 μmol/l) compared with that in the HSPNP group but not in the group administered a lower concentration of PDGF-B HSPNPs (0.104 μmol/l). Shown is mean ± SD (n = 5–8; *p < 0.01; n.s., not significant). D, MRI on days 3 and 7 after administration of HSPNPs, PDGF-B HSPNPs (low), and PDGF-B HSPNPs. E, MAP-2 staining demonstrated that the infarct volume decreased in the PDGF-B HSPNP group compared with that in the HSPNP group on day 7. MAP-2-negative ratio = (ipsilateral MAP-2-negative area)/(contralateral hemispheric area × 2). Values are mean ± SD (n = 5; *p < 0.05; n.s., not significant). F, MAP-2 staining on days 3 and 7 after administration of HSPNPs and PDGF-B HSPNPs. Scale bars: 100 μm. Dotted areas indicate infarct areas. G, H, Motor functional evaluation using the cylinder test before MCAO, before administration of NPs (day 0), 3 d after administration (day 3), and 7 d after administration (day 7). D, Motor function improved significantly on day 7 in the PDGF-B HSPNP group (1.04 μmol/l) compared with the PBS or PDGF-BB group. E, Motor function improved significantly on day 7 in the PDGF-B HSPNP group (1.04 μmol/l) compared with that in the groups administered HSPNP or lower concentration of PDGF-B HSPNP (0.104 μmol/l). Values are mean ± SD (n = 5–8; †p < 0.01, PBS and PDGF-BB vs PDGF-B HSPNP), *p < 0.05, HSPNP versus PDGF-B HSPNP.

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    Figure 4.

    Akt phosphorylation by PDGF-B HSPNPs. A, Temporal profile of phospho-Akt (Ser 473) expression using immunohistochemistry on days 3 and 7 after administration of HSPNPs and PDGF-B HSPNPs. Scale bars: 100 μm. B, Phospho-Akt-positive cells were counted by hybrid cell count in the peri-infarct area and ischemic core. Data are presented as mean ± SD (n = 5; *p < 0.05; n.s., not significant). C, Immunoblot analyses for Akt and phospho-Akt (Ser 473) 3 d after administration of HSPNPs and PDGF-B HSPNPs. D, Densitometry for phospho-Akt/total Akt. Data are presented as mean ±SD (n = 9; *p < 0.05). E, Immunofluorescent double labeling of phospho-Akt (p-Akt; red) and PDGFRβ (green) in the ischemic core on day 3 after PDGF-B HSPNP administration. Scale bar: 50 μm.

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    Figure 5.

    Effects of PDGF-B HSPNPs on the expression of NTs and astrogliosis in peri-infarct area in a murine transient middle cerebral artery occlusion model of stroke. NT expression 3 d after administration of PDGF-B HSPNPs was investigated with ELISA using a multi-NT rapid screening ELISA kit. A, Neurotrophin-3 (NT-3) (n = 10; *p < 0.05). B, Nerve growth factor (NGF) (n = 8; n.s., not significant.). C, Brain-derived neurotrophic factor (BDNF) (n = 8). D, Neurotrophin-4/5 (NT-4/5) (n = 8). E, Immunoblot analyses for GFAP 7 d after administration of HSPNPs and PDGF-B HSPNPs. GFAP–positive cells were counted by hybrid cell count in the peri-infarct area. Data are presented as mean ± SD (*p < 0.05).

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    Figure 6.

    PDGF-B HSPNPs reduced neuronal apoptosis in peri-infarct area. A, TUNEL staining with DAPI in peri-infarct area; 1 and 3 are representative images of the HSPNP group, and 2 and 4 are images of the PDGF-B HSPNP group (1 and 2: 3 d after administration; 3 and 4: 7 d after administration). Scale bar: 100 μm. B, The number of TUNEL-positive cells in peri-infarct area 3 and 7 d after administration of HSPNPs and PDGF-B HSPNPs (n = 5 for each group; **p < 0.01). C, Fluorescent TUNEL/NeuN (green/red, respectively) double staining 3 d after administration of HSPNPs (left) and PDGF-B HSPNPs (right). Scale bar: 50 μm. D, The number of TUNEL/NeuN double-positive cells scaled to the number of NeuN-positive cells in peri-infarct area 3 d after administration of HSPNPs and PDGF-B HSPNPs (n = 5 for each group; *p < 0.05).

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    Table 1

    Numbers of biological replicates

    ExperimentDrug administeredExperiment dayNumbers of animals analyzed/used (sex)Body
    weight (g)
    MRIPBS75/6* (male)26.4 ± 2.0
    HPSPNP311/12** (male)
    2/2 (female)
    26.7 ± 0.7
    18.7 ± 0.3
    76/7** (male)
    2/2 (female)
    26.7 ± 0.9
    18.6 ± 0.1
    PDGF-BB75/5 (male)27.0 ± 1.8
    PDGF-B HSPNP (low)75/5 (male)24.1 ± 1.0
    PDGF-B HSPNP313/13 (male)
    2/2 (female)
    27.0 ± 2.5
    18.2 ± 0.2
    78/9* (male)
    2/2 (female)
    27.6 ± 2.4
    18.1 ± 0.2
    Cylinder testPBS75/6* (male)26.4 ± 2.0
    HPSPNP38/9** (male)26.5 ± 0.4
    75/6** (male)26.3 ± 0.4
    PDGF-BB75/5 (male)27.0 ± 1.8
    PDGF-B HSPNP (low)75/5 (male)24.1 ± 1.0
    PDGF-B HSPNP312/12 (male)26.9 ± 2.6
    78/9** (male)27.6 ± 2.4
    Western blottingHSPNP32/2 (male)27.0 ± 0.3
    73/3 (male)27.2 ± 1.0
    PDGF-B HSPNP32/2 (male)23.5 ± 1.1
    74/4 (male)25.7 ± 1.9
    ImmunostainingHSPNP32/2 (male)26.3 ± 0.0
    sample75/5 (male)26.3 ± 0.4
    PDGF-B HSPNP34/4 (male)25.9 ± 2.5
    75/5 (male)25.3 ± 2.1
    Pilot behavioral experiment
    using the IVIS
    1, 3, 7, 1525/32 (male)
    (*, 4; **, 1; ***, 2)
    25.1 ± 2.8
    Cumulative total161/176
    • Body weight values are shown as mean ± SD. The exclusion criteria were as follows: *, premature death; **, hemorrhagic infarction on MRI; ***, failure of surgery. PBS, vehicle; HSPNPs, heat shock protein nanoparticles; PDGF-BB, dimer of PDGF B; PDGF-B HSPNPs, PDGF B conjugated to HSPNPs, dose = 1.04 μmol/l; PDGF-B HSPNPs (low), same but dose = 0.104 μmol/l.

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Protein Nanoparticles Modified with PDGF-B as a Novel Therapy After Acute Cerebral Infarction
Soh Takagishi, Koichi Arimura, Masaharu Murata, Katsuma Iwaki, Tomohiro Okuda, Keisuke Ido, Ataru Nishimura, Sayoko Narahara, Takahito Kawano, Koji Iihara
eNeuro 30 August 2021, 8 (5) ENEURO.0098-21.2021; DOI: 10.1523/ENEURO.0098-21.2021

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Protein Nanoparticles Modified with PDGF-B as a Novel Therapy After Acute Cerebral Infarction
Soh Takagishi, Koichi Arimura, Masaharu Murata, Katsuma Iwaki, Tomohiro Okuda, Keisuke Ido, Ataru Nishimura, Sayoko Narahara, Takahito Kawano, Koji Iihara
eNeuro 30 August 2021, 8 (5) ENEURO.0098-21.2021; DOI: 10.1523/ENEURO.0098-21.2021
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Keywords

  • cerebral infarction
  • nanoparticle
  • neuroprotection
  • pericyte
  • platelet-derived growth factor PDGF-B

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