Proline-Loaded Chitosan Nanoparticles Penetrate the Blood-Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

Jingchen Gao; Xiyuran Wang; Xiangyi Kong; Xujin Yao; Jinyang Ren; Shujun Chen; Na Shen; Zhuo Li; Yitian Wang; Ye Wei; Oleg Glebov; Fengyuan Che; Qi Wan

doi:10.1021/acsapm.3c02034

Proline-Loaded Chitosan Nanoparticles Penetrate the Blood-Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

Jingchen Gao, Xiyuran Wang, Xiangyi Kong, Xujin Yao, Jinyang Ren, Shujun Chen, Na Shen, Zhuo Li, Yitian Wang, Ye Wei, Oleg Glebov, Fengyuan Che^*, Qi Wan^*

^*Corresponding author for this work

Psychological Medicine

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia-reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood-brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBB-permeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.

Original language	English
Pages (from-to)	10234-10244
Number of pages	11
Journal	ACS Applied Polymer Materials
Volume	5
Issue number	12
DOIs	https://doi.org/10.1021/acsapm.3c02034
Publication status	Published - 8 Dec 2023

Keywords

blood−brain barrier
chitosan nanoparticles
ischemic stroke
localized drug delivery
proline

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsapm.3c02034

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@article{c4b858ef35864a4f87626f2ef608a68c,

title = "Proline-Loaded Chitosan Nanoparticles Penetrate the Blood-Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury",

abstract = "Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia-reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood-brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBB-permeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.",

keywords = "blood−brain barrier, chitosan nanoparticles, ischemic stroke, localized drug delivery, proline",

author = "Jingchen Gao and Xiyuran Wang and Xiangyi Kong and Xujin Yao and Jinyang Ren and Shujun Chen and Na Shen and Zhuo Li and Yitian Wang and Ye Wei and Oleg Glebov and Fengyuan Che and Qi Wan",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2023",

month = dec,

day = "8",

doi = "10.1021/acsapm.3c02034",

language = "English",

volume = "5",

pages = "10234--10244",

journal = "ACS Applied Polymer Materials",

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TY - JOUR

T1 - Proline-Loaded Chitosan Nanoparticles Penetrate the Blood-Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

AU - Gao, Jingchen

AU - Wang, Xiyuran

AU - Kong, Xiangyi

AU - Yao, Xujin

AU - Ren, Jinyang

AU - Chen, Shujun

AU - Shen, Na

AU - Li, Zhuo

AU - Wang, Yitian

AU - Wei, Ye

AU - Glebov, Oleg

AU - Che, Fengyuan

AU - Wan, Qi

PY - 2023/12/8

Y1 - 2023/12/8

N2 - Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia-reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood-brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBB-permeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.

AB - Proline, a nonessential amino acid, has been demonstrated to possess neuroprotective capabilities in the central nervous system (CNS). However, the mechanisms through which it impacts cerebral ischemia-reperfusion (I/R) injuries remain unclear. Our study observed a decrease in proline concentrations within the ischemic brain tissues of I/R mice. Supplementing proline protected against ischemic neuronal death, both in vivo and in vitro, suggesting its potential as a neuroprotectant. However, our data indicated that proline has a low permeability to the blood-brain barrier (BBB) in mice. Therefore, it is clinically infeasible to develop proline as a stroke therapy. To develop an approach to deliver proline into the injured brain, we engineered a method to transport proline to the injured brain. We prepared chitosan nanoparticles (NPs) loaded with proline utilizing the ion cross-linking method. Our findings demonstrated that the proline-loaded chitosan NPs efficiently passed through the BBB and delivered proline into the injured brain, thereby conferring neuroprotection. Further exploration revealed that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which, in turn, increased the phosphorylation of cell-survival-promoting kinase Akt. This sequence of events consequently promotes neuronal survival following I/R. In conclusion, our study has developed a neuroprotection approach by which low-BBB-permeable proline is delivered by chitosan NPs into the brain. Furthermore, this study suggests that the neuroprotective role of proline in I/R is mediated by the ANX6/β1 integrin/Akt signaling pathway.

KW - blood−brain barrier

KW - chitosan nanoparticles

KW - ischemic stroke

KW - localized drug delivery

KW - proline

UR - http://www.scopus.com/inward/record.url?scp=85177767418&partnerID=8YFLogxK

U2 - 10.1021/acsapm.3c02034

DO - 10.1021/acsapm.3c02034

M3 - Article

AN - SCOPUS:85177767418

SN - 2637-6105

VL - 5

SP - 10234

EP - 10244

JO - ACS Applied Polymer Materials

JF - ACS Applied Polymer Materials

IS - 12

ER -

Proline-Loaded Chitosan Nanoparticles Penetrate the Blood-Brain Barrier to Confer Neuroprotection in Mice Cerebral Ischemia Injury

Abstract

Keywords

UN SDGs

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