Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke
Author(s)
Type
Journal Article
Abstract
Background: Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms.
Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA).
Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed.
Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P<0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm3; P<0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; P<0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (P<0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation.
Conclusion: LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.
Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA).
Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed.
Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P<0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm3; P<0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; P<0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (P<0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation.
Conclusion: LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.
Date Issued
2019-03-18
Date Acceptance
2018-12-28
Citation
International Journal of Nanomedicine, 2019, 14, pp.1979-1991
ISSN
1176-9114
Publisher
Dove Medical Press
Start Page
1979
End Page
1991
Journal / Book Title
International Journal of Nanomedicine
Volume
14
Copyright Statement
© 2019 So et al. This work is published by Dove Medical Press Limited, and licensed under a Creative Commons Attribution License. The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/. The license permits unrestricted use, distribution,
and reproduction in any medium, provided the original author and source are credited.
and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000462306500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Nanoscience & Nanotechnology
Pharmacology & Pharmacy
Science & Technology - Other Topics
ischemic stroke
acetate
liposomes
neuroinflammation
microglia
mid-cerebral artery occlusion
TISSUE-PLASMINOGEN ACTIVATOR
BLOOD-BRAIN-BARRIER
STEALTH LIPOSOMES
THROMBOLYSIS
INFLAMMATION
MICROGLIA
SCIENCE
TIME
Publication Status
Published