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Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke

Authors So PW, Ekonomou A, Galley K, Brody L, Sahuri-Arisoylu M, Rattray I, Cash D, Bell JD

Received 9 November 2018

Accepted for publication 28 December 2018

Published 18 March 2019 Volume 2019:14 Pages 1979—1991


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

Po-Wah So,1 Antigoni Ekonomou,1 Kim Galley,1 Leigh Brody,2 Meliz Sahuri-Arisoylu,2 Ivan Rattray,3 Diana Cash,1 Jimmy D Bell2

1King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Neuroimaging, London, UK; 2University of Westminster, Research Centre for Optimal Health, London, UK; 3King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, London, UK

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.

Keywords: ischemic stroke, acetate, liposomes, neuroinflammation, microglia, mid-cerebral artery occlusion

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