Intraperitoneal Delivery of Acetate-Encapsulated Liposomal Nanoparticles for Neuroprotection of the Penumbra in a Rat Model of Ischemic Stroke

TY - JOUR

T1 - Intraperitoneal Delivery of Acetate-Encapsulated Liposomal Nanoparticles for Neuroprotection of the Penumbra in a Rat Model of Ischemic Stroke

AU - So, Po-Wah

AU - Ekonomou, Antigoni

AU - Galley, Kim

AU - Brody, Leigh P

AU - Sahuri-Arisoylu, Meliz

AU - Rattray, Ivan

AU - Cash, Diana

AU - Bell, Jimmy

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. In this study, we investigated the effects of acetate, a metabolite that modulates many pathways including inflammation to attenuate brain injury. 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). Transient ischemic stroke 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 performed. Lesion volumes were decreased by ~80% from the 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. In conclusion, LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.

AB - Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. In this study, we investigated the effects of acetate, a metabolite that modulates many pathways including inflammation to attenuate brain injury. 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). Transient ischemic stroke 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 performed. Lesion volumes were decreased by ~80% from the 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. In conclusion, LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.

KW - Acetate

KW - Ischemic stroke

KW - Liposomes

KW - Microglia

KW - Mid-cerebral artery occlusion

KW - Neuroinflammation

UR - http://www.scopus.com/inward/record.url?scp=85064218375&partnerID=8YFLogxK

U2 - 10.2147/IJN.S193965

DO - 10.2147/IJN.S193965

M3 - Article

SN - 1178-2013

VL - 14

SP - 1979—1991

JO - International Journal of Nanomedicine

JF - International Journal of Nanomedicine

ER -