Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Abstract

Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE−/−) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3 days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE−/− mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE−/− mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE−/− mice. At 42 days after injury, the inflammation was still robust in the injured spinal cord in apoE−/− but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE−/− mice. The spared white matter was significantly decreased in apoE−/− mice compared to wild type ones. Locomotor function was significantly decreased in apoE−/− mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE−/− mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE−/− mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D-enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies

“…The ability of CARPs to reduce cell surface levels of NR2B is at least one mechanism whereby the peptides reduce the damaging effects of glutamate-induced excitotoxicity. Furthermore, based on other CARP neuroprotection studies, which include many TAT-fused putative neuroprotective peptides, they have been demonstrated to down-regulate and/or antagonise other neuronal calcium channels/receptors [ 12 , 25 – 34 ], activate pro-survival signalling pathways in neurons [ 34 – 36 ], assist in maintaining neuronal mitochondrial integrity [ 11 , 37 ] and reduce neuro-inflammation [ 38 , 39 ]. In addition, it is likely that the ability of CARPs to exert their neuroprotective actions is mediated in part, to the positively charged guanidino group that is only present in arginine residues [ 2 , 3 , 11 , 12 ].…”

Apolipoprotein E Deficiency Exacerbates Spinal Cord Injury in Mice: Inflammatory Response and Oxidative Stress Mediated by NF-κB Signaling Pathway

“…For instance, APOE mimetic peptide significantly suppressed microglial activation in rats with SCI. Conversely, the excessive inflammation may be caused by the increased permeability of BSCB leading to the influx of inflammatory cells in peripheral blood in Apoe −/− mice after SCI (Wang et al, 2014 ; Cheng et al, 2018 ). Moreover, Apoe −/− mice showed that increased oxidative stress caused an exaggerated neuronal deposition and contributed to the neurodegenerative processes (Nuriel et al, 2017 ).…”

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

“…AMPAR, NCX, TRPV1, CaV2.2, CaV3.3) that may exacerbate excitotoxic ionic disturbances in the brain following stroke [221][222][223][224][225][226][227][228][229][230][231], and is one likely mechanism whereby the peptides reduce the damaging effects of glutamate-induced excitotoxicity. In addition to the confirmed neuroprotective properties of CARPs, they possess other properties that may be beneficial following stroke; they induce the internalization of cell surface TNF receptors [231], scavenge free radicals and reduce lipid peroxidation [189][190][191][192], inhibit the activity of the proteasome [232][233][234], reduce inflammatory responses [235][236][237][238][239][240][241], activate pro-cell survival signalling [218,229,242], and inhibit pro-protein convertases that activate matrix metalloproteinases [243][244][245]. In vitro studies examining the cytoprotective properties of SS-peptides have revealed several potential mechanisms of actions.…”