Research articleAn apoE-derived mimic peptide, COG1410, alleviates early brain injury via reducing apoptosis and neuroinflammation in a mouse model of subarachnoid hemorrhage
Introduction
Subarachnoid hemorrhage (SAH) is a fatal neurovascular disease with high mortality and morbidity [1]. Traditional explanations for the poor prognosis of SAH include delayed cerebral ischemia caused by cerebral vasospasm (CVS). In recent years, the direct brain injury induced by the initial bleeding in the acute phase of SAH, termed as early brain injury (EBI), has attracted more attention [2]. Considering intact neurons as the basis of normal neurological functions, SAH has long been reported to cause neuronal apoptosis leading to declines in neurological functions [3], [4]. Indeed, inhibition of neuronal apoptosis alleviates neurological deficits in SAH animal models [4], [5]. Neuroinflammation is another major pathological process in EBI following a SAH event [6], and anti-neuroinflammation has been proven to be beneficial for SAH animal models [7]. Therefore, targeting apoptosis and neuroinflammation is a promising therapeutic strategy for EBI after SAH.
Apolipoprotein E (apoE) is the major apolipoprotein in the central nervous system (CNS). ApoE not only participates in lipid metabolism, but also exerts anti-neuroinflammatory and anti-apoptotic effects via binding to its functional receptors [8], [9]. Like most other proteins, apoE holoprotein has not been found to cross the blood brain barrier (BBB) for reasons that include its 34-kDa molecular weight. COG1410 is an apoE-mimic peptide derived from amino acids 138–149 of the receptor region of the apoE holoprotein with aminoisobutyric acid (Aib) substitutions at positions 140 and 145 (acetyl-AS-Aib-LRKL-Aib-KRLL-amide). COG1410 has been shown to penetrate the BBB [10]. The therapeutic window for the treatment of traumatic brain injury (TBI) animals expands to 120 min [11], making it a potential neuroprotective agent for SAH treatment via intravenous administration. COG1410 has been proven to protect against neurological deficits and cerebral-vasospasm (CVS) after SAH [12]. However, the detailed mechanisms and the role of COG1410 in neural apoptosis and neuroinflammation in the acute phase of SAH are poorly understood. The present study aimed to investigate the anti-apoptotic and anti-inflammatory effects of COG1410 against EBI after SAH.
Section snippets
Animals and experimental design
All experiments were conducted in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of China. The protocol was approved by the committee on the Ethics of Animal Experiments of the Chongqing Medical University. Adult (10–12 weeks) male C57BL/6 J mice were obtained from the Laboratory Animal Center of Chongqing Medical University. Mice (n = 68) were randomly divided in three groups: (1) the sham group (n = 15): mice underwent a sham operation and
Statistical analysis
All data was expressed as the mean ± standard deviation (SD) and compared with repeated measures of analysis of variance (ANOVA). Bonferroni’s post hoc method was applied for comparison among groups. The difference of mortality rate was analyzed using chi-square test. All statistic values were calculated using SPSS 19.0 (SPSS, Inc. Chicago, USA). Significance was assumed at P < 0.05.
SAH grade and mortality
The severity of SAH based upon bleeding scale scoring was divided into 3 levels [15]: mild SAH, 0–7; moderate SAH, 8–12; severe SAH, 13–18. It is reported that the behavioral deficits of mild SAH animals is similar to that of the sham [18]. A total of 6 mice with mild SAH were excluded from this study. The group severity scores were 0, 13.3 ± 2.8, and 12.8 ± 3.3 in the sham group, SAH + vehicle group and SAH + COG1410 group, respectively (Fig. 1A). There was no significant difference between the two
Discussion
Experimentally applied SAH induced evident mortality and neurological deficits accompanied by neuronal apoptosis and neuroinflammation in mice. COG1410 alleviated apoptosis in the cortex and modulated the apoptosis-related signaling pathways. Microglial activation and pro-inflammatory cytokines production was efficiently suppressed by COG1410 treatment. The attenuation of these pathological changes may contribute to the improvement of neurological function of SAH mice treated with COG1410.
The
Author contributions
Y.J. and XC.S. conceived and designed the experiments. Y.W., JW.P. and JH.P. performed the experiments. Y.W. interpreted the data and drafted the manuscript. F.C., M.P.V. and FQ.L contributed to the data analysis and manuscript revision.
Author disclosure statement
No conflicting interests exist.
Acknowledgement
This work was supported by grants from the National Natural Science Foundation of China (No. 81371319 and No. 81571159), the Program for New Century Excellent Talents in University (NCET-12-1057), the Foundation for Outstanding Youth Academic Technology Leaders of Sichuan province (2014JQ0022), and the National Key Clinical Specialty Construction Project of China (No.{2011}170).
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