New monocyte locomotion inhibitory factor analogs protect against cerebral ischemia-reperfusion injury in rats.

Jingman Ni,Chao Wang,Xiaoping Wang,Yan Yang

doi:10.17305/bjbms.2017.1622

Abstract

Monocyte locomotion inhibitory factor (MLIF) is an oligopeptide with anti-inflammatory properties. The carboxyl-terminal end group Cys-Asn-Ser serves as the pharmacophore of MLIF. The aim of this study was to investigate the neuroprotective effects of two new synthetic analogs, Arg-Cys-Asn-Ser and D-Cys-Asn-Ser, on focal cerebral ischemia, which were designed and synthesized to increase the penetrability and enzymatic stability of Cys-Asn-Ser. Ninety-one male Sprague-Dawley rats were randomly divided into six groups: I - Sham; II - Ischemia-reperfusion (I/R); III - Nimodipine; IV - Cys-Asn-Ser; V - D-Cys-Asn-Ser; and VI - Arg-Cys-Asn-Ser. The rats in groups II-VI were subjected to middle cerebral artery occlusion. After 24 hours of reperfusion, the neurological deficit, cerebral infarct volume, and levels of the pro-inflammatory factors interleukin-1β (IL-1β) and tumor necrosis factor-alpha in brain tissue homogenates were assessed. Compared with the sham group, the mean neurological deficit scores were significantly higher in groups II-VI (p ≤ 0.019 for all). The mean infarct volumes were significantly higher in I/R and Cys-Asn-Ser groups compared with the sham group (both p ≤ 0.046). The mean IL-1β level was significantly lower in D-Cys-Asn-Ser and Arg-Cys-Asn-Ser groups compared with I/R group (both p ≤ 0.046). In conclusion, the results showed that Arg-Cys-Asn-Ser and D-Cys-Asn-Ser have the potential for protective effects against focal cerebral ischemia injury.

Highlights

In cerebral ischemia, various pathogenic factors play a role in increased morbidity and mortality
The aim of this study was to investigate the effects of two new derivatives of Monocyte locomotion inhibitory factor (MLIF), Arg-Cys-Asn-Ser and D-CysAsn-Ser, on focal cerebral ischemia-perfusion injuries, that were designed and synthesized to enhance the blood-brain barrier (BBB) penetrability and enzymatic stability of CysAsn-Ser [19,20,22]
The mean infarct volume was significantly higher in I/R and CysAsn-Ser groups compared with the sham group (313.6 and 203.24 mm3 versus 0 mm3 respectively, both p ≤ 0.046)

Summary

Introduction

Various pathogenic factors play a role in increased morbidity and mortality. It has been speculated that the reduced capability to biosynthesize catecholamines in the brain, after acute ischemic stroke, may be attributable to the inflammatory response. The inflammatory response may Submitted: 23 August 2016/Accepted: 16 October 2016 be involved in mediating neurotoxic effects [3]. Both mild and substantial cerebral hypoxia-ischemia influence cerebral microglial/macrophage activation (ED1), pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α]), and nitrosative stress (nitrotyrosine), resulting in permanent brain damage [4]. The blocking of various factors involved in the inflammatory cascade reduces damage in experimental ischemia [5,6,7] This has been found for both, endogenous and synthesized factors. Targeting inflammation and monitoring the injury processes with imaging or biomarkers may help guide treatment of patients with acute ischemic stroke [4,13]

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