Protective Effect of CXCR4 Antagonist CX807 in a Rat Model of Hemorrhagic Stroke

Abstract

Intracerebral hemorrhage (ICH) is a major cause of stroke, with high mortality and morbidity. There is no effective pharmacological therapy for ICH. Previous studies have indicated that CXCR4 antagonists reduced microglia activation, attenuated infiltration of T cells, and improved functional recovery in ischemic stroke animals. The interaction of CXCR4 antagonists and ICH has not been characterized. The purpose of this study is to examine the neuroprotective action of a novel CXCR4 antagonist CX807 against ICH. In primary cortical neuronal and BV2 microglia co-culture, CX807 reduced glutamate-mediated neuronal loss and microglia activation. Adult rats were locally administered with collagenase VII to induce ICH. CX807 was given systemically after the ICH. Early post-treatment with CX807 improved locomotor activity in ICH rats. Brain tissues were collected for qRTPCR and histological staining. ICH upregulated the expression of CXCR4, CD8, TNFα, IL6, and TLR4. The immunoreactivity of IBA1 and CD8, as well as TUNEL labeling, were enhanced in the perilesioned area. CX807 significantly mitigated these responses. In conclusion, our data suggest that CX807 is neuroprotective and anti-inflammatory against ICH. CX807 may have clinical implications for the treatment of hemorrhagic stroke.

Human Milk Oligosaccharide 2′-Fucosyllactose Induces Neuroprotection from Intracerebral Hemorrhage Stroke

“…Several studies have supported the effectiveness of anti-inflammatory treatment in animal models of ICH [11,12]. We recently demonstrated that early post-treatment with a CXCR4 antagonist CX807 inhibited inflammation and improved behavioral function in experimental ICH rats [13]. These data suggest that anti-inflammatory therapy may reduce brain damage after ICH.…”

“…ICH promotes the migration of peripheral immune cells, such as CD4 + and CD8 + T cells, to the lesioned brain [28,29]. We previously reported the expression of cytotoxic T-cell markers in the ICH brain [13]. In addition, the peak infiltration of CD4 T cells was between days 3 and 4 after ischemic injury in the mice [30].…”

“…We demonstrated that 2FL antagonized hemin-mediated activation of microglia. Type VII collagenase was used to generate focal ICH in adult rats [13]. We found that 2FL significantly mitigated ICH-induced microglia activation, CD4 + lymphocyte infiltration, and ER stress in the lesioned brain and improved behavioral function.…”

“…Previously, we demonstrated that local collagenase infusion resulted in ICH and bradykinesia in rats [13]. In this study, a similar animal model was used to examine the protective effect of 2FL in vivo.…”

“…Sci. 2021, 22, x FOR PEER REVIEW 2 of 12 rats [13]. These data suggest that anti-inflammatory therapy may reduce brain damage after ICH.…”