Suppression of CXCL2 upregulation underlies the therapeutic effect of the retinoid Am80 on intracerebral hemorrhage in mice

Abstract

We previously demonstrated that a synthetic retinoic acid receptor agonist, Am80, attenuated intracerebral hemorrhage (ICH)-induced neuropathological changes and neurological dysfunction. Because inflammatory events are among the prominent features of ICH pathology that are affected by Am80, this study investigated the potential involvement of proinflammatory cytokines/chemokines in the effect of Am80 on ICH. ICH induced by collagenase injection into mouse striatum caused prominent upregulation of mRNAs for interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, CXCL1, CXCL2, and CCL3. We found that dexamethasone (DEX) and Am80 differently modulated the increase in expression of these cytokines/chemokines; TNF-α expression was attenuated only by DEX, whereas CXCL2 expression was attenuated only by Am80. Expression of IL-1β and IL-6 was inhibited both by DEX and Am80. Neurological assessments revealed that Am80, but not DEX, significantly alleviated motor dysfunction of mice after ICH. From these results, we suspected that CXCL2 might be critically involved in determining the extent of motor dysfunction. Indeed, magnetic resonance imaging-based classification of ICH in individual mice revealed that invasion of hematoma into the internal capsule, which has been shown to cause severe neurological disabilities, was associated with higher levels of CXCL2 expression than ICH without internal capsule invasion. Moreover, a CXCR1/2 antagonist reparixin ameliorated neurological deficits after ICH. Overall, suppression of CXCL2 expression may contribute to the beneficial effect of Am80 as a therapeutic agent for ICH, and interruption of CXCL2 signaling may provide a promising target for ICH therapy.

Naringin Reverses Neurobehavioral and Biochemical Alterations in Intracerebroventricular Collagenase-Induced Intracerebral Hemorrhage in Rats

“…Poststroke neuropathic pain is common among 2-8% of patients [55]. ICH and intracerebral blood involve in activation of resident microglia, infiltration of immune cells and subsequent production of cytokine (TNF-α and interleukin (IL)-1β) [6], chemokines [56], extracellular proteases and reactive oxygen species [57,58]. Expression of MMPs is also increased in neurological diseases by inflammation and cell death, particularly in ICH [59].…”

An Update on Inflammation in the Acute Phase of Intracerebral Hemorrhage

“…The analysis of brain tissue has indicated that chemokine receptors and their downstream effector molecules were activated after ICH [18]. In a collagenase injection ICH model, prominent upregulation of mRNAs for CXCL1, CXCL2, and CCL3 was observed [19]. In 85 patients with ICH, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 [20].…”

Intracerebral Hemorrhage as an Axonal Tract Injury Disorder with Inflammatory Reactions

“…Moreover, when we administered reparixin, an antagonist at chemokine receptors CXCR1/CXCR2, we observed a significant recovery of motor performance of mice after ICH in the internal capsule. 25) These results suggest that CXCL2 plays an important role in the pathogenic events in ICH with axonal tract injury.…”

“…27) Neutrophil infiltration into tissues can be promoted by several kinds of chemotactic factors including CXCL2. Although we have demonstrated a therapeutic effect of a CXCR antagonist reparixin on the basis of motor performance, 25) the precise modes of action of this drug such as those on neutrophil infiltration and axonal tract injury should be elucidated by further investigations. We should also note here that ICH may be accompanied by increases in several other factors that stimulate neutrophil chemotaxis into the brain.…”

“…25) At the same time, we found that Am80 inhibited ICH-induced increase in the expression of mRNAs encoding several cytokines and chemokines, which include interleukin (IL)-1β, IL-6 and CXCL2. On the other hand, a glucocorticoid dexamethasone inhibited expression of IL-1β and IL-6 but had no effect of CXCL2 expression, while it did not ameliorate ICH-induced impairment of motor performance.…”