The Interleukin-1 Receptor Antagonist (rhIL-1ra) Protects against Cerebral Infarction in a Rat Model of Hypoxia-Ischemia

doi:10.1006/exnr.1994.1215

Experimental Neurology

Volume 130, Issue 2, December 1994, Pages 362-367

https://doi.org/10.1006/exnr.1994.1215 Get rights and content

Abstract

We assessed the cerebral protective effects of the competitive interleukin-1 antagonist rhIL-1ra in 7-day-old rats that were subjected to brain hypoxia-ischemia by unilateral carotid artery ligation and subsequent exposure to 2 h of 7.5% O₂-balanced N₂. This procedure leads to atrophy in the cerebral hemisphere ipsilateral to carotid occlusion, with prominent foci of neuronal infarction in the striatum. Systemic administration of 100 mg/kg of rhIL-1ra before and/or after the hypoxic exposure limited the insult. The results indicate that rhIL-1ra has potent neuroprotective properties against morphologic brain injury from hypoxia-ischemia. rhIL-1ra may prove to be clinically useful in protecting against hypoxia-ischemia-related disorders.

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Perinatal hypoxic-ischemic reperfusion (I/R)-related brain injury is a leading cause of neurologic morbidity and life-long disability in children. Infants exposed to I/R brain injury develop long-term cognitive and behavioral deficits, placing a large burden on parents and society. Therapeutic strategies are currently not available for infants with I/R brain damage, except for hypothermia, which can only be used in full term infants with hypoxic-ischemic encephalopathy (HIE). Moreover, hypothermia is only partially protective. Pro-inflammatory cytokines are key contributors to the pathogenesis of perinatal I/R brain injury. Interleukin-1β (IL-1β) is a critical pro-inflammatory cytokine, which has been shown to predict the severity of HIE in infants. We have previously shown that systemic infusions of mouse anti-ovine IL-1β monoclonal antibody (mAb) into fetal sheep resulted in anti-IL-1β mAb penetration into brain, reduced I/R-related increases in IL-1β expression and blood-brain barrier (BBB) dysfunction in fetal brain. The purpose of the current study was to examine the effects of systemic infusions of anti-IL-1β mAb on short-term I/R-related parenchymal brain injury in the fetus by examining: 1) histopathological changes, 2) apoptosis and caspase-3 activity, 3) neuronal degeneration 4) reactive gliosis and 5) myelin basic protein (MBP) immunohistochemical staining. The study groups included non-ischemic controls, placebo-treated ischemic, and anti-IL-1β mAb treated ischemic fetal sheep at 127 days of gestation. The systemic intravenous infusions of anti-IL-1β mAb were administered at fifteen minutes and four hours after in utero brain ischemia. The duration of each infusion was two hours. Parenchymal brain injury was evaluated by determining pathological injury scores, ApopTag® positive cells/mm², caspase-3 activity, Fluoro-Jade B positive cells/mm², glial fibrillary acidic protein (GFAP) and MBP staining in the brains of fetal sheep 24 h after 30 min of ischemia. Treatment with anti-IL-1β mAb reduced (P < 0.05) the global pathological injury scores, number of apoptotic positive cells/mm², and caspase-3 activity after ischemia in fetal sheep. The regional pathological scores and Fluoro-Jade B positive cells/mm² did not differ between the placebo- and anti-IL-1β mAb treated ischemic fetal sheep. The percent of the cortical area stained for GFAP was lower (P < 0.05) in the placebo ischemic treated than in the non-ischemic group, but did not differ between the placebo- and anti-IL-1β mAb treated ischemic groups. MBP immunohistochemical expression did not differ among the groups. In conclusion, infusions of anti-IL-1β mAb attenuate short-term I/R-related histopathological tissue injury, apoptosis, and reduce I/R-related increases in caspase-3 activity in ovine fetal brain. Therefore, systemic infusions of anti-IL-1β mAb attenuate short-term I/R-related parenchymal brain injury in the fetus.
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Traumatic brain injury (TBI) elicits a complex secondary injury response, with neuroinflammation as a crucial central component. Long thought to be solely a deleterious factor, the neuroinflammatory response has recently been shown to be far more intricate, with both beneficial and detrimental consequences depending on the timing, magnitude and specific immune composition of the response post-injury. Despite extensive preclinical and clinical research into mechanisms of secondary injury after TBI, no effective neuroprotective therapy has been identified, with potential candidates repeatedly proving disappointing in the clinic. The neuroinflammatory response offers a promising avenue for therapeutic targeting, aiming to quell the deleterious consequences without influencing its function in providing a neurotrophic environment supportive of repair. The present review firstly describes the findings of recent clinical trials that aimed to modulate inflammation as a means of neuroprotection. Secondly, we discuss promising multifunctional and single-target anti-inflammatory candidates either currently in trial, or with ample experimental evidence supporting clinical application.
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Citation Excerpt :
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Citation Excerpt :
In contrast, postnatal treatment is a more clinically attractive option since diagnosis of prenatal inflammation and HI are most often made postnatally due to clinical investigations routinely performed in human neonates. Human neuropathological studies and experimental animal models of perinatal brain injury revealed that pro-inflammatory cytokines, especially those from the IL-1 system, are implicated in the cascade leading to brain damage occurring at different developmental stages (Allan et al., 2005; Cai et al., 2004; Denes et al., 2011; Girard et al., 2008, 2010a; Hagberg et al., 1996; Kadhim et al., 2006, 2003; Martin et al., 1994). In addition to their direct neurotoxic effects, cytokine imbalances are also suspected to affect brain development since cytokines play an active role in neurogenesis and synaptogenesis (Deverman and Patterson, 2009; Dziegielewska et al., 2000).
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Regular ArticleThe Interleukin-1 Receptor Antagonist (rhIL-1ra) Protects against Cerebral Infarction in a Rat Model of Hypoxia-Ischemia

Abstract

Regular Article
The Interleukin-1 Receptor Antagonist (rhIL-1ra) Protects against Cerebral Infarction in a Rat Model of Hypoxia-Ischemia