Abstract
BackgroundHypothermia is increasingly tested in several neurological conditions, such as neonatal encephalopathy, stroke, traumatic brain injury, subarachnoid hemorrhage, spinal cord injury, and neurological outcomes of cardiac arrest. Current studies aim to increase benefits of hypothermia with new add-on therapies including immunomodulatory agents. Hypothermia has been shown to affect the metabolism of commonly used drugs, including those acting on neuroimmune pathways.ObjectiveThis study focuses on the effect of hypothermia on interleukin-1 receptor antagonist pharmacodynamics in a model of neonatal encephalopathy.MethodsThe effect of hypothermia on (i) the tissue concentration of the interleukin-1 receptor antagonist, (ii) the interleukin-1 inflammatory cascade, and (iii) the neuroprotective potential of interleukin-1 receptor antagonist has been assessed on our rat model of neonatal encephalopathy resulting from inflammation induced by bacterial compound plus hypoxia-ischemia.ResultsHypothermia reduced the surface of core and penumbra lesions, as well as alleviated the brain weight loss induced by LPS+HI exposure. Hypothermia compared to normothermia significantly increased (range 50–65%) the concentration of the interleukin-1 receptor antagonist within the central nervous system. Despite this increase of intracerebral interleukin-1 receptor antagonist concentration, the intracerebral interleukin-1-induced tumor necrosis factor-alpha cascade was upregulated. In hypothermic condition, the known neuroprotective effect of interleukin-1 receptor antagonist was neutralized (50 mg/kg/12 h for 72 h) or even reversed (200 mg/kg/12 h for 72 h) as compared to normothermic condition.ConclusionHypothermia interferes with the pharmacodynamic parameters of the interleukin-1 receptor antagonist, through a bioaccumulation of the drug within the central nervous system and a paradoxical upregulation of the interleukin-1 pathway. These effects seem to be at the origin of the loss of efficiency or even toxicity of the interleukin-1 receptor antagonist when combined with hypothermia. Such bioaccumulation could happen similarly with the use of other drugs combined to hypothermia in a clinical context.
Highlights
Pure hypoxia-ischemia (HI) and inflammatory-sensitized HI are the most prevalent clinical scenarios underlying neonatal encephalopathy (NE) of term newborns, one of the leading causes of neonatal death or cerebral palsy [1]
Hypothermia interferes with the pharmacodynamic parameters of the interleukin-1 receptor antagonist, through a bioaccumulation of the drug within the central nervous system and a paradoxical upregulation of the interleukin-1 pathway
These effects seem to be at the origin of the loss of efficiency or even toxicity of the interleukin-1 receptor antagonist when combined with hypothermia
Summary
Pure hypoxia-ischemia (HI) and inflammatory-sensitized HI are the most prevalent clinical scenarios underlying neonatal encephalopathy (NE) of term newborns, one of the leading causes of neonatal death or cerebral palsy [1]. Interleukin-1 receptor antagonist (IL-1Ra) has already demonstrated a protective perinatal efficacy on several organs, especially the brain, exposed to inflammation induced by bacterial compounds and/or HI [11, 12, 15, 16]. These results support a potential neuroprotective benefit of IL-1Ra as a targeted add-on therapy to HT. Our objectives will test the effect of HT on (i) the tissue concentration of IL-1Ra, including the central nervous system; (ii) the inflammatory cascade of the IL-1 system; and (iii) the neuroprotective potential of IL-1Ra. Hypothermia is increasingly tested in several neurological conditions, such as neonatal encephalopathy, stroke, traumatic brain injury, subarachnoid hemorrhage, spinal cord injury, and neurological outcomes of cardiac arrest. Hypothermia has been shown to affect the metabolism of commonly used drugs, including those acting on neuroimmune pathways
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