Effect of hypothermia on interleukin-1 receptor antagonist pharmacodynamics in inflammatory-sensitized hypoxic-ischemic encephalopathy of term newborns

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.

NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats

“…Few therapies tested in preclinical HI or lipopolysaccharide-sensitized HI (LPS-HI) models show synergetic effects with hypothermia [ 11 , 12 , 13 , 14 , 15 , 16 ]. While this may be due to the fact that therapeutic hypothermia already encompasses multiple mechanisms of neuroprotection, it may also be the case that pre-existing neuroinflammation requires much more rapid and targeted treatment of specific vulnerabilities [ 8 ], such as reduced glutathione (GSH) depletion.…”

Benefits of hypothermia in neonatal arterial ischemic strokes: A preclinical study

“…An open field test was used to measure spontaneous locomotor activity and exploratory behavior of the juvenile rats (P20‐35), as previously described (Chevin et al, 2018; Girard, Kadhim, Beaudet, Sarret, & Sébire, 2009). The following parameters were assessed in the open field apparatus using Any‐Maze Video Tracking System ™ (IL, USA) software: total distance traveled during the test period, mobile time, time in the center, and the number of squares visited.…”

“…The experimental protocol was approved by the Institutional Animal Care Committee of McGill University (protocol #2015-7691) in accordance with the Canadian Council on Animal Care Guidelines: http://www.ccac.ca/en_/stand ards/guide lines. As attempts to model neonatal selective occlusion of the middle cerebral artery were difficult (Gennaro, Mattiello, & Pizzorusso, 2019), we adapted the Rice-Vanucci rat model (Chevin et al, 2016(Chevin et al, , 2018Savard et al, 2013Savard et al, , 2015 (perinatal inflammation, unilateral common carotid occlusion, and global hypoxia) to reproduce the most prevalent human physiopathological scenario of NAIS. A total of 35 Lewis pups at postnatal day (P) 6from five different litters-were obtained from Charles River Laboratories (Kingston, NY) (Chevin et al, 2018).…”

“…To date, no controlled clinical trials have addressed the safety and efficacy of hypothermia (HT) in NAIS (Austin, Shanmugalingam, & Clarke, 2013;Harbert et al, 2011). The few preclinical studies assessing the effect of HT in inflammatory-sensitized hypoxic-ischemic (HI) brain injuries provided inconsistent results (Chevin et al, 2016;Chevin, Guiraut, & Sébire, 2018;Osredkar et al, 2014Osredkar et al, , 2015. Hence, the potential benefit of HT in NAIS remains to be determined.…”

“…Using a preclinical model, our aim was to test the efficacy of HT in treating NAIS and reducing the likelihood of its unfavorable outcomes (Chevin et al, 2016(Chevin et al, , 2018Savard et al, 2015). We hypothesized that HT would lessen the effects of NAIS on: (a) the volume of stroke measured by magnetic resonance imaging (MRI), (b) the [ 18 F] fluorodeoxyglucose (FDG) metabolic activity measured by positron emission tomography/computed tomography (PET/CT), and (c) the motor behavior at a juvenile age.…”