Therapeutic Hypothermia and Interleukin-1 Blockade as Neuroprotective Strategies in Neonatal Encephalopathy and Arterial Ischemic Stroke PDF Download

Author: Mathilde Chevin
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Languages : en
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Book Description
"Neonatal encephalopathy (NE) and neonatal arterial ischemic stroke (NAIS) are either diffuse or focal brain injuries resulting both from hypoxic-ischemic events and/or pathogen-induced inflammation. NE affects up to 1% of live births. NAIS affects 0.3% of live births. Treatment options are symptomatic in both diseases. A curative therapeutic option is only available in NE due to pure HI and consists in therapeutic hypothermia (HT). HT, however, provides limited neuroprotection and around 50% of treated neonates will experience moderate to severe neurologic disabilities. It is still unclear if HT confers beneficial effects when there is combined aggression of hypoxia-ischemia (HI) and pathogen-induced inflammation, which is one of the most common pathophysiological scenario of both NE and NAIS.Human neuropathological studies and experimental animal models of perinatal brain injury reveal that Interleukin (IL)-1[beta] – among other pro-inflammatory cytokines – is implicated in the pathophysiological cascade leading to brain injury. Besides, preclinical studies did not bring evidence of an effect of HT on the IL-1 cascade. Therefore, postnatal systemic administration of Interleukine-1 receptor antagonist (IL-1Ra: a natural blocker of IL-1) may be a potential therapeutic intervention of postnatal brain injury, such as NE and NAIS. However, IL-1Ra is not approved for the treatment or prevention of postnatal brain injury, and further studies are needed to determine its safety and efficacy. No studies have been conducted to assess the efficacy of IL-1Ra with other therapies, such as HT.In this thesis, I hypothesized that HT alone or in combination with IL-1Ra would provide neuroprotective effects in a rat model of both NE and NAIS resulting from inflammatory-sensitized-HI. We further hypothesized that IL-1Ra will provide an added value to HT in alleviating brain injuries and improving motor behavioural outcomes. I aimed to investigate (1) the safety of HT treatment in combination with IL-1Ra and (2) the efficacy of HT combined or not with IL-1Ra in terms of mortality, brain injuries, and short and long-term motor behaviour in our model of NE resulting from inflammatory-sensitized HI. This thesis shows for the first time that (i) HT has an impact on the pharmacodynamic parameters of IL-1Ra; revealing a future need to refine the dose of IL-1Ra used in combination to HT; (ii) this combined therapy is able to reduce the mortality rate and improve short-term motor behaviour; and (iii) HT alone reduces the occurrence and the volume of brain infarct, improves brain metabolic activity, and alleviates the long-term motor outcomes of inflammatory plus HI- induced brain injuries.This thesis reveals the importance of studying the influence of HT on the distribution, metabolism, elimination and clinical efficacy of drugs in order to avoid toxicity or ineffectiveness. Current and future studies investigating the beneficial effect of HT in other neurological pathologies, such as stroke, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, should take into account this particular effect. In addition, we observed a potential combined effect of IL-1Ra plus HT that needs further preclinical evaluation before moving to human clinical therapeutic trials. Our results provide evidence of the neuroprotective effect of HT in NE and NAIS resulting from inflammatory-sensitized HI. This thesis opens new research avenues on the potential benefit of HT in other postnatal brain injury sharing common determinants with NE, such as NAIS. This could pave the way towards further clinical evaluation of the benefit of HT in NAIS"--