Role of perinatal inflammation in neonatal arterial ischemic stroke

Antoine Giraud1, Clémence Guiraut,  Mathilde Chevin,  Stéphane Chabrier, Guillaume Sébire. Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke.  Front. Neurol., 16 November 2017 | https://doi.org/10.3389/fneur.2017.00612

Based on the review of the literature, perinatal inflammation often induced by infection is the only consistent independent risk factor of neonatal arterial ischemic stroke (NAIS). Preclinical studies show that acute inflammatory processes take place in placenta, cerebral arterial wall of NAIS-susceptible arteries and neonatal brain. A top research priority in NAIS is to further characterize the nature and spatiotemporal features of the inflammatory processes involved in multiple levels of the pathophysiology of NAIS, to adequately design randomized control trials using targeted anti-inflammatory vasculo- and neuroprotective agents.

Given that the diagnosis of NAIS is often delayed due, in most cases, to the prenatal onset and/or to the absence, or paucity and diagnostic delays, of neonatal symptoms, future therapies should focus on the control of preinsult determinants most often acting prenatally—e.g., through anti-inflammatory intervention, such as IL-1Ra, or on postinsult neonatal mechanisms—e.g., through hypothermia therapy (HT)—rather than on less feasible per-insult acute interventions...

IL-1 Blockade

Our team and others uncovered that the upregulation of IL-1 plays a key role in chorioamnionitis, and in associated neonatal ischemic brain injuries. Our preclinical studies, and others, showed that prenatal IL-1 blockade using IL-1Ra is protective against chorioamnionitis, associated FIRS, and subsequent brain injuries. Postnatal administration of IL-1Ra is also effective in alleviating mortality (from 40 to 18%) as well as morbidities arising from postnatal inflammatory-sensitized NAIS: 66% decrease of the core (cavitary lesion), and 54% decrease of the penumbra (rim of mild to moderately ischemic tissue lying between the core and the unaffected tissue), and preventing the loss of motor skills. IL-1Ra is an already approved drug to treat chronic inflammatory conditions, including those affecting pregnant mothers and newborns. IL-1Ra is, among the various molecules interfering with the IL-1 signaling, the one which dominates its pharmacological field due to its: (i) blocking effect on both IL-1α and IL-1β; (ii) short 4–6 h half-life (blood levels falling within a few hours of treatment stoppage); (iii) multiple routes of administration; (iv) approval for several pediatric inflammatory conditions (1–10 mg/kg/24 h), knowing that the repurposing of well-studied drugs used in the pediatric population is a cost-effective and efficient strategy to identify new therapies for pediatric diseases; and (v) excellent safety record (absence of opportunistic infection; reversible increase of liver enzyme, decrease of polymorphonuclear cells, slight increase of infection, that are mostly observed in patients on chronic treatment) after more than 10 years of use in more than 150,000 patients. Altogether, this provides encouraging preclinical evidence in favor of the efficacy and feasibility of end-gestational or neonatal interventions using IL-1Ra.

Hypothermia Therapy

Hypothermia therapy is now a mandatory standard of care for term newborns suffering for diffuse HI encephalopathy. However, cooling treatment is modestly effective and leaves 50% of the treated patients with major sequelae. Besides, it is uncertain why HT is effective for some, but not all, human newborns. Clinical studies reported that HT might have less beneficial effects on newborns exposed to infection-inflammation plus HI, than those exposed to HI alone. Furthermore, evidence in favor of an anti-inflammatory role of HT within the newborn brain is limited and conflicted. Only a few clinical or preclinical models address this question. However, a well-established anti-inflammatory effect of HT is the down regulation of oxidative stress within the brain. It has also been reported that HT is neuroprotective by limiting apoptotic cascades in human term newborns. The potential effect of HT on neuroinflammatory cytokines expression has been poorly investigated up to now in preclinical models as well as in term newborns. It has been recently shown that HT did not modulate inflammatory molecules, including IL-1β, TNF-α, IL-1Ra and MMP-9, on LPS plus HI-exposed pups. Other downregulating effect of HT within preclinical NAIS brains remained unclear. In the clinical settings, HT has not been tested yet in NAIS patients, even though it is feasible and possibly effective.

Erythropoietin

Erythropoietin presents anti-inflammatory and neuroprotective properties mainly through dampening free radical release and neural cells apoptosis that have been well-established on preclinical models of neonatal brain infarcts. Erythropoietin seems to be well-tolerated and neuroprotective against perinatal brain lesions of premature newborns: Benders et al. performed a study in 21 consecutive NAIS patients diagnosed by magnetic resonance imaging (MRI) using erythropoietin (1,000 IU/kg intravenously administered just after the diagnostic confirmation by MRI, and repeated at 24 and 48 h).

There was no adverse effect on blood cells counts, or coagulation. The residual versus initial MRI injuries were quantitatively compared at 3 months of age between the erythropoietin-treated patients versus 10 untreated matched historical controls. The percentage of tissue loss within the ischemic area was not different between the treated versus untreated group. Hence, the effectiveness of erythropoietin in terms of neuroprotection in the NAIS context remains to be established.