Early Versus Late Postnatal Treatment with Caffeine and/or NSAID's for Prevention of Intermittent Hypoxia-Induced Neuroinflammation in a Rat Model.

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ESPR141
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Background: Extremely preterm infants often experience frequent arterial oxygen desaturations or intermittent hypoxia (IH) during supplemental oxygen therapy. This can lead to reperfusion injury and neuroinflammation, associated with generation of pro-inflammatory prostanoids. Individual use of caffeine or non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to confer neuroprotection.

Objectives: To test the hypotheses that: 1) Caffeine and Ibuprofen/Ketorolac co-treatment has synergistic benefits for reducing IH-induced neuroinflammation in the neonatal rat brain; and 2) Early postnatal treatment during IH is more beneficial than late treatment during reperfusion.

Materials & Methods: Newborn rats were exposed to 3 types of oxygen environments- brief hypoxia (12% O2) and hyperoxia (50% O2) from birth (P0) to P14), to simulate intermittent hypoxia(IH). Hyperoxia(50% O2), or room air (RA). For early treatment, the pups were administered: 1) a single daily IP injection of caffeine citrate (Cafcit, 10 mg/kg loading on P0, followed by 5 mg/kg maintenance from P1-P14); 3) Ketorolac topical ocular solution from P0 to P14; 3) Ibuprofen (Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) Caffeine+Ketorolac co-treatment; 5) Caffeine+Ibuprofen co-treatment; or 6) Placebo saline. On P14, animals were placed in RA. For late treatment, the pups received similar treatments except Ibuprofen was given at P14-16 to represent late therapy group. At P21, whole brains were assessed for histopathology, immunohistochemistry (NFkB, IkB) and myelination; and cerebral cortex was assessed for pro-inflammatory cytokines (IL-1β, TNFα, IL-6 IL-10).

Results: Neonatal IH resulted in impaired cortical cellular layers' differentiation and myelination irrespective of treatment in the late treated groups, whereas cortical layers were relatively better preserved in the early treatment groups. All cytokines were induced with IH, an effect that was curtailed with early treatment. The most beneficial treatments were caffeine with and without NSAID co-treatment.

Conclusions: Data suggest that early NSAID treatment during IH may confer better neurologic protection than later treatment during reperfusion. Caffeine appears to have potent anti-inflammatory effects in the setting of neonatal IH.


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SUNY Downstate Medical Centre
SUNY Downstate Medical Center
SUNY Downstate Medical Centre
SUNY Downstate Medical Centre

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