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Objective: We examined the neuroprotective efficacy, including dose-responses and therapeutic window of 1) LAU-0901, receptor antagonist of the bioactive phospholipid mediator platelet-activating factor (PAF-R) that downregulates pro-inflammatory signaling and has been shown efficacy in a stroke model and, 2) AT-NPD1 (Aspirin- triggered NPD1), its synthesis in the brain was discovered upon aspirin + DHA administration (Bazan et al. Exp Neurol., 2012) and induced cell-survival pathways, anti-inflammatory and neuroprotective activity in focal cerebral ischemia. Methods: Male SD rats underwent 2 hours of MCAo. Behavior testing (days 1-7) and ex vivo MRI on day 7 were conducted. In dose-response, rats were treated with LAU-0901 (45 and 60 mg/kg; IP), AT-NPD1 (111, 222, 333 μg/kg; IV), LAU-0901+AT-NPD1 (LAU-0901 at 3h and AT-NPD1 at 3.15h) or vehicle. In the therapeutic window, vehicle LAU-0901 (60 mg/kg), AT-NPD1 (222 μg/kg), and LAU-0901+AT-NPD1 were administered at 3, 4, 5, and 6h after onset of MCAo. Rats were perfused on day 7, and an ex vivo brain MRI was conducted using 11.7 T MRI. Hierarchal region splitting was used to distinguish the core from the penumbra. Results: LAU-0901 and AT-NPD1 treatments alone improved behavior by 40-42% and 20-30%, respectively, and LAU-0901+AT-NPD1 by 40% compared to the vehicle group. T2-weighted imaging (T2WI) volumes were reduced with all doses of LAU-0901 and AT-NPD1 by 73-90% and 67-83% and LAU-0901+AT-NPD1 by 94% compared to vehicle. In the therapeutic window, treatment with LAU-0901 and AT-NPD1 alone, when administered at 3h, improved behavior on day 7 by 35 and 28%. In contrast, LAU-0901+AT-NPD1, when administered at 3, 4, 5, and 6 hours, improved behavior by 50, 56, 33, and 26%. Ischemic core, penumbra, and total lesion volumes were dramatically reduced with LAU-0901+AT-NPD1 when administered at 3, 4, 5, and 6h by 93, 90, 82, and 84% compared to the vehicle. Conclusion: These data suggest that LAU-0901 and AT-NPD1 alone in low doses provide high-grade neuroprotection in the MCAo model. Combination therapy with LAU-0901 and AT-NPD1 is more effective than the single therapy, affording synergistic neuroprotection with improved neurological recovery when administered up to 6 h after focal cerebral ischemia in rats.

Objective: Cerebral ischemia causes irreversible brain damage, which involves oxidative stress, the release of endogenous substances and inflammation. We tested the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAF-R) plus administering a selected docosanoid after middle cerebral artery occlusion (MCAo) would lead to neurological recovery. Following small bioactive molecules were investigated: LAU-0901 (LAU), PAF-R antagonist that blocks pro-inflammatory signaling, and aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways, and their combination that exerts potent anti-inflammatory activity in the brain. This study investigated the dose-response and therapeutic window in a model of focal cerebral ischemia. Methods: Male SD rats were subjected to 2h of MCAo, behavior was evaluated on days 1-7, and an ex vivo MRI was conducted on day 7. In Dose-response, rats were treated with LAU (45 and 60mg/kg, IP, at 3h), AT-NPD1 (111, 222, and 333μg/kg, IV, at 3.15 h after onset of stroke), LAU+AT-NPD1 or vehicle (n=5-6 per group). In Therapeutic window, LAU (60mg/kg, IP), AT-NPD1 (222μg/kg, IV), LAU+AT-NPD1 were administered at 3, 4, 5, and 6 h after onset of MCAo. Results: Treatments with LAU (45 and 60 mg/kg) alone improved behavior on days 1-7 by 32-38%; AT-NPD1 (all doses) by 20-30% compared to vehicle groups. The neuroprotective effect was enhanced using the LAU+AT-NPD1, which resulted in improved behavior up to 35-40% on days 1-7. Total lesion volumes, which were computed using T2WI, were significantly reduced with LAU-0901 (45 and 60mg/kg) by 76-85% and AT-NPD1 (all doses) alone by 62-77% compared to the vehicle group. Ischemic core, penumbra, and total lesion volumes were dramatically reduced with LAU+AT-NPD1 by 92-94% compared to the vehicle. LAU and AT-NPD1 alone, improved behavior on day 7 by 35 and 28%. In contrast, LAU+AT-NPD1 improved behavior by 46% when administered at 3h, by 52% at 4h, 34% at 5h, and 19% at 6h. Conclusion: LAU-0901 and AT-NPD1 alone provide high-grade neuroprotection. Combination therapy with LAU-0901 and AT-NPD1 is more effective than the single therapy, affording synergistic neuroprotection with improved behavior when administered up to 6 h after MCAo in rats.

Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown.The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y.Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression.Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: -1.81, 95% CI: -2.75, -0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition.A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.