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Objective: Pediatric sudden cardiac arrest (CA) is an unfortunate and devastating condition, often leading to poor neurologic outcomes. However, little is known about the pathophysiology of pediatric CA. We have developed a unique pediatric cardiac arrest and cardiopulmonary (CA/CPR) mouse model to characterize the sex-specific response of the adolescent brain to global cerebral ischemia and assess the neuroprotective effect of estrogen at this developmental stage.Methods: C57BL/6 male and female mice (postnatal day 20 to 25 ) were subjected to 8 min of CA followed by CPR. Juvenile male and female mice were randomized to estradiol (E2, 100μg/kg, iv) or vehicle, administered 30 min after resuscitation. P38-MAPK inhibitor SB203580 (2 mg/kg) alone or in combination with E2 was given 30 min after resuscitation (iv) in females. Hippocampal neuronal damage was analyzed 3 days after CA/CPR by H&E staining. Statistical analyses were performed using ANOVA and t tests, with P<0.05 considered significant.Results: Analysis of histological damage 72 hrs after CA/CPR showed no difference between male (49.4 ± 10.2%, n=5) and female (62.8 ± 1.3%, n=5) pediatric mice. However, estrogen reduced neuronal injury from 62.8 ± 1.3% to 30.6 ± 5.6% (n=6, P<0.05) in female mice. In contrast, estrogen did not alter injury in juvenile males (55.8 ± 6.0%, n=6). P38-MAPK inhibitor blocked the neuroprotection of estrogen in female mice when given simultaneously with E2, increasing injury from 30.6 ± 5.6% to 55.1 ± 8.1% (n=4, P<0.05). However, P38-MAPK inhibitor alone had no effect on injury level in juvenile females (53.7 ± 6.6%, n=5).Conclusions: Pre-pubertal male and female animals exhibit equvalent injury following global cerebral ischemia, in contrast to the extensive literature demonstrating relative protection in the adult female provided by estrogen. Interestingly, estradiol decreases neuronal damage in juvenile females, but not males following CA/CPR, indicating that there is sex difference in neuronal damage in the P20-25 mice after global cerebral ischemia. Moreover, this sex-specific estrogen neuroprotective signaling requires P38-MAPK pathway.