While extensive studies report that neonatal
hypoxia-
ischemia (HI) induces long-term
cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral
inflammation response in HI injury. Here we used a neonatal
hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic
hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of
minocycline (45 mg/kg) was injected intraperitoneally (i.
p.) 2 h after the
hypoxia exposure ended, followed by half dosage (22.5 mg/kg)
minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral
inflammation responded to
hypoxia and whether this peripheral
inflammation response was associated to cognitive deficits. We found that neonatal
hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of
C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2
protein expression level. The early onset of peripheral
inflammation response was followed by a late onset of
brain inflammation that was demonstrated by level of
cytokine IL-1β and ionized
calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and
memory deficits were seen after
hypoxia. Interestingly, the cognitive function was highly correlated with
hypoxia-induced leukocyte response. Notably, administration of
minocycline even after the onset of
hypoxia significantly suppressed leukocyte-mediated
inflammation as well as
brain inflammation, demonstrating neuroprotection in systemic
hypoxia-induced brain damage. Our data provided new insights that systemic
hypoxia induces
cognitive dysfunction, which involves the leukocyte-mediated peripheral
inflammation response.