Progesterone in the treatment of neonatal arterial ischemic stroke and acute seizures: Role of BDNF/TrkB signaling

Abstract

Neonatal stroke is among the top ten causes of childhood death and permanent disability in survivors, but no safe and effective acute treatments exist. To advance understanding of its neuroprotective mechanisms, we examined the effects of progesterone (PROG) on local and systemic inflammation (IL-1β, IL-6, TNFα), brain derived neurotrophic factor/Tropomyosin receptor kinase B (BDNF/TrkB) signaling, vascular damage (vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9)), acute behavioral seizures and brain infarction size following neonatal arterial ischemic stroke in mice. CD1 mouse pups (postnatal day 12, mixed gender) received permanent unilateral right common carotid ligation (pUCCL) or sham surgery. Pups showing seizure activity during the first hour post-pUCCL were randomly assigned to receive PROG (8 mg/kg) or vehicle injections. PROG treatment significantly (p < 0.05) reduced seizure occurrence by ∼44% compared to vehicle and attenuated the expression of pro-inflammatory cytokines in serum and brain at different time-points. PROG differentially regulated the expression of BDNF and TrkB and the activity of VEGF and MMP-9 over the 7d period. Permanent UCCL resulted in severe hemispheric damage measured at 7 days post-pUCCL but PROG treatment produced a significant (p < 0.05) reduction in infarct volume (∼70%) compared to vehicle. A gender-based comparison of data revealed significantly greater seizure activity in males compared to females. However, we did not observe significant sex differences on any other markers of the injury at this early stage of development. PROG treatment is neuroprotective through a number of signaling pathways and can be beneficial in treating neonatal arterial ischemic stroke in CD1 mice.