Antioxidant pyrrolidine dithiocarbamate activates Akt–GSK signaling and is neuroprotective in neonatal hypoxia–ischemia

Abstract

Pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of transcription factor nuclear factor kappa-B (NF-κB), has been reported to reduce inflammation and apoptosis. Because PDTC was recently found to protect in various models of adult brain ischemia with a wide therapeutic time window, we tested the effect of PDTC in a rodent model of neonatal hypoxia–ischemia (HI) brain injury. T 2-weighed magnetic resonance imaging ( T 2-MRI) 7 days after the insult showed that a single PDTC (50 mg/kg) injection 2.5 h after the HI reduced the mean brain infarct size by 59%. PDTC reduced the HI-induced dephosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), expression of cleaved caspase-3, and nuclear translocation of NF-κB in the neonatal brain. PDTC targeted directly neurons, as PDTC reduced hypoxia–reoxygenation-induced cell death in pure hippocampal neuronal cultures. It is suggested that in addition to the previously indicated NF-κB inhibition as a protective mechanism of PDTC treatment, PDTC may reduce HI-induced brain injury at least partially by acting as an antioxidant, which reduces the Akt-GSK-3β pathway of apoptotic cell death. The clinically approved PDTC and its analogues may be beneficial after HI insults with a reasonable time window.