title: 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-kappaB), 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. T2-weighed magnetic resonance imaging (T2-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-3beta (GSK-3beta), expression of cleaved caspase-3, and nuclear translocation of NF-kappaB 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-kappaB 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-3beta pathway of apoptotic cell death. The clinically approved PDTC and its analogues may be beneficial after HI insults with a reasonable time window.
authors: Department of Neurobiology, A.I.Virtanen Institute of Molecular Sciences, University of Kuopio, Finland.
authors: Antti
authors: A
authors: Nurmi
authors: Gundars
authors: G
authors: Goldsteins
authors: Johanna
authors: J
authors: Närväinen
authors: Rea
authors: R
authors: Pihlaja
authors: Toni
authors: T
authors: Ahtoniemi
authors: Olli
authors: O
authors: Gröhn
authors: Jari
authors: J
authors: Koistinaho