Pyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibitor of transcription factor nuclear factor kappa-B (NFjB). Because the role of NF-jB in brain injury is controversial and another NF-jB inhibiting thiocarbamate, DDTC, was recently shown to increase ischaemic brain damage, we investigated the effect of PDTC on transient brain ischaemia. Ischaemia was induced by occlusion of the middle cerebral artery (MCAO). In Wistar rats, the PDTC treatment started even 6 h after MCAO reduced the infarction volume by 48%. PDTC protected against MCAO also in spontaneously hypertensive rats and against forebrain ischaemia in Mongolian gerbils. PDTC prevented NF-jB activation in the ischaemic brain as determined by reduced DNA binding and nuclear translocation of NF-jB in neurons. PDTC had anti-inflammatory effect by preventing induction of NF-jB-regulated proinflammatory genes. In ischaemic rats, NF-jB was localized in cyclo-oxygenase-2-immunoreactive neurons. Blood cytokine levels were not altered by ischaemia or PDTC. When cultured neurons were exposed to an excitotoxin, no production of reactive oxygen species was detected, but PDTC provided protection and prevented nuclear translocation of NF-jB. The clinically approved PDTC and its analogues may act as antiinflammatories and may be safe therapies in stroke with a wide time window. Keywords: cytokines, inflammation, neuroimmunology, rodent. Stroke is the third leading cause of death in industrialized countries and a major cause of severe disability in the elderly (Centers for Disease Control 1992; Wolf et al. 1997). There is no other acute stroke therapy than intravenous thrombolysis and it is safe and effective only for a fraction of the patients (Bednar and Gross 1999;Lindsberg and Kaste 2003). Even though animal research conducted on acute ischaemic injury has revealed several pathophysiological cascades contributing to brain infarction, no breakthroughs in developing clinically relevant stroke therapy have been achieved. One factor is that laboratory studies on a single animal species or stroke model are not sufficient for modelling more variable human strokes (STAIR 1999). Another valid reason is that the compounds, which are protective in animal models, have a limited therapeutic time window or toxic secondary effects in humans (STAIR 1999).Reactive oxygen species (ROS) and inflammation are involved in human stroke and play a crucial role in animal models of stroke during the first days after the onset of ischaemia ( Abbreviations used: COX-2, cyclo-oxygenase-2; DDTC, diethyldithiocarbamate; div, days in vitro; FBS-HI, fetal bovine serum heat inactivated; IjB, inhibitor of NF-jB; IL-1b, interleukin-1b; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; MAPKs, mitogen-activated protein kinases; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MEM, minimal essential medium; NF-jB, nuclear factor kappa-B; NMDA, N-methyl-D-asparatate; PDTC, pyrrolidine dithiocarbamate; ROS, reactive oxygen species; SHR, spontaneously ...