Pyrrolidine dithiocarbamate inhibits translocation of nuclear factor kappa-B in neurons and protects against brain ischaemia with a wide therapeutic time window.
Pyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibitor of transcription factor nuclear factor kappa-B (NF-kappa B). Because the role of NF-kappa B in brain injury is controversial and another NF-kappa B 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-kappa B activation in the ischaemic brain as determined by reduced DNA binding and nuclear translocation of NF-kappa B in neurons. PDTC had anti-inflammatory effect by preventing induction of NF-kappa B-regulated pro-inflammatory genes. In ischaemic rats, NF-kappa B 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-kappa B. The clinically approved PDTC and its analogues may act as anti-inflammatories and may be safe therapies in stroke with a wide time window.
A. I. Virtanen Institute, Department of Neurobiology, University of Kuopio, FIN-70211 Kuopio, Finland.
Antti
A
Nurmi
Nina
N
Vartiainen
Rea
R
Pihlaja
Gundars
G
Goldsteins
Juha
J
Yrjänheikki
Jari
J
Koistinaho
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases