Pyrrolidine dithiocarbamate protects the piriform cortex in the pilocarpine status epilepticus model.
Pyrrolidine dithiocarbamate (PDTC) has a dual mechanism of action as an antioxidant and an inhibitor of the transcription factor kappa-beta. Both, production of reactive oxygen species as well as activation of NF-kappaB have been implicated in severe neuronal damage in different sub-regions of the hippocampus as well as in the surrounding cortices. The effect of PDTC on status epilepticus-associated cell loss in the hippocampus and piriform cortex was evaluated in the rat fractionated pilocarpine model. Treatment with 150 mg/kg PDTC before and following status epilepticus significantly increased the mortality rate to 100%. Administration of 50 mg/kg PDTC (low-dose) did not exert major effects on the development of a status epilepticus or the mortality rate. In vehicle-treated rats, status epilepticus caused pronounced neuronal damage in the piriform cortex comprising both pyramidal cells and interneurons. Low-dose PDTC treatment almost completely protected from lesions in the piriform cortex. A significant decrease in neuronal density of the hippocampal hilar formation was identified in vehicle- and PDTC-treated rats following status epilepticus. In conclusion, the NF-kappaB inhibitor and antioxidant PDTC protected the piriform cortex, whereas it did not affect hilar neuronal loss. These data might indicate that the generation of reactive oxygen species and activation of NF-kappaB plays a more central role in seizure-associated neuronal damage in the temporal cortex as compared to the hippocampal hilus. However, future investigations are necessary to exactly analyze the biochemical mechanisms by which PDTC exerted its beneficial effects in the piriform cortex.
Soerensen
Jonna
J
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
Pekcec
Anton
A
Fuest
Christina
C
Nickel
Astrid
A
Potschka
Heidrun
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002452:Cell Count; D019610:Cytoprotection; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000819:agonists; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009833:Olfactory Pathways / Q000187:drug effects* / Q000473:pathology; D010862:Pilocarpine / Q000633:toxicity*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013859:Thiocarbamates / Q000494:pharmacology*
D000975:Antioxidants; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D013859:Thiocarbamates; D010862:Pilocarpine; C020972:pyrrolidine dithiocarbamic acid