Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent.
Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase expressed in the CNS during events that require neuronal plasticity. In this study we demonstrate that endogenous tPA mediates the progression of kainic acid-induced (KA-induced) seizures by promoting the synchronization of neuronal activity required for seizure spreading, and that, unlike KA-induced cell death, this activity is plasminogen-independent. Specifically, seizure induction by KA injection into the amygdala induces tPA activity and cell death in both hippocampi, and unilateral treatment of rats with neuroserpin, a natural inhibitor of tPA in the brain, enhances neuronal survival in both hippocampi. Inhibition of tPA within the hippocampus by neuroserpin treatment does not prevent seizure onset but instead markedly delays the progression of seizure activity in both rats and wild-type mice. In tPA-deficient mice, seizure progression is significantly delayed, and neuroserpin treatment does not further delay seizure spreading. In contrast, plasminogen-deficient mice show a pattern of seizure spreading and a response to neuroserpin that is similar to that of wild-type animals. These findings indicate that tPA acts on a substrate other than plasminogen and that the effects of neuroserpin on seizure progression and neuronal cell survival are mediated through the inhibition of tPA.
Yepes
Manuel
M
Department of Vascular Biology, American Red Cross Holland Laboratory, Rockville, Maryland 20855, USA.
Sandkvist
Maria
M
Coleman
Timothy A
TA
Moore
Elizabeth
E
Wu
Jiang-Young
JY
Mitola
David
D
Bugge
Thomas H
TH
Lawrence
Daniel A
DA
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000378:metabolism; D006023:Glycoproteins / Q000008:administration & dosage / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000009:adverse effects / Q000378:metabolism; D008032:Limbic System / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000008:administration & dosage / Q000378:metabolism*; D009498:Neurotoxins / Q000009:adverse effects / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D015843:Serpins / Q000008:administration & dosage / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000097522:Neuroserpin
D018690:Excitatory Amino Acid Agonists; D006023:Glycoproteins; D007608:Kainic Acid; D009479:Neuropeptides; D009498:Neurotoxins; D010958:Plasminogen; D010960:Plasminogen Activators; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin