title: Tissue plasminogen activator does not alter development of acquired epilepsy.
abstract: OBJECTIVE
  Tissue plasminogen activator (t-PA), a proven therapy for acute ischemic stroke, is an endogenous serine protease associated with neuronal activity and synaptic plasticity in the brain. Its expression is enhanced after seizures, and is involved in seizure propagation throughout the brain. Therefore, the increased use of t-PA to treat stroke may have important implications for the development of poststroke epilepsy. Using experimental and clinical approaches, we investigated the role of t-PA in the development of epilepsy.
  
  
  METHODS
  Mice deficient in t-PA (t-PA(-/-) ) or mice transgenically modified to overexpress neuronal t-PA (T4) underwent amygdala kindling, and seizure threshold and rates of kindling were compared to those in wild-type mice. For the clinical study, we recruited acute ischemic stroke patients who either received intravenous t-PA treatment on admission to hospital (n = 177; cases) or did not (n = 158; controls). We then assessed the incidence of early and late onset seizures and epilepsy in these patients.
  
  
  RESULTS
  T4 mice were more seizure-prone than wild-type mice, exhibiting lower seizure thresholds (p = 0.002), but there were no significant differences observed in the rate of kindling development when comparing either T4 mice, or t-PA(-/-) mice, to their wild-type controls. Furthermore, we found no significant differences between the proportion of poststroke patients experiencing early or late seizures, or developing epilepsy, between those who received t-PA and those who did not.
  
  
  CONCLUSIONS
  Overexpression of endogenous t-PA lowers seizure threshold but does not influence kindling epileptogenesis. Moreover, the therapeutic administration of t-PA in humans does not influence the development of acquired poststroke epilepsy.
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3052, Australia.
authors.forename: Mei-Lyn
authors.initials: ML
authors.lastname: Tan
authors.forename: Ashley
authors.initials: A
authors.lastname: Ng
authors.forename: Puneet S
authors.initials: PS
authors.lastname: Pandher
authors.forename: Maithili
authors.initials: M
authors.lastname: Sashindranath
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Davis
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
authors.forename: Bernard
authors.initials: B
authors.lastname: Yan
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D004827:Epilepsy / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000172:deficiency / Q000627:therapeutic use
chemical_list: D010959:Tissue Plasminogen Activator