title: Losartan prevents acquired epilepsy via TGF-β signaling suppression.
abstract: OBJECTIVE
  Acquired epilepsy is frequently associated with structural lesions after trauma, stroke, and infections. Although seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin-mediated transforming growth factor β (TGF-β) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin-mediated TGF-β signaling and tested the efficacy of blocking the TGF-β pathway in preventing epilepsy.
  
  
  METHODS
  We addressed the role of TGF-β signaling in epileptogenesis in 2 different rat models of vascular injury, combining in vitro and in vivo biochemical assays, gene expression, and magnetic resonance and direct optical imaging for blood-brain barrier permeability and vascular reactivity. Long-term electrocorticographic recordings were acquired in freely behaving animals.
  
  
  RESULTS
  We demonstrate that serum-derived albumin preferentially induces activation of the activin receptor-like kinase 5 pathway of TGF-β receptor I in astrocytes. We further show that the angiotensin II type 1 receptor antagonist, losartan, previously identified as a blocker of peripheral TGF-β signaling, effectively blocks albumin-induced TGF-β activation in the brain. Most importantly, losartan prevents the development of delayed recurrent spontaneous seizures, an effect that persists weeks after drug withdrawal.
  
  
  CONCLUSIONS
  TGF-β signaling, activated in astrocytes by serum-derived albumin, is involved in epileptogenesis. We propose losartan, a drug approved by the US Food and Drug Administration, as an efficient antiepileptogenic therapy for epilepsy associated with vascular injury.
authors.affiliation: Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Bar-Klein
authors.forename: Luisa P
authors.initials: LP
authors.lastname: Cacheaux
authors.forename: Lyn
authors.initials: L
authors.lastname: Kamintsky
authors.forename: Ofer
authors.initials: O
authors.lastname: Prager
authors.forename: Itai
authors.initials: I
authors.lastname: Weissberg
authors.forename: Karl
authors.initials: K
authors.lastname: Schoknecht
authors.forename: Paul
authors.initials: P
authors.lastname: Cheng
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Lydia
authors.initials: L
authors.lastname: Wood
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000927:Anticonvulsants; D001549:Benzamides; D004149:Dioxoles; D016212:Transforming Growth Factor beta; D010751:Phosphopyruvate Hydratase; D019808:Losartan