authors equally contributed to the paper.
Losartan prevents acquired epilepsy via TGF-β signaling suppression
Article first published online: 28 MAY 2014
© 2014 American Neurological Association
Annals of Neurology
Volume 75, Issue 6, pages 864–875, June 2014
How to Cite
Bar-Klein, G., Cacheaux, L. P., Kamintsky, L., Prager, O., Weissberg, I., Schoknecht, K., Cheng, P., Kim, S. Y., Wood, L., Heinemann, U., Kaufer, D. and Friedman, A. (2014), Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol., 75: 864–875. doi: 10.1002/ana.24147
- Issue published online: 30 JUN 2014
- Article first published online: 28 MAY 2014
- Accepted manuscript online: 21 MAR 2014 04:11AM EST
- Manuscript Revised: 19 MAR 2014
- Manuscript Accepted: 19 MAR 2014
- Manuscript Received: 19 DEC 2013
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.
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.
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.
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. Ann Neurol 2014;75:864–875