Editors' ChoiceEpilepsy

Stopping Seizures After Brain Injury

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Science Translational Medicine  16 Apr 2014:
Vol. 6, Issue 232, pp. 232ec69
DOI: 10.1126/scitranslmed.3009250

Acute brain injury resulting from trauma, surgery, stroke, or infection can lead to epilepsy—a brain disorder characterized by seizures. As awareness of military- and sports-related traumatic brain injury (TBI) increases, research has begun to focus on the mechanisms of post-injury epilepsy and how this long-term consequence of brain injury might be avoided. In a new study, Bar-Klein and colleagues shed light on this mechanism, implicating a specialized brain cell called astrocytes in the pathogenesis of epilepsy.

Brain injury is associated with local breakdown of the blood-brain barrier, allowing blood contents to seep into the brain parenchyma. In rodents, the presence of the plasma protein albumin in the parenchyma is sufficient to cause persisting seizures, similar to epilepsy in humans. Bar-Klein et al. showed that albumin binds to the astrocytic transforming growth factor–β (TGF-β) receptors and induces further expression of TGF-β1, setting in motion a feed-forward loop that leads to increasing astrocyte activation. Astrocyte activation is a general damage response seen in the brain after injury, such as TBI or stroke, which can fan the flames of inflammation and promote seizure. Infusion of albumin into the rat cortex led to increased astrocyte activation, neuronal hyperexcitability, and spontaneous seizures in adult rats. Co-application of losartan, an inhibitor of TGF-β signaling, either through direct brain infusion or intraperitoneal injection, blocked the inflammatory response to albumin and prevented seizures for 3 months. Although losartan is a blood pressure medicine, its protective effect in this study was not due to effects on blood vessels, suggesting that modulation of TGF-β is indeed the critical target.

Although these initial findings by Bar-Klein et al. are promising, the efficacy of losartan in the prevention of injury-induced seizures needs to be replicated in other seizure models, such as TBI- or stroke-induced epilepsy. Because losartan is well tolerated, widely available, and U.S. Food and Drug Administration–approved for hypertension, treatment at the time of brain trauma, infection, or surgery is a potentially appealing therapeutic strategy for the prevention of subsequent epilepsy and could be readily evaluated in humans.

G. Bar-Klein et al., Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann. Neurol. 10.1002/ana.24147 (2014). [Abstract]

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