Should losartan be administered following brain injury?

Abstract

Brain injury is a major health concern and associated with delayed neurological complications, including post-injury epilepsy, cognitive and emotional disabilities. Currently, there is no strategy to prevent post-injury delayed complications. We recently showed that dysfunction of the blood–brain barrier, often reported in brain injuries, can lead to epilepsy and neurodegeneration via activation of inflammatory TGF-β signaling in astrocytes. We further showed that the FDA approved angiotensin II type 1 receptor antagonist, losartan, blocks brain TGF-β signaling and prevents epilepsy in the albumin or blood–brain barrier breakdown models of epileptogenesis. Here we discuss the potential of losartan as an anti-epileptogenic and a neuroprotective drug, the rationale of its use following brain injury and the challenges of designing clinical trials. We highlight the urgent need to develop reliable biomarkers for epileptogenesis (and other complications) after brain injury as a pre-requisite to challenge neuroprotective therapies.

Keywords::

• blood–brain barrier
• brain injury
• epileptogenesis
• losartan
• post-injury epilepsy
• transforming growth factor β

Acknowledgement

The authors declare that they have no financial interest and therefore nothing to disclose.

Financial & competing interests disclosure

This work was supported by the German Research Foundation (DFG UH&AF), the European Union’s Seventh Framework Programs (FP7/2007–2013) under grant agreement 602102 (EPITARGET, AF), the Israel Science Foundation (713/11, AF) and the National Institute of Health (RO1/NINDS NS066005 DK, AF). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Epilepsy and neurocognitive disabilities may develop after traumatic and ischemic injuries to the brain.

• Currently, there is no strategy to prevent the development of post-injury neural complications and no validated biomarker to identify patients at risk.

• Breakdown and dysfunction of the blood–brain barrier is a common pathology after injury and may lead to epileptogenic reorganization of the neural network.

• Activation of inflammatory TGF-β signaling in astrocytes was shown to underlie network modifications and epileptogenesis in rodents.

• Losartan, an angiotensin II type 1 receptor antagonist and a common anti-hypertensive drug, was shown to block TGF-β signaling in peripheral tissue and in the brain and prevent epilepsy in rodent models.

• Losartan is a promising anti-epileptogenic drug; however, clinical studies designed to treat all injured patients are likely to fail due to the required large sample size and side effects.

• There is an urgent need to develop reliable biomarkers for BBB dysfunction, neuroinflammation and network reorganization in injured patients. Ideal biomarkers will allow recognizing high-risk patients and be used to adjust dose and treatment duration.

Notes