Editors' ChoiceTraumatic Brain Injury

Add ARBs to injury?

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Science Translational Medicine  22 Jul 2015:
Vol. 7, Issue 297, pp. 297ec123
DOI: 10.1126/scitranslmed.aac8565

The 1.74 million patients who experience traumatic brain injury (TBI) each year can only be treated with supportive care and rehabilitation. Promising studies in mice, however, show that angiotensin receptor blockers (ARBs) given at the time of TBI can mitigate the resulting brain damage. Building on these results, a new study by Villapol and colleagues assessed whether ARBs could improve outcomes if given after TBI, a situation more closely resembling the likely patient experience.

The investigators tested two different ARBs, candesartan and telmisartan, administered 6 hours after controlled cortical impact in mouse. The ARBs decreased lesion volume, macrophage and neutrophilic infiltration, apoptotic cells, and reactive oxygen species. Cerebral blood flow improved to preimpact values within 1 to 3 days of ARB treatment, while remaining inhibited in control mice. Cognitive recovery, as measured by Morris water maze performance, was improved 1 month after injury with candesartan but not telmisartan.

ARBs can act as partial agonists at peroxisome proliferator–activated receptor γ (PPARγ) or as inhibitors of angiotensin II type 1a receptor (AT1aR). Administration of a PPARγ antagonist along with candesartan or telmisartan attenuated the effect of ARBs. AT1aR knockout mice had reduced lesion volumes, numbers of reactive astrocytes, and numbers of apoptotic cells compared with wild-type mouse; block of PPARγ did not change the differences between AT1aR knockout and wild-type mice. Thus, after TBI, ARBs act beneficially separately through both PPARγ activation and AT1aR blockade.

The major strength of this study is that the dose and timing of ARBs are translatable to humans. Since reduction in blood pressure may be harmful in TBI, the investigators used the lowest effective dose of ARBs, which did not affect blood pressure. The 6-hour delay before administration of ARBs after TBI is realistic, since most TBI patients are treated in emergency rooms. Many potential neuroprotective or neurorestorative agents have failed in translation to humans. ARBs, however, are already widely used to treat hypertension and so have already passed the hurdles of toxicity and distribution that have stymied other potential therapies. This study paves the way for a clinical study of ARBs in human TBI.

S. Villapol et al., Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 10.1093/brain/awv172 (2015). [Abstract]

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