See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic
brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective
therapeutics.
Traumatic brain injury results in neuronal injury and death, acute and prolonged
inflammation and decreased blood flow. Drugs that block
angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or
sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating
traumatic brain injury, we selected two
sartans,
candesartan and
telmisartan, of proven therapeutic efficacy in animal models of
brain inflammation,
neurodegenerative disorders and
stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for
candesartan and
telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both
candesartan and
telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis,
astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced
cognitive impairment was ameliorated 30 days after injury only by
candesartan. The neurorestorative effects of
candesartan and
telmisartan were reduced by concomitant administration of the
peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist
T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these
sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the
sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that
sartans with dual AT1R blocking and PPARγ activating properties have therapeutic potential for
traumatic brain injury.