Key result
Post-traumatic treatment with the selective AT2 agonist compound 21 or AT2 knockdown did not significantly alter lesion volume or neurological outcomes within 5 days after experimental traumatic brain injury in mice.
Why the study?
AT1 antagonism improves outcomes after experimental TBI, possibly via enhanced indirect AT2 stimulation, and AT2 is upregulated after TBI suggesting a protective mechanism.
Does AT2 activation or deficiency reduce brain damage and neurological impairment in mice after experimental traumatic brain injury?
Does AT2 activation or deficiency reduce brain damage and neurological impairment in mice after experimental traumatic brain injury?
Absolute Event Rate: 15.7% vs 15.9%
AT2 modulation via pharmacological agonism or genetic knockdown does not influence the initial pathophysiological mechanisms of traumatic brain injury in the first 5 days, suggesting AT2 plays only a minor role in early trauma-induced brain damage.
AT2 modulation shows no acute benefit in experimental TBI; hypothesis-generating for later phases and requires confirmation before any translational consideration.
Antagonism of the angiotensin II type 1 receptor (AT1) improves neurological function and reduces brain damage after experimental traumatic brain injury (TBI), which may be partly a result of enhanced indirect angiotensin II type 2 receptor (AT2) stimulation. AT2 stimulation was demonstrated to act neuroprotective via anti-inflammatory, vasodilatory, and neuroregenerative mechanisms in experimental cerebral pathology models. We recently demonstrated an upregulation of AT2 after TBI suggesting a protective mechanism. The present study investigated the effect of post-traumatic (5 days after TBI) AT2 activation via high and low doses of a selective AT2 agonist, compound 21 (C21), compared to vehicle-treated controls. No differences in the extent of the TBI-induced lesions were found between both doses of C21 and the controls. We then tested AT2-knockdown animals for secondary brain damage after experimental TBI. Lesion volume and neurological outcomes in AT2-deficient mice were similar to those in wild-type control mice at both 24 hours and 5 days post-trauma. Thus, in contrast to AT1 antagonism, AT2 modulation does not influence the initial pathophysiological mechanisms of TBI in the first 5 days after the insult, indicating that AT2 plays only a minor role in the early phase following trauma-induced brain damage.
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Timaru‐Kast et al. (2021) studied Traumatic Brain Injury (TBI) (n=102). Compound 21 (C21) vs. Vehicle (0.9% saline) was evaluated on Lesion volume at 5 days post-injury (% of contralateral hemisphere). Post-traumatic treatment with the selective AT2 agonist compound 21 or AT2 knockdown did not significantly alter lesion volume or neurological outcomes within 5 days after experimental traumatic brain injury in mice.
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