This study investigated whether therapeutic hypercapnia (TH) ameliorated blood-brain barrier (BBB) damage and improved the neurologic outcome in a rat model of lateral fluid percussion injury (FPI), and explored the possible underlying mechanism. Methods: Rats underwent lateral FPI and received inhalation of 30%O 2 -70%N 2 or 30%O 2 -N 2 plus CO 2 to maintain arterial blood CO 2 tension (PaCO 2 ) between 80 and 100 mmHg for 3 h. To further explore the possible mechanisms for the protective

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... ts of TH, a PKC inhibitor staurosporine or PKCαβ inhibitor GÖ6976 was administered via intracerebral ventricular injection. Results: TH significantly improved neurological function 24 h, 48 h, 7 d, and 14 d after FPI. The wet/dry ratio, computed tomography values, Evans blue content, and histological lesion volume were significantly reduced by TH. Moreover, numbers of survived neurons and the expression of tight junction proteins (ZO-1, occludin, and claudin-5) were significantly elevated after TH treatment at 48-h post-FPI. TH significantly increased the expression of protein kinase Cε (PKCε) at 48-h post-FPI, but did not significantly change the expression of PKCα and PKCβII. PKC inhibitor staurosporine (but not the selective PKCαβ inhibitor-GÖ6976) inhibited the protective effect of TH. Conclusions: Therapeutic hypercapnia is a promising candidate that should be further evaluated for clinical treatment. It not only protects the traumatic penumbra from secondary injury and improves histological structure but also maintains the integrity of BBB and reduces neurologic deficits after trauma in a rat model of FPI.