Activation of bradykinin B2 receptor induced the inflammatory responses of cytosolic phospholipase A2 after the early traumatic brain injury

Abstract

Phospholipase A₂ is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A₂ (cPLA₂)-related inflammatory responses after TBI. We found that cPLA₂ and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA₂ expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA₂ inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA₂ in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA₂-related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA₂ activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA₂ activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA₂-related inflammatory response from the PKC pathway.

Keywords: Arachidonic acid; Bradykinin B2 receptor; Cytosolic phospholipase A(2); Inflammation; Protein kinase C δ; Traumatic brain injury.