Detrimental role of bradykinin B2 receptor in a murine model of diffuse brain injury.
Inhibition of the bradykinin B2 receptor type (B2R) has been shown to improve neurological outcome in models of focal traumatic brain injury. However, the involvement of B2R in trauma-induced diffuse injury has not yet been explored. This is an important point, since in humans a pattern of diffuse injury is commonly found in severely injured patients and has been associated with a poor neurological outcome and prognosis. Using the non-peptide B2R antagonist LF 16-0687 Ms and B2R null (B2R-/-) mice, we investigated the role of B2R in a model of closed head trauma (CHT). LF 16-0687 Ms given 30 min after injury reduced the neurological deficit by 26% and the cerebral edema by 22% when evaluated 4 h after CHT. Neurological function after CHT was improved in B2R-/- mice compared to B2R+/+ mice, although there was no difference in the development of brain edema. Treatment with LF 16-0687 Ms and B(2)R gene deletion decreased the accumulation of neutrophils at 24 h after CHT (50% and 36%, respectively). In addition, the inducible NO synthase (iNOS) mRNA level increased markedly, and this was reduced by LF 16-0687 Ms. Taken together, these data support a detrimental role of B2R in the development of the neurological deficit and of the inflammatory secondary damage resulting from diffuse traumatic brain injury. Therefore, blockade of bradykinin B2 receptors might represent an attractive therapeutic approach in the pharmacological treatment of traumatic brain injury.
Hellal
F
F
UPRES EA2510, Laboratoire de Pharmacologie, Université René Descartes, 4 avenue de l'Observatoire, F-75006 Paris, France.
Pruneau
D
D
Palmier
B
B
Faye
P
P
Croci
N
N
Plotkine
M
M
Marchand-Verrecchia
C
C
D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists; D001930:Brain Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
D065094:Bradykinin B2 Receptor Antagonists; C403051:LF 16-0687; D011804:Quinolines; D043782:Receptor, Bradykinin B2