Tacrolimus depresses local immune cell infiltration but fails to reduce cortical contusion volume in brain-injured rats.
The immunosuppressant drug tacrolimus (FK-506) failed to show an anti-edematous effect despite suppressing pro-inflammatory cytokines in cerebrospinal fluid following focal traumatic brain injury. By questioning the role of the inflammatory response as a pharmacological target, we investigated the effects of FK-506 on immune cell infiltration in brain-injured rats. Following induction of a cortical contusion, male Sprague-Dawley rats received FK-506 or physiological saline intraperitoneally. Brains were removed at 24 h, 72 h or 7 days, respectively. Frozen brain sections (7 microm) were stained immunohistologically for markers of endothelial activation (intercellular adhesion molecule-1--ICAM-1), neutrophil infiltration (His-48), and microglial and macrophage activation (Ox-6; ED-1), respectively. Immunopositive cells were counted microscopically. Contusion volume (CV) was quantified morphometrically 7 days after trauma. Inflammatory response was confined to the ipsilateral cortex and hippocampal formation, predominating in the contusion and pericontusional cortex. Strongest ICAM-1 expression coincided with sustained granulocyte accumulation at 72h which was suppressed by FK-506. Ox-6+ cells prevailing at 72 h were also significantly reduced by FK-506. ED-1+ cells reaching highest intensity at 7 days were significantly attenuated at 72 h. Cortical CV was not influenced. FK-506 significantly decreased post-traumatic local inflammation which, however, was not associated with a reduction in cortical CV. These results question the importance of post-traumatic local immune cell infiltration in the secondary growth of a cortical contusion.
Department of Neurosurgery, Charité, Medical University of Berlin, Campus Virchow Medical Center, D-13353 Berlin, Germany, and University Hospital Zürich, Division of Surgical Instensive Care Medicine, Switzerland. uthomale@charite.de
Ulrich W
UW
Thomale
Marcel
M
Bender
Pablo
P
Casalis
Stefan
S
Rupprecht
Martin
M
Griebenow
Konrad
K
Neumann
Christian
C
Woiciechowsky
Andreas W
AW
Unterberg
John F
JF
Stover
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008262:Macrophage Activation; D008297:Male; D009504:Neutrophils; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D016559:Tacrolimus