Modulation of nuclear factor-kappaB activation and decreased markers of neurological injury associated with hypothermic therapy in experimental bacterial meningitis.
OBJECTIVE
This study was designed to evaluate the use of moderate hypothermia in a model of meningitis-induced brain injury and its effect on the activation of nuclear factor-kappaB, biological markers of neuronal injury, and neurobehavioral performance.


METHODS
Randomized, prospective animal study.


METHODS
University research laboratory.


METHODS
Male Wistar rats.


METHODS
Animals underwent a basilar cistern tap receiving either sterile saline as a placebo or an equivalent volume of a group B streptococcal suspension. Sixteen hours after inoculation, animals were stratified by their clinical severity score, were randomized to either hypothermic (32-34 degrees C) or normothermic (37-39 degrees C) conditions, and received antibiotics. Hypothermic animals were kept under these temperature conditions for 6 hrs before rewarming. Two protocols were used. For the first protocol, changes in nuclear factor-kappaB activation and heat shock protein induction at 24 hrs and 48 hrs after inoculation were evaluated. In the second protocol, serum C-tau concentrations at 5 days and neurobehavioral performances at 3 wks were assessed.


RESULTS
Meningitis triggered a >50% increase in cerebral nuclear factor-kappaB activation. The addition of a 6-hr period of hypothermia reduced nuclear factor-kappaB activation by 32% when measured at the end of the hypothermic period. At 48 hrs, this decrease in nuclear factor-kappaB activation was no longer apparent, but there was a significant decrease in the heat shock response. Serum C-tau concentrations at 5 days postinjury, a biomarker of brain injury, were reduced by 69% in hypothermic treated animals. Furthermore, hypothermia reduced the brain water content of infected animals. However, hypothermia did not improve the animals' neurobehavioral performance.


CONCLUSIONS
The findings from this study suggest that hypothermia produces a transitory attenuation of nuclear factor-kappaB activation in meningitic brain injury and improvement in some biomarkers of neuronal injury. The consequence of intermittent suppression of nuclear factor-kappaB activation by inducing specific periods of hypothermia requires further study.
Irazuzta
Jose E
JE
Division of Critical Care Medicine, Tufts University, The Floating Hospital for Children, New England Medical Center, Boston, MA, USA.
Pretzlaff
Robert K
RK
Zingarelli
Basilia
B
Xue
Vivian
V
Zemlan
Frank
F
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers; D001930:Brain Injuries / Q000097:blood / Q000517:prevention & control*; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D016920:Meningitis, Bacterial / Q000628:therapy*; D016328:NF-kappa B / Q000097:blood*; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D015415:Biomarkers; D016328:NF-kappa B