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[Toll-like receptor 4 signal pathway may be involved in cerebral ischemic tolerance induced by hypoxic preconditioning: experiment with rats].

OBJECTIVE
To investigate the role of Toll-like receptor 4 (TLR4) inflammatory signal pathway in brain ischemic tolerance induced by hypoxia preconditioning (HP).


METHODS
160 Wistar rats were randomly divided into 4 groups: asphyxial cardiac arrest (ACA) group (n = 54, subjected to ACA for 4 min and then resuscitation), HP + ACA group [n = 44, subjected to apnea and ventilation (HP) for 1 min 4 times with an interval of 5 min between each 2 times, and then subjected to apnea for 4 min and resuscitation 24 h later), HP group (n = 42, subjected to HP 4 times only), and sham operation group (Group C, n = 20). The mortality within 24 h after resuscitation and circulatory functions were observed. Neurodeficit score (NDS) was recorded 24, 48, and 72 hours after successful resuscitation. Rats were killed 1, 3, 6, 12, 24, 48, and 72 h after preconditioning or operation to take out the left brain cortex. RT-PCR was used to detect the mRNA expression of TLR4. The levels of nuclear factor-kappaB (NFkappaB), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 were detected by relevant kits.


RESULTS
The mortality of the HP + ACA group was 5%, significantly lower than that of ACA group (30%, P < 0.01). The NDS levels at different time points of the HP group and Group C were all 100 +/- 0. The NDS levels of the HP + ACA group and ACA group at different time points were all significantly lower than those of the control group and HP group (all P < 0.01). The NDS levels at different time points of the ACA group were all significantly lower than those of the HP + ACA group (all P < 0.05). The NDS levels 72 h later of the HP + ACA and ACA groups were both significantly higher than those 24 h later of the corresponding groups (both P < 0.05). The TLR4 mRNA expression of the control group at any time points were all very weak, and the TLR4 mRNA expression level of the other groups increased since 1 h after hypoxia gradually and decreased 72 h later. The NFkappaB expression levels of the control group at any time points were all very weak, and the NFkappaB expression level of the other groups increased time-dependently since 1 h later, peaked 3 - 6 h later, and began to decrease 24 h later. There was a tendency of increase of NFkappaB expression level in the order of HP group < HP + ACA group < ACA group. The expression of TNF-alpha and IL-6 showed the same tendency as seen in the expression of TLR2 and NFkappaB.


CONCLUSION
HP induces brain ischemic tolerance via a possible mechanism of activating TLR4 signal pathway and then inhibiting inflammatory response induced by ACA.