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Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats

View Article: PubMed Central - PubMed

ABSTRACT

Although delayed cerebral vasospasm (DCV) following subarachnoid hemorrhage (SAH) is closely related to the progression of brain damage, little is known about the molecular mechanism underlying its development. High mobility group box-1 (HMGB1) plays an important role as an initial inflammatory mediator in SAH. In this study, an SAH rat model was employed to evaluate the effects of anti-HMGB1 monoclonal antibody (mAb) on DCV after SAH. A vasoconstriction of the basilar artery (BA) associated with a reduction of nuclear HMGB1 and its translocation in vascular smooth muscle cells were observed in SAH rats, and anti-HMGB1 mAb administration significantly suppressed these effects. Up-regulations of inflammation-related molecules and vasoconstriction-mediating receptors in the BA of SAH rats were inhibited by anti-HMGB1 mAb treatment. Anti-HMGB1 mAb attenuated the enhanced vasocontractile response to thrombin of the isolated BA from SAH rats and prevented activation of cerebrocortical microglia. Moreover, locomotor activity and weight loss recovery were also enhanced by anti-HMGB1 mAb administration. The vasocontractile response of the BA under SAH may be induced by events that are downstream of responses to HMGB1-induced inflammation and inhibited by anti-HMGB1 mAb. Anti-HMGB1 mAb treatment may provide a novel therapeutic strategy for DCV and early brain injury after SAH.

No MeSH data available.


Related in: MedlinePlus

Effect of anti-HMGB1 mAb on the contractile response to thrombin on the isolated BA from SAH rats.The BA was isolated at 48 hr after the SAH in rats administered anti-HMGB1 mAb or control IgG at both 5 min and 24 hr after blood injection. (a) Tension responses to thrombin stimulation in a BA segment are shown as representative recordings. Arrows show the time point of accumulative thrombin addition. Solid lines under the recording waveform indicate the stimulating phase at the indicated concentration of thrombin. (b) The minimum concentration of thrombin stimuli required for the initial contractile response was evaluated. Results are shown for the sham group (Sham, n = 3), the control IgG-treated group (Cont IgG, n = 5), and the anti-HMGB1 mAb-treated group (α-HMGB1, n = 5). Values represent the means ± SE. **P < 0.01 compared with the sham group. #P < 0.05 compared with the control IgG-treated group.
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f4: Effect of anti-HMGB1 mAb on the contractile response to thrombin on the isolated BA from SAH rats.The BA was isolated at 48 hr after the SAH in rats administered anti-HMGB1 mAb or control IgG at both 5 min and 24 hr after blood injection. (a) Tension responses to thrombin stimulation in a BA segment are shown as representative recordings. Arrows show the time point of accumulative thrombin addition. Solid lines under the recording waveform indicate the stimulating phase at the indicated concentration of thrombin. (b) The minimum concentration of thrombin stimuli required for the initial contractile response was evaluated. Results are shown for the sham group (Sham, n = 3), the control IgG-treated group (Cont IgG, n = 5), and the anti-HMGB1 mAb-treated group (α-HMGB1, n = 5). Values represent the means ± SE. **P < 0.01 compared with the sham group. #P < 0.05 compared with the control IgG-treated group.

Mentions: The vasocontractile response to thrombin was examined ex vivo using the isolated BA from SAH rats to assess changes in the vasocontractile property after SAH and their prevention by anti-HMGB1 mAb administration. Under a stepwise increase in thrombin concentrations, the thresholds of thrombin concentrations were determined on each preparation from three groups (Fig. 4). The isolated BA from the sham group did not show the contractile response to thrombin until the concentration reached 2133 ± 267 μU/mL and above. In the control IgG-treated group, the contractile response of the isolated BA occurred at much lower concentrations of 112 ± 20 μU/mL thrombin, demonstrating the hyper-contractile property. On the other hand, the threshold of the thrombin concentration in the isolated BA from the anti-HMGB1 mAb-treated group was significantly higher than that in the control IgG-treated group (560 ± 44 μU/mL).


Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats
Effect of anti-HMGB1 mAb on the contractile response to thrombin on the isolated BA from SAH rats.The BA was isolated at 48 hr after the SAH in rats administered anti-HMGB1 mAb or control IgG at both 5 min and 24 hr after blood injection. (a) Tension responses to thrombin stimulation in a BA segment are shown as representative recordings. Arrows show the time point of accumulative thrombin addition. Solid lines under the recording waveform indicate the stimulating phase at the indicated concentration of thrombin. (b) The minimum concentration of thrombin stimuli required for the initial contractile response was evaluated. Results are shown for the sham group (Sham, n = 3), the control IgG-treated group (Cont IgG, n = 5), and the anti-HMGB1 mAb-treated group (α-HMGB1, n = 5). Values represent the means ± SE. **P < 0.01 compared with the sham group. #P < 0.05 compared with the control IgG-treated group.
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Related In: Results  -  Collection

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f4: Effect of anti-HMGB1 mAb on the contractile response to thrombin on the isolated BA from SAH rats.The BA was isolated at 48 hr after the SAH in rats administered anti-HMGB1 mAb or control IgG at both 5 min and 24 hr after blood injection. (a) Tension responses to thrombin stimulation in a BA segment are shown as representative recordings. Arrows show the time point of accumulative thrombin addition. Solid lines under the recording waveform indicate the stimulating phase at the indicated concentration of thrombin. (b) The minimum concentration of thrombin stimuli required for the initial contractile response was evaluated. Results are shown for the sham group (Sham, n = 3), the control IgG-treated group (Cont IgG, n = 5), and the anti-HMGB1 mAb-treated group (α-HMGB1, n = 5). Values represent the means ± SE. **P < 0.01 compared with the sham group. #P < 0.05 compared with the control IgG-treated group.
Mentions: The vasocontractile response to thrombin was examined ex vivo using the isolated BA from SAH rats to assess changes in the vasocontractile property after SAH and their prevention by anti-HMGB1 mAb administration. Under a stepwise increase in thrombin concentrations, the thresholds of thrombin concentrations were determined on each preparation from three groups (Fig. 4). The isolated BA from the sham group did not show the contractile response to thrombin until the concentration reached 2133 ± 267 μU/mL and above. In the control IgG-treated group, the contractile response of the isolated BA occurred at much lower concentrations of 112 ± 20 μU/mL thrombin, demonstrating the hyper-contractile property. On the other hand, the threshold of the thrombin concentration in the isolated BA from the anti-HMGB1 mAb-treated group was significantly higher than that in the control IgG-treated group (560 ± 44 μU/mL).

View Article: PubMed Central - PubMed

ABSTRACT

Although delayed cerebral vasospasm (DCV) following subarachnoid hemorrhage (SAH) is closely related to the progression of brain damage, little is known about the molecular mechanism underlying its development. High mobility group box-1 (HMGB1) plays an important role as an initial inflammatory mediator in SAH. In this study, an SAH rat model was employed to evaluate the effects of anti-HMGB1 monoclonal antibody (mAb) on DCV after SAH. A vasoconstriction of the basilar artery (BA) associated with a reduction of nuclear HMGB1 and its translocation in vascular smooth muscle cells were observed in SAH rats, and anti-HMGB1 mAb administration significantly suppressed these effects. Up-regulations of inflammation-related molecules and vasoconstriction-mediating receptors in the BA of SAH rats were inhibited by anti-HMGB1 mAb treatment. Anti-HMGB1 mAb attenuated the enhanced vasocontractile response to thrombin of the isolated BA from SAH rats and prevented activation of cerebrocortical microglia. Moreover, locomotor activity and weight loss recovery were also enhanced by anti-HMGB1 mAb administration. The vasocontractile response of the BA under SAH may be induced by events that are downstream of responses to HMGB1-induced inflammation and inhibited by anti-HMGB1 mAb. Anti-HMGB1 mAb treatment may provide a novel therapeutic strategy for DCV and early brain injury after SAH.

No MeSH data available.


Related in: MedlinePlus