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Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation.

Sun M, Deng B, Zhao X, Gao C, Yang L, Zhao H, Yu D, Zhang F, Xu L, Chen L, Sun X - Sci Rep (2015)

Bottom Line: The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra.Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP.In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.

ABSTRACT
Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment.

No MeSH data available.


Related in: MedlinePlus

Preconditioning with 2% isoflurane alleviated neurological deficits, reduced infarct volumes, and attenuated apoptosis in the cerebral ischemic penumbra after stroke (n = 6).(a) The NDSs were recorded in each animal 24 h after reperfusion. The NDSs of the IP + I/R group were significantly better than were those of the I/R group 24 h after reperfusion. The results are expressed as the median (range). *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (b) Representative brain infarct size according to TTC staining at 24 h after reperfusion. (c) Statistical analysis of the infarct sizes of each group. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (d) Representative TUNEL staining (red) at 24 h after reperfusion. Scale bars = 100 μm. (e) Statistical analyses of the numbers of TUNEL-positive cells. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group.
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f1: Preconditioning with 2% isoflurane alleviated neurological deficits, reduced infarct volumes, and attenuated apoptosis in the cerebral ischemic penumbra after stroke (n = 6).(a) The NDSs were recorded in each animal 24 h after reperfusion. The NDSs of the IP + I/R group were significantly better than were those of the I/R group 24 h after reperfusion. The results are expressed as the median (range). *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (b) Representative brain infarct size according to TTC staining at 24 h after reperfusion. (c) Statistical analysis of the infarct sizes of each group. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (d) Representative TUNEL staining (red) at 24 h after reperfusion. Scale bars = 100 μm. (e) Statistical analyses of the numbers of TUNEL-positive cells. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group.

Mentions: At 24 h after reperfusion, the NDSs in the IP + I/R group were higher than were those in the Sham group (P < 0.05). However, the NDSs in the IP + I/R group were lower than were those in the I/R group (P < 0.05) (Fig. 1a).


Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation.

Sun M, Deng B, Zhao X, Gao C, Yang L, Zhao H, Yu D, Zhang F, Xu L, Chen L, Sun X - Sci Rep (2015)

Preconditioning with 2% isoflurane alleviated neurological deficits, reduced infarct volumes, and attenuated apoptosis in the cerebral ischemic penumbra after stroke (n = 6).(a) The NDSs were recorded in each animal 24 h after reperfusion. The NDSs of the IP + I/R group were significantly better than were those of the I/R group 24 h after reperfusion. The results are expressed as the median (range). *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (b) Representative brain infarct size according to TTC staining at 24 h after reperfusion. (c) Statistical analysis of the infarct sizes of each group. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (d) Representative TUNEL staining (red) at 24 h after reperfusion. Scale bars = 100 μm. (e) Statistical analyses of the numbers of TUNEL-positive cells. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4471883&req=5

f1: Preconditioning with 2% isoflurane alleviated neurological deficits, reduced infarct volumes, and attenuated apoptosis in the cerebral ischemic penumbra after stroke (n = 6).(a) The NDSs were recorded in each animal 24 h after reperfusion. The NDSs of the IP + I/R group were significantly better than were those of the I/R group 24 h after reperfusion. The results are expressed as the median (range). *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (b) Representative brain infarct size according to TTC staining at 24 h after reperfusion. (c) Statistical analysis of the infarct sizes of each group. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group. (d) Representative TUNEL staining (red) at 24 h after reperfusion. Scale bars = 100 μm. (e) Statistical analyses of the numbers of TUNEL-positive cells. The results are shown as the means ± SEM. *P < 0.05 vs. Sham group, #P < 0.05 vs. I/R group.
Mentions: At 24 h after reperfusion, the NDSs in the IP + I/R group were higher than were those in the Sham group (P < 0.05). However, the NDSs in the IP + I/R group were lower than were those in the I/R group (P < 0.05) (Fig. 1a).

Bottom Line: The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra.Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP.In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.

ABSTRACT
Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment.

No MeSH data available.


Related in: MedlinePlus