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Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress.

Yang JW, Hu ZP - Neural Regen Res (2015)

Bottom Line: Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain.After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain.Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.

ABSTRACT
Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway.

No MeSH data available.


Related in: MedlinePlus

Effect of atorvastatin on the ultrastructure of neurons in infarcted brain tissue of rats with cerebral ischemia/reperfusion injury (transmission electron microscopy, × 20,000).Neuronal damage was most obvious in the ischemia/reperfusion group, showing the swelling, vacuoles and debris of mitochondria, Golgi complex and endoplasmic reticulum (arrows), unclear or disappeared mitochondria, and nuclear enrichment. (A) Sham group; (B) ischemia/reperfusion group; (C) atorvastatin + salubrinal group; (D) atorvastatin group.
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Figure 2: Effect of atorvastatin on the ultrastructure of neurons in infarcted brain tissue of rats with cerebral ischemia/reperfusion injury (transmission electron microscopy, × 20,000).Neuronal damage was most obvious in the ischemia/reperfusion group, showing the swelling, vacuoles and debris of mitochondria, Golgi complex and endoplasmic reticulum (arrows), unclear or disappeared mitochondria, and nuclear enrichment. (A) Sham group; (B) ischemia/reperfusion group; (C) atorvastatin + salubrinal group; (D) atorvastatin group.

Mentions: Under transmission electron microscopy, we found that brain tissue in the sham-operated rats was normal in the ischemia/reperfusion group of rats, the mitochondria, Golgi complex and endoplasmic reticulum were swollen with some vacuoles and debris, mitochondria were unclear or had disappeared, and nuclear membrane depression and nuclear enrichment were observed. In the atorvastatin and atorvastatin + salubrinal groups, the mitochondria, Golgi complex and endoplasmic reticulum were swollen in the brain tissue at the infarction side, but their structure was intact and no nuclear condensation was found (Figure 2).


Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress.

Yang JW, Hu ZP - Neural Regen Res (2015)

Effect of atorvastatin on the ultrastructure of neurons in infarcted brain tissue of rats with cerebral ischemia/reperfusion injury (transmission electron microscopy, × 20,000).Neuronal damage was most obvious in the ischemia/reperfusion group, showing the swelling, vacuoles and debris of mitochondria, Golgi complex and endoplasmic reticulum (arrows), unclear or disappeared mitochondria, and nuclear enrichment. (A) Sham group; (B) ischemia/reperfusion group; (C) atorvastatin + salubrinal group; (D) atorvastatin group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590235&req=5

Figure 2: Effect of atorvastatin on the ultrastructure of neurons in infarcted brain tissue of rats with cerebral ischemia/reperfusion injury (transmission electron microscopy, × 20,000).Neuronal damage was most obvious in the ischemia/reperfusion group, showing the swelling, vacuoles and debris of mitochondria, Golgi complex and endoplasmic reticulum (arrows), unclear or disappeared mitochondria, and nuclear enrichment. (A) Sham group; (B) ischemia/reperfusion group; (C) atorvastatin + salubrinal group; (D) atorvastatin group.
Mentions: Under transmission electron microscopy, we found that brain tissue in the sham-operated rats was normal in the ischemia/reperfusion group of rats, the mitochondria, Golgi complex and endoplasmic reticulum were swollen with some vacuoles and debris, mitochondria were unclear or had disappeared, and nuclear membrane depression and nuclear enrichment were observed. In the atorvastatin and atorvastatin + salubrinal groups, the mitochondria, Golgi complex and endoplasmic reticulum were swollen in the brain tissue at the infarction side, but their structure was intact and no nuclear condensation was found (Figure 2).

Bottom Line: Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain.After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain.Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.

ABSTRACT
Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway.

No MeSH data available.


Related in: MedlinePlus