The neuroprotective effect of losartan through inhibiting AT1/ASK1/MKK4/JNK3 pathway following cerebral I/R in rat hippocampal CA1 region

Autor: Xiaojiang Sun, Zhi Geng, Jian-Liang Fu, Jia-Jun Yang, Tian-Ling Zhang
Rok vydání: 2012
Předmět:
Male
medicine.medical_specialty
MAP Kinase Kinase 4
In Vitro Techniques
MAP Kinase Kinase Kinase 5
Neuroprotection
Losartan
Receptor
Angiotensin
Type 1
Brain Ischemia
Oligodeoxyribonucleotides
Antisense
Rats
Sprague-Dawley
Mitogen-Activated Protein Kinase 10
Physiology (medical)
Internal medicine
medicine
Animals
Immunoprecipitation
Pharmacology (medical)
ASK1
Protein kinase A
Receptor
CA1 Region
Hippocampal
Pharmacology
Neurons
Analysis of Variance
Angiotensin II receptor type 1
biology
Cell Death
Dose-Response Relationship
Drug
Chemistry
Original Articles
Angiotensin II
Mitochondria
Rats
Psychiatry and Mental health
Disease Models
Animal
Endocrinology
Neuroprotective Agents
Mitogen-activated protein kinase
Reperfusion Injury
biology.protein
cardiovascular system
hormones
hormone substitutes
and hormone antagonists
circulatory and respiratory physiology
medicine.drug
Signal Transduction
Zdroj: CNS neurosciencetherapeutics. 18(12)
ISSN: 1755-5949
Popis: Summary Aims It has been well documented that angiotensin II type 1 (AT1) receptor blockers (ARBs) are known to attenuate neural damage and the c-Jun N-terminal protein kinase 3 (JNK3) pathway and caspase-3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion (I/R). In this study, we first showed that losartan could protect neurons against cerebral I/R-induced injury. Methods Cerebral ischemia model was induced by four-vessel occlusion. Antisense oligodeoxynucleotides (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between β-arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R. Results First, losartan decreased cerebral I/R-induced neuronal death. Second, losartan depressed the β-arrestin-2-assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c-jun, JNK3, Bcl-2, caspase-3 and the release of cytochrome c from mitochondria to cytoplasm. Conclusion Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the β-arrestin-2-assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c-jun, JNK3, and caspase-3 and the release of cytochrome c.
Databáze: OpenAIRE
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