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Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP ‐activated protein kinase‐dependent autophagy in a rat cerebral ischemic/reperfusion injury model
Author(s) -
Shen Pingping,
Hou Shuai,
Zhu Mingqin,
Zhao Mingming,
Ouyang Yibing,
Feng Jiachun
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13922
Subject(s) - ampk , autophagy , neuroprotection , penumbra , protein kinase a , ischemic preconditioning , ischemia , cortical spreading depression , amp activated protein kinase , pharmacology , reperfusion injury , medicine , apoptosis , chemistry , endocrinology , kinase , microbiology and biotechnology , biology , biochemistry , migraine
Cortical spreading depression ( CSD ), based on its similarities with peri‐infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic‐reperfusion (I/R) injury model to determine whether AMP ‐activated protein kinase ( AMPK )‐dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KC l solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3‐methyladenine (3‐ MA , 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC 3‐ II , Beclin‐1 and the p‐ AMPK (Thr 172 )/ AMPK ratio at 12 h and decreased P62 and p‐P70S6K (Thr 389 ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down‐regulated the LC 3‐ II , p‐ AMPK (Thr 172 )/ AMPK and ULK 1 levels, up‐regulated the P62 and p‐P70S6K (Thr 389 ) levels induced by CSD . The neuroprotection of CSD is likely a result of AMPK ‐mediated autophagy activity and autophagy‐induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD ‐induced ischemic tolerance. AMPK ‐mediated autophagy may represent a new target for stroke.