Role of the AMPK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

被引:24
作者
An, Ji-Yang [1 ,2 ]
Zhou, Li-Li [3 ]
Sun, Peng [1 ]
Pang, Hong-Gang [1 ]
Li, Dan-Dong [1 ]
Li, Yu [1 ]
Zhang, Ming [1 ]
Song, Jin-Ning [1 ]
机构
[1] Xi An Jiao Tong Univ, Dept Neurosurg, Affiliated Hosp 1, OfMed Coll, Xian 710049, Shaanxi, Peoples R China
[2] Zhengzhou Univ, Dept Neurosurg, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China
[3] Coll Med, Affiliated Hosp 2, Dept Gen Surg, Xian, Shaanxi, Peoples R China
基金
中国国家自然科学基金;
关键词
Subarachnoid hemorrhage; Early brain injury; Apoptosis; Adenosine monophosphate-activated protein kinase; Bim; ACTIVATED PROTEIN-KINASE; PROMOTES NEURONAL SURVIVAL; N-TERMINAL KINASE; PROVIDES NEUROPROTECTION; TRANSCRIPTION FACTOR; ENERGY DEPLETION; APOPTOSIS; BIM; EXPRESSION; INHIBITION;
D O I
10.1007/s00701-015-2370-3
中图分类号
R74 [神经病学与精神病学];
学科分类号
100204 [神经病学];
摘要
AMP-activated protein kinase (AMPK) is a key metabolic and stress sensor/effector. Few investigations have been performed to study the role of AMPK in subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was undertaken to investigate the time course of AMPK activation in the early stage of SAH and to evaluate the influence of AICAR (which is known to mimic AMP and activates AMPK) and compound C (a commonly used AMPK inhibitor) on EBI in rats following SAH. Adult male rats were divided into six groups: control, sham, SAH, SAH + vehicle, SAH + AICAR and SAH + compound C. SAHs were induced by a modified endovascular perforation method. Immunohistochemistry, real-time PCR and Western blot were used to detect the spatial and dynamic expression of AMPK after SAH. Cortical apoptosis and the expressions of apoptosis-related proteins such as FOXO3a (forkhead box, class O, 3a) and Bim (Bcl-2-interacting mediator of cell death) were detected after different drug interventions. We found SAH induced prolonged activation of AMPK. Treatment with AICAR markedly induced overactivation of AMPK and upregulation of FOXO3a and Bim. AICAR also significantly exacerbated cerebral apoptosis and neurological impairment following SAH. On the other hand, pre-administration of compound C attenuated EBI in this SAH model by modulating cerebral apoptosis by inhibiting FOXO3a and Bim. Our findings suggest that the AMPK pathway may play an important role in SAH-induced neuronal apoptosis, and the use of AMPK inhibitors can provide neuroprotection in EBI after SAH.
引用
收藏
页码:781 / 792
页数:12
相关论文
共 34 条
[1]
CORTICAL BLOOD-FLOW AND CEREBRAL PERFUSION-PRESSURE IN A NEW NONCRANIOTOMY MODEL OF SUBARACHNOID HEMORRHAGE IN THE RAT [J].
BEDERSON, JB ;
GERMANO, IM ;
GUARINO, L .
STROKE, 1995, 26 (06) :1086-1091
[2]
Pro-apoptotic Bim induction in response to nerve growth factor deprivation requires simultaneous activation of three different death signaling pathways [J].
Biswas, Subhas C. ;
Shi, Yijie ;
Sproul, Andrew ;
Greene, Lloyd A. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (40) :29368-29374
[3]
Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].
Brunet, A ;
Bonni, A ;
Zigmond, MJ ;
Lin, MZ ;
Juo, P ;
Hu, LS ;
Anderson, MJ ;
Arden, KC ;
Blenis, J ;
Greenberg, ME .
CELL, 1999, 96 (06) :857-868
[4]
AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis [J].
Concannon, Caoimhin G. ;
Tuffy, Liam P. ;
Weisova, Petronela ;
Bonner, Helena P. ;
Davila, David ;
Bonner, Caroline ;
Devocelle, Marc C. ;
Strasser, Andreas ;
Ward, Manus W. ;
Prehn, Jochen H. M. .
JOURNAL OF CELL BIOLOGY, 2010, 189 (01) :83-U122
[5]
AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation [J].
Culmsee, C ;
Monnig, J ;
Kemp, BE ;
Mattson, MP .
JOURNAL OF MOLECULAR NEUROSCIENCE, 2001, 17 (01) :45-58
[6]
Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate [J].
Davila, D. ;
Connolly, N. M. C. ;
Bonner, H. ;
Weisova, P. ;
Dussmann, H. ;
Concannon, C. G. ;
Huber, H. J. ;
Prehn, J. H. M. .
CELL DEATH AND DIFFERENTIATION, 2012, 19 (10) :1677-1688
[7]
BEHAVIORAL DEFICITS FOLLOWING EXPERIMENTAL SUBARACHNOID HEMORRHAGE IN THE RAT [J].
GERMANO, AF ;
DIXON, CE ;
DAVELLA, D ;
HAYES, RL ;
TOMASELLO, F .
JOURNAL OF NEUROTRAUMA, 1994, 11 (03) :345-353
[8]
FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons [J].
Gilley, J ;
Coffer, PJ ;
Ham, J .
JOURNAL OF CELL BIOLOGY, 2003, 162 (04) :613-622
[9]
The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor [J].
Greer, Eric L. ;
Oskoui, Philip R. ;
Banko, Max R. ;
Maniar, Jay M. ;
Gygi, Melanie P. ;
Gygi, Steven P. ;
Brunet, Anne .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (41) :30107-30119
[10]
Harris CA, 2001, J BIOL CHEM, V276, P37754