Autophagy:A Double-edged Sword in Cerebral Ischemia

Abstract

Abstract:

Autophagy may be a new therapeutic target for stroke according to recent research, but whether activation of autophagy plays a positive role or negative role in neuronal survival is still controversial. This review summarizes the dual effects of autophagy in ischemia/hypoxiainduced neuronal injury and its possible signaling pathways.

Key words: Autophagy; Neuron; Cerebral ischemic/hypoxic injury; Signaling pathways

摘要：

近来研究表明，自噬可能成为卒中治疗过程中的新靶点，但是自噬在脑缺血过程中的激活是否提升神经元存活率一直存在争议，关于其对于脑缺血后神经元发挥的作用是保护还是加重损伤尚不明确。本文主要综述脑缺血后自噬在缺血/低氧损伤中可能发挥的双重作用及其可能的信号通路。

关键词: 自噬; 神经元; 脑缺血/低氧损伤; 信号通路

LI Wei-Wei*, WANG Qun, GUO An-Chen, WANG Yong-Jun, LI Jun-Fa.. Autophagy:A Double-edged Sword in Cerebral Ischemia[J]. Chinese Journal of Stroke, 2015, 10(04): 319-325.

李巍巍1，2，3，王群2，3，4，5，郭安臣2，3，5，王拥军2，3，4，5，李俊发1，2，3. 自噬——脑缺血损伤中的双刃剑[J]. 中国卒中杂志, 2015, 10(04): 319-325.

References

1 Marsh JD, Keyrouz SG. Stroke prevention and

treatment[J]. J Am Coll Cardiol, 2010, 56:683-691.

2 Stemer A, Lyden P. Evolution of the thrombolytic

treatment window for acute ischemic stroke[J]. Curr

Neurol Neurosci Rep, 2010, 10:29-33.

3 Go AS, Mozaffarian D, Roger VL, et al. Heart disease

and stroke statistics--2014 update:a report from the

American Heart Association[J]. Circulation, 2014,

129:e28-e292.

4 Adeoye O, Hornung R, Khatri P, et al. Recombinant

tissue-type plasminogen activator use for ischemic

stroke in the United States:a doubling of treatment

rates over the course of 5 years[J]. Stroke, 2011,

42:1952-1955.

5 Wen YD, Sheng R, Zhang LS, et al. Neuronal injury

in rat model of permanent focal cerebral ischemia

is associated with activation of autophagic and

lysosomal pathways[J]. Autophagy, 2008, 4:762-769.

6 Carloni S, Buonocore G, Balduini W. Protective role

of autophagy in neonatal hypoxia-ischemia induced

brain injury[J]. Neurobiol Dis, 2008, 32:329-339.

7 Koike M, Shibata M, Tadakoshi M, et al. Inhibition of

autophagy prevents hippocampal pyramidal neuron

death after hypoxic-ischemic injury[J]. Am J Pathol,

2008, 172:454-469.

8 Kuma A, Hatano M, Matsui M, et al. The role of

autophagy during the early neonatal starvation

period[J]. Nature, 2004, 432:1032-1036.

9 Mizushima N, Klionsky DJ. Protein turnover via

autophagy:implications for metabolism[J]. Annu Rev

Nutr, 2007, 27:19-40.

10 Kl io n s k y DJ. T h e mol e c u l a r ma c h i n e r y of

autophagy:unanswered questions[J]. J Cell Sci, 2005,

118:7-18.

11 Massey AC, Zhang C, Cuervo AM. Chaperonemediated

autophagy in aging and disease[J]. Curr Top

Dev Biol, 2006, 73:205-235.

12 Mi z u sh ima N, Lev i ne B, Cue r vo AM, e t a l.

Autophagy f ights disease through cellular selfdigestion[

J]. Nature, 2008, 451:1069-1075.

13 Zhu C, Wang X, Xu F, et al. The influence of age on

apoptotic and other mechanisms of cell death after

cerebral hypoxia-ischemia[J]. Cell Death Differ, 2005,

12:162-176.

14 Xi a DY, Li W, Qi a n HR , e t a l . I s c h emi a

preconditioning is neuroprotective in a rat cerebral

ischemic injury model through autophagy activation

and apoptosis inhibition[J]. Brazi J Med Biol Res,

2013, 46:580-588.

15 Yan W, Zhang H, Bai X, et al. Autophagy activation

is involved in neuroprotection induced by hyperbaric

oxygen preconditioning against focal cerebral

ischemia in rats[J]. Brain Res, 2011, 1402:109-121.

16 Yang Y, Gao K, Hu Z, et al. Autophagy upregulation

and apoptosis downregulation in DAHP and triptolide

treated cerebral ischemia[J]. Mediators Inflamm, 2015,

2015:120198.

17 Gao L, Jiang T, Guo J, et al. Inhibition of autophagy

contributes to ischemic postconditioning-induced

neuroprotection against focal cerebral ischemia in

rats[J]. PLoS one, 2012, 7:e46092.

18 Puyal J, Vaslin A, Mottier V, et al. Postischemic

treatment of neonatal cerebral ischemia should target

autophagy[J]. Ann Neurol, 2009, 66:378-389.

19 Zheng YQ, Liu JX, Li XZ, et al. RNA interferencemediated

downregulation of Beclin1 attenuates

cerebral ischemic injury in rats[J]. Acta Pharmacol

Sin, 2009, 30:919-927.

20 Yang Z, Zhong L, Zhong S, et al. Hypoxia induces

microglia autophagy and neural inflammation injury

in focal cerebral ischemia model[J]. Exp Mole Pathol,

2015, 98:219-224.

21 Wu Z, Zou Z, Zou R, et al. Electroacupuncture

pretreatment induces tolerance against cerebral

ischemia/reperfusion injury through inhibition of the

autophagy pathway[J]. Mol Med Rep, 2015, 11:4438-

4446.

22 Chong ZZ, Shang YC, Wang S, et al. A critical kinase

cascade in neurological disorders:PI3K, Akt, and

mTOR[J]. Future Neurol, 2012, 7:733-748.

23 Glick D, Barth S, Macleod KF. Autophagy:cellular

and molecular mechanisms[J]. J Pathol, 2010, 221:3-

12.

24 Xingyong C, Xicui S, Huanxing S, et al. Upregulation

of myeloid cell leukemia-1 potentially modulates

beclin-1-dependent autophagy in ischemic stroke in

rats[J]. BMC Neurosci, 2013, 14:56.

25 Xu F, Li J, Ni W, et al. Peroxisome proliferatoractivated

receptor-gamma agonist 15d-prostaglandin

J2 mediates neuronal autophagy after cerebral

ischemia-reperfusion injury[J]. PLoS One, 2013,

8:e55080.

26 Qi Z, Dong W, Shi W, et al. Bcl-2 phosphorylation

triggers autophagy switch and reduces mitochondrial

damage in limb remote ischemic conditioned rats after

ischemic stroke[J]. Transl Stroke Res, 2015, Mar 7.

[Epub ahead of print].

27 Poels J, Spasic MR, Callaerts P, et al. Expanding roles

for AMP-activated protein kinase in neuronal survival

and autophagy[J]. Bioessays, 2009, 31:944-952.

28 Li J, McCullough LD. Effects of AMP-activated protein kinase in cerebral ischemia[J]. J Cereb Blood

Flow Metab, 2010, 30:480-492.

29 Chen AC, Arany PR, Huang YY, et al. Low-level laser

therapy activates NF-κB via generation of reactive

oxygen species in mouse embryonic fibroblasts[J].

PLoS One, 2011, 6:e22453.

30 Li WL, Yu SP, Chen D, et al. The regulatory role of

NF-kappaB in autophagy-like cell death after focal

cerebral ischemia in mice[J]. Neuroscience, 2013,

244:16-30.

31 Cui DR, Wang L, Jiang W, et al. Propofol prevents

cerebral ischemia-triggered autophagy activation and

cell death in the rat hippocampus through the NFkappaB/

p53 signaling pathway[J]. Neuroscience, 2013,

246:117-132.

32 Wang PR, Wang JS, Zhang C, et al. Huang-Lian-Jie-

Du-Decotion induced protective autophagy against the

injury of cerebral ischemia/reperfusion via MAPKmTOR

signaling pathway[J]. J Ethnopharmacol, 2013,

149:270-280.

33 Althaus J, Bernaudin M, Petit E, et al. Expression of

the gene encoding the pro-apoptotic BNIP3 protein

and stimulation of hypoxia-inducible factor-1alpha

(HIF-1alpha) protein following focal cerebral ischemia

in rats[J]. Neurochem Int, 2006, 48:687-695.

34 Xin XY, Pan J, Wang XQ, et al. 2-methoxyestradiol

at t enuat e s autophag y a ct ivat ion af t e r global

ischemia[J]. Can J Neurol Sci, 2011, 38:631-638.

35 Cho B, Choi SY, Park OH, et al. Differential

expression of BNIP family members of BH3-only

proteins during the development and after axotomy in

the rat[J]. Mol Cells, 2012, 33:605-610.

36 Zhang J, Ney PA. Mechanisms and biology of B-cell

leukemia/lymphoma 2/adenovirus E1B interacting

protein 3 and Nip-like protein X[J]. Antioxid Redox

Signal, 2011, 14:1959-1969.

37 Kubota C, Torii S, Hou N, et al. Constitutive reactive

oxygen species generation from autophagosome/

lysosome in neuronal oxidative toxicity[J]. J Biol

Chem, 2010, 285:667-674.

38 Mehta SL, Kumari S, Mendelev N, et al. Selenium

preser ves mitochondr ial f unct ion, st imulates

mitochondrial biogenesis, and reduces infarct volume

after focal cerebral ischemia[J]. BMC Neurosci, 2012,

13:79.

39 Puyal J, Ginet V, Grishchuk Y, et al. Neuronal

autophagy as a mediator of life and death:contrasting

roles in chronic neurodegenerative and acute neural

disorders[J]. Neuroscientist, 2012, 18:224-236.

40 Kulbe JR, Mulcahy Levy JM, Coultrap SJ, et al.

Excitotoxic glutamate insults block autophagic flux in

hippocampal neurons[J]. Brain Res, 2014, 1542:12-19.

41 Ouyang YB, Giffard R. ER-mitochondria crosstalk

during cerebral ischemia:molecular Chaperones and

ER-mitochondrial calcium transfer[J]. Int J Cell Biol,

2012, 2012:493934.

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