Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats.
Autophagy plays an important role in spinal cord ischemia reperfusion (I/R) injury, but its neuroprotective or neurodegenerative role remains controversial. The extent and persistence of autophagy activation may be the critical factor to explain the opposing effects. In this study, the different roles and action mechanisms of autophagy in the early and later stages after I/R injury were investigated in rats. Thespinal cord I/R injury was induced by 14-min occlusion of the aortic arch, after which rats were treated with autophagic inhibitor (3-methyladenine, 3-MA) or agonist (rapamycin) immediately or 48h following the injury. Autophagy markers, microtubule-associated protein light chain 3-II (LC3-II) and Beclin 1 increased and peaked at the early stage (8h) and the later stage (72h) after spinal cord I/R injury. Beclin 1 was mostly expressed in neurons, but was also expressed to an extent in astrocytes, microglia and vascular endothelial cells. 8h after injury, rats treated with 3-MA showed a decrease in the hind-limb Basso-Beattie-Bresnahan (BBB) motor function scores, surviving motor neurons, and B-cell lymphoma-2 (Bcl-2) expression, and increase in the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells, Bcl-2-associated X protein (Bax), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) expression, and activation of microglia, while those treated with rapamycin showed opposing effects. However, 72h after injury, rats treated with 3-MA improved the BBB scores, and the surviving motor neurons, and reduced the autophagic cell death, while those treated with rapamycin had adverse effects. These findings provide the first evidence that early activated autophagy alleviates spinal cord I/R injury via inhibiting apoptosis and inflammation; however later excessively elevated autophagy aggravates I/R injury through inducing autophagic cell death.
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: drunk0630@126.com.
Bo
B
Fang
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: shirley037305@hotmail.com.
Xiao-Qian
XQ
Li
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: bnrlzh@sina.com.
Na-Ren
NR
Bao
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: winfieldtan@hotmail.com.
Wen-Fei
WF
Tan
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: haoxiu19881988@126.com.
Feng-Shou
FS
Chen
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: cmupxl@hotmail.com.
Xiao-Li
XL
Pi
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: wojiaotielihua@126.com.
Ying
Y
Zhang
Department of Anesthesiology, First Affiliated Hospital, China Medical University, North Nanjing Street, No. 155, Shenyang, Liaoning 110001, PR China. Electronic address: mahong5466@yahoo.com.
Hong
H
Ma
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D020123:Sirolimus / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D020760:Spinal Cord Ischemia / Q000473:pathology / Q000503:physiopathology*
D002491:Central Nervous System Agents; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus
apoptosis; autophagic cell death; autophagy; ischemia reperfusion injury; microglia; spinal cord