Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats

Fang, Bo; Li, Xiaoqian; Bao, Naren two ya; Tan, Wen-Fei; Chen, Fengshou; Pi, Xiao-Li; Zhang, Ying; Ma, Hong

doi:10.1016/j.neuroscience.2016.04.019

Cited by 44 publications

(44 citation statements)

References 49 publications

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“…Conversely, chronic autophagy could result in depletion of mitochondria and other essential organelles, and thus cell death 17. Such a bimodal response has also been observed after spinal cord ischemia reperfusion injury in rats 41. In our current study, B355252 treatment was able to significantly reduce the conversion of LC3-I to LC3-II, confirming that the compound limits autophagy induction.…”

Section: Discussionsupporting

confidence: 82%

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

Chimeh¹,

Zimmerman²,

Gilyazova³

et al. 2018

Int. J. Med. Sci.

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Cerebral hypoxia as often occurs in cases of stroke, hemorrhage, or other traumatic brain injuries, is one of the leading causes of death worldwide and a main driver of disabilities in the elderly. Using a chemical mimetic of hypoxia, cobalt chloride (CoCl2), we tested the ability of a novel small molecule, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252), to alleviate CoCl2-induced damage in mouse hippocampal HT22 cells. A dose-dependent decrease in cell viability was observed during CoCl2 treatment along with increases in mitochondrial membrane potential and generation of reactive oxygen species (ROS). B355252 conferred protection against these changes. We further found that mitochondrial dynamics, the balance between mitochondrial fusion and fission, were perturbed by CoCl2 treatment. Mitochondrial fusion, which was assessed by measuring the expression of proteins optic atrophy protein 1 (OPA1) and mitofusin 2 (Mfn2), declined due to CoCl2 exposure, but B355252 addition was able to elevate Mfn2 expression while OPA1 expression was unchanged. Mitochondrial fission, measured by phosphorylated dynamin-related protein 1 (p-DRP1) and fission protein 1 (FIS1) expression, also decreased following CoCl2 exposure, and was stabilized by B355252 addition. Finally, autophagy was assessed by measuring the conversion of cytosolic microtubule-associated protein 1A/1B-light chain three-I (LC3-I) to autophagosome-bound microtubule-associated protein 1A/1B-light chain three-II (LC3-II) and was found to be increased by CoCl2. B355252 addition significantly reduced autophagy induction. Taken together, our results indicate B355252 has therapeutic potential to reduce the damaging effects caused by CoCl2 and should be further evaluated for applications in cerebral ischemia therapy.

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Section: Discussionsupporting

confidence: 82%

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

Chimeh¹,

Zimmerman²,

Gilyazova³

et al. 2018

Int. J. Med. Sci.

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“…Recently, researchers have focused on the temporal patterns of autophagic activity in IRSCI, but the results have been inconsistent. In a previous study, rats received thoracic aortic arch exposure and clamping for 14 min to establish the spinal ischemia/reperfusion (I/R) injury model [63]. After spinal cord ischemia, both the ratio of LC3II/LC3I and Beclin1 expression increased and peaked twice, once at 8 h (early stage) and once at 72 h (late stage), and then slowly reduced to baseline.…”

Section: Temporal Pattern Of Autophagic Activation In Scimentioning

confidence: 99%

“…In some experimental SCI studies, instead of cytoprotection, worse outcomes were found after the pharmacological stimulation of autophagy; therefore, ACD was considered [28,63]. However, the molecular marker to define the presence of autophagic cell death is still not well understood.…”

Section: Autophagic Cell Death In Scimentioning

confidence: 99%

“…There are potentially many common signal transduction pathways that influence both autophagy and apoptosis such as p53 protein, Bcl-2-homology-3-only (BH3‑only) proteins, Ser/Thr kinases, oncogenes and so on, and these processes demonstrate the ability for autophagy and apoptosis to cross-regulate each other through inhibition [87]. In autophagic studies of TSCI and IRSCI, such inhibitory crosstalk was found, and stimulation of autophagy significantly decreased the level of apoptosis in neurons, thus a neuroprotection and functional recovery was reported [26,27,44,63]. …”

Section: Relationship Between Autophagy and Apoptosis After Scimentioning

confidence: 99%

“…Both protective and detrimental functions of autophagy in SCI have been reported with rapamycin treatment. On one hand, the behavior improvement (the significant increase in Basso, Beattie, and Bresnahan (BBB) testing scores) and mitigation of histological destruction (the reduction of spinal cord cavity, suppression of the motor neuron loss, and inhibition of demyelination) strongly supports the benefit of autophagy in TSCI [26,27,44,63]. Its intrinsic biochemical mechanism is considered to be involved in anti-inflammation [56,58], anti-apoptosis [26,27], suppression of astrocyte proliferation [101], promotion of microtubule stabilization, and axon regeneration [105].…”

Section: Pharmacological Intervention Of Autophagy In Scimentioning

confidence: 99%

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The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury

Zhou

Sansur

et al. 2017

IJMS

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Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial points: (1) temporal pattern results of autophagic activation after SCI are not consistent across studies; (2) effect of accumulation of autophagosomes due to the blockade or enhancement of autophagic flux is uncertain; (3) overall effect of enhanced autophagy remains undefined, with both beneficial and detrimental outcomes reported in SCI literature. In this review, the temporal pattern of autophagic activation, autophagic flux, autophagic cell death, relationship between autophagy and apoptosis, and pharmacological intervention of autophagy in TSCI (contusion injury, compression injury and hemisection injury) and IRSCI are discussed. Types of SCI and severity appear to contribute to differences in outcomes regarding temporal pattern, flux, and function of autophagy. With future development of specific strategies on autophagy intervention, autophagy may play an important role in improving functional recovery in patients with SCI.

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