Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury

Abstract Background Spinal cord injury (SCI) is a devastating central neurological trauma that causes a loss of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95 (Hi95), is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in neuron response to endoplasmic reticulum (ER) stress and potential mechanism remains undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated a underlying molecular mechanism after SCI. Methods The induction of sestrin2 after traumatic injury and ER stress insult were investigated in vitro and in vivo. West blot and immunofluorescence were used to analyze the potential mechanisms of sestrin2 on autophagy and ER stress after SCI. Behavior assessment were used to evaluated the effect of sestrin2 on function recovery in vivo. Results Elevated sestrin2 is a protective process in neurons against chemical ER stress induced by tunicamycin (TM) or traumatic invasion. While treatment with PERK inhibitor or knockdown of ATF4 reduces sestrin2 expression upon ER stress. In addition, overexpression of sestrin2 limits ER stress, promotes the survival of neuron and improves functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Meanwhile, sestrin2 activates autophagy dependent on AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Conclusion Upregulation of sestrin2 as an important resistance mechanism of neuron to ER stress, and its potential role as a therapeutic target for SCI.

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Decreased angiogenesis as a possible pathomechanism in cervical degenerative myelopathy

Scientific Reports ◽

10.1038/s41598-021-81766-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Christian Blume ◽

M. F. Geiger ◽

M. Müller ◽

H. Clusmann ◽

V. Mainz ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neurological Status ◽

Consecutive Series ◽

Inflammatory Reactions ◽

Immune Mediated ◽

Elisa Testing ◽

Cord Injury ◽

Blood Spinal Cord Barrier ◽

Angiopoietin 2

AbstractEndogenous immune mediated reactions of inflammation and angiogenesis are components of the spinal cord injury in patients with degenerative cervical myelopathy (DCM). The aim of this study was to identify alteration of certain mediators participating in angiogenetic and inflammatory reactions in patients with DCM. A consecutive series of 42 patients with DCM and indication for surgical decompression were enrolled for the study. 28 DCM patients were included, as CSF samples were taken preoperatively. We enrolled 42 patients requiring surgery for a thoracic abdominal aortic aneurysm (TAAA) as neurologically healthy controls. In 38 TAAA patients, CSF samples were taken prior to surgery and thus included. We evaluated the neurological status of patients and controls prior to surgery including NDI and mJOA. Protein-concentrations of factors with a crucial role in inflammation and angiogenesis were measured in CSF via ELISA testing (pg/ml): Angiopoietin 2, VEGF-A and C, RANTES, IL 1 beta and IL 8. Additionally, evaluated the status of the blood-spinal cord barrier (BSCB) by Reibers´diagnostic in all participants. Groups evidently differed in their neurological status (mJOA: DCM 10.1 ± 3.3, TAAA 17.3 ± 1.2, p < .001; NDI: DCM 47.4 ± 19.7, TAAA 5.3 ± 8.6, p < .001). There were no particular differences in age and gender distribution. However, we detected statistically significant differences in concentrations of mediators between the groups: Angiopoietin 2 (DCM 267.1.4 ± 81.9, TAAA 408.6 ± 177.1, p < .001) and VEGF C (DCM 152.2 ± 96.1, TAAA 222.4 ± 140.3, p = .04). DCM patients presented a mild to moderate BSCB disruption, controls had no signs of impairment. In patients with DCM, we measured decreased concentrations of angiogenic mediators. These results correspond to findings of immune mediated secondary harm in acute spinal cord injury. Reduced angiogenic activity could be a relevant part of the pathogenesis of DCM and secondary harm to the spinal cord.

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Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Scientific Reports ◽

10.1038/s41598-017-08052-4 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 13

Author(s):

Zili He ◽

Shuang Zou ◽

Jiayu Yin ◽

Zhengzheng Gao ◽

Yanlong Liu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Diabetic Rats ◽

Cord Injury ◽

Blood Spinal Cord Barrier

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Near-infrared light-triggered NO release for spinal cord injury repair

Science Advances ◽

10.1126/sciadv.abc3513 ◽

2020 ◽

Vol 6 (39) ◽

pp. eabc3513

Author(s):

Yaqin Jiang ◽

Pengfei Fu ◽

Yanyan Liu ◽

Chaochao Wang ◽

Peiran Zhao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Near Infrared ◽

Nerve Repair ◽

Infrared Light ◽

Zeolitic Imidazolate Framework ◽

No Donor ◽

Cord Injury ◽

No Release ◽

Blood Spinal Cord Barrier

Traumatic spinal cord injury (SCI) is caused by external physical impacts and can induce complex cascade events, sometimes converging to paralysis. Existing clinical drugs to traumatic SCI have limited therapeutic efficacy because of either the poor blood–spinal cord barrier (BSCB) permeability or a single function. Here, we suggest a “pleiotropic messenger” strategy based on near-infrared (NIR)–triggered on-demand NO release at the lesion area for traumatic SCI recovery via the concurrent neuroregeneration and neuroprotection processing. This NO delivery system was constructed as upconversion nanoparticle (UCNP) core coated by zeolitic imidazolate framework–8 (ZIF-8) with NO donor (CysNO). This combined strategy substantial promotes the repair of SCI in vertebrates, ascribable to the pleiotropic effects of NO including the suppression of gliosis and inflammation, the promotion of neuroregeneration, and the protection of neurons from apoptosis, which opens intriguing perspectives not only in nerve repair but also in neurological research and tissue engineering.

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