Research progress of subcellular structure-targeted therapy in spinal cord injury

doi:10.3969/j.issn.1674-8115.2023.02.013

Abstract

Abstract:

Spinal cord injury is a serious disease that greatly affects the sensory function, motor function and autonomic nervous function of patients. It not only brings serious physical and mental harm to patients but also causes huge economic burden to the society. With the development of medical technology, the research on the internal mechanism of spinal cord injury is also deepening, and the treatment methods of spinal cord injury emerge in endlessly. However, the therapeutic effect is not satisfactory, so it is urgent to further explore new therapeutic strategies and expand new therapeutic ideas for spinal cord injury. Many studies have shown that various subcellular structures are closely related to nerve regeneration and functional recovery after spinal cord injury. Therefore, targeting subcellular structures to treat spinal cord injury plays an important role in promoting nerve regeneration and repair after spinal cord injury. This targeted therapy mainly refers to targeting a variety of subcellular structures such as mitochondria, lysosomes/autophagosomes, endoplasmic reticulum, intracellular bodies and proteasomes. A variety of therapeutic strategies targeting subcellular structures have significant therapeutic effects on spinal cord injury. Among them, mitochondrial targeting or endoplasmic reticulum targeting mainly focuses on maintaining mitochondrial energy metabolism at the injury site, while endoplasmic reticulum targeting mainly focuses on inhibiting endoplasmic reticulum stress. This article reviews the research progress of subcellular structure-targeted therapy in spinal cord injury, which is expected to be a new targeted therapy strategy for spinal cord injury and provide a new idea for the treatment of spinal cord injury.

Key words: spinal cord injury, subcellular structure, endoplasmic reticulum stress, mitochondrial dysfunction, targeted therapy

CLC Number:

R651.2

LIU Tiexin, LIN Junqing, ZHENG Xianyou. Research progress of subcellular structure-targeted therapy in spinal cord injury[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(2): 230-236.

Figures/Tables 1

TrendMD

References 58

1	COURTINE G, SOFRONIEW M V. Spinal cord repair: advances in biology and technology[J]. Nat Med, 2019, 25(6): 898-908.
2	FEHLINGS M G, TETREAULT L A, WILSON J R, et al. A clinical practice guideline for the management of acute spinal cord injury: introduction, rationale, and scope[J]. Global Spine J, 2017, 7(3 Suppl): 84S-94S.
3	陈星月, 陈栋, 陈春慧, 等. 中国创伤性脊髓损伤流行病学和疾病经济负担的系统评价[J]. 中国循证医学杂志, 2018, 18(2): 143-150.
	CHEN X Y, CHEN D, CHEN C H, et al. The epidemiology and disease burden of traumatic spinal cord injury in China: a systematic review[J]. Chinese Journal of Evidence-Based Medicine, 2018, 18(2): 143-150.
4	PETROVA V, NIEUWENHUIS B, FAWCETT J W, et al. Axonal organelles as molecular platforms for axon growth and regeneration after injury[J]. Int J Mol Sci, 2021, 22(4): 1798.
5	BARTOLÁK-SUKI E, IMSIROVIC J, NISHIBORI Y, et al. Regulation of mitochondrial structure and dynamics by the cytoskeleton and mechanical factors[J]. Int J Mol Sci, 2017, 18(8): 1812.
6	HAN S M, BAIG H S, HAMMARLUND M. Mitochondria localize to injured axons to support regeneration[J]. Neuron, 2016, 92(6): 1308-1323.
7	CAVALLUCCI V, BISICCHIA E, CENCIONI M T, et al. Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons[J]. Cell Death Dis, 2014, 5(11): e1545.
8	MALLA B, NIESNER R, HAUSER A, et al. Imaging and analysis of neuronal mitochondria in murine acute brain slices[J]. J Neurosci Methods, 2022, 372: 109558.
9	BALLABIO A, BONIFACINO J S. Lysosomes as dynamic regulators of cell and organismal homeostasis[J]. Nat Rev Mol Cell Biol, 2020, 21(2): 101-118.
10	STAVOE A K H, HOLZBAUR E L F. Autophagy in neurons[J]. Annu Rev Cell Dev Biol, 2019, 35: 477-500.
11	SAKAMOTO K, OZAKI T, KO Y C, et al. Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis[J]. Nat Chem Biol, 2019, 15(7): 699-709.
12	WEI X Y, LUO L F, CHEN J Z. Roles of mTOR signaling in tissue regeneration[J]. Cells, 2019, 8(9): 1075.
13	RABANAL-RUIZ Y, KOROLCHUK V I. mTORC1 and nutrient homeostasis: the central role of the lysosome[J]. Int J Mol Sci, 2018, 19(3): 818.
14	JEHAN C, CARTIER D, BUCHARLES C, et al. Emerging roles of ER-resident selenoproteins in brain physiology and physiopathology[J]. Redox Biol, 2022, 55: 102412.
15	JACQUEMYN J, CASCALHO A, GOODCHILD R E. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis[J]. EMBO Rep, 2017, 18(11): 1905-1921.
16	TOJIMA T, KAMIGUCHI H. Exocytic and endocytic membrane trafficking in axon development[J]. Dev Growth Differ, 2015, 57(4): 291-304.
17	WOJNACKI J, GALLI T. Membrane traffic during axon development[J]. Dev Neurobiol, 2016, 76(11): 1185-1200.
18	YAP C C, WINCKLER B. Harnessing the power of the endosome to regulate neural development[J]. Neuron, 2012, 74(3): 440-451.
19	KORHONEN L, LINDHOLM D. The ubiquitin proteasome system in synaptic and axonal degeneration: a new twist to an old cycle[J]. J Cell Biol, 2004, 165(1): 27-30.
20	LEE M, LIU Y C, CHEN C, et al. Ecm29-mediated proteasomal distribution modulates excitatory GABA responses in the developing brain[J]. J Cell Biol, 2020, 219(2): e201903033.
21	DI PAOLO A, GARAT J, EASTMAN G, et al. Functional genomics of axons and synapses to understand neurodegenerative diseases[J]. Front Cell Neurosci, 2021, 15: 686722.
22	NJOMEN E, TEPE J J. Proteasome activation as a new therapeutic approach to target proteotoxic disorders[J]. J Med Chem, 2019, 62(14): 6469-6481.
23	TAKABATAKE M, GOSHIMA Y, SASAKI Y. Semaphorin-3A promotes degradation of fragile X mental retardation protein in growth cones via the ubiquitin-proteasome pathway[J]. Front Neural Circuits, 2020, 14: 5.
24	JIN E J, KO H R, HWANG I, et al. Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation[J]. Sci Rep, 2018, 8(1): 2557.
25	HE L H, LEMASTERS J J. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?[J]. FEBS Lett, 2002, 512(1/2/3): 1-7.
26	MCEWEN M L, SULLIVAN P G, SPRINGER J E. Pretreatment with the cyclosporin derivative, NIM811, improves the function of synaptic mitochondria following spinal cord contusion in rats[J]. J Neurotrauma, 2007, 24(4): 613-624.
27	PATEL S P, SULLIVAN P G, LYTTLE T S, et al. Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery[J]. Neuroscience, 2012, 210: 296-307.
28	PATEL S P, SULLIVAN P G, PANDYA J D, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma[J]. Exp Neurol, 2014, 257: 95-105.
29	PATEL S P, COX D H, GOLLIHUE J L, et al. Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery[J]. Exp Neurol, 2017, 293: 74-82.
30	WANG Q Q, CAI H X, HU Z X, et al. Loureirin B promotes axon regeneration by inhibiting endoplasmic reticulum stress: induced mitochondrial dysfunction and regulating the Akt/GSK-3β pathway after spinal cord injury[J]. J Neurotrauma, 2019, 36(12): 1949-1964.
31	SCHOLPA N E, WILLIAMS H, WANG W X, et al. Pharmacological stimulation of mitochondrial biogenesis using the food and drug administration-approved β₂-adrenoreceptor agonist formoterol for the treatment of spinal cord injury[J]. J Neurotrauma, 2019, 36(6): 962-972.
32	GOLLIHUE J L, PATEL S P, RABCHEVSKY A G. Mitochondrial transplantation strategies as potential therapeutics for central nervous system trauma[J]. Neural Regen Res, 2018, 13(2): 194-197.
33	GOLLIHUE J L, PATEL S P, ELDAHAN K C, et al. Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury[J]. J Neurotrauma, 2018, 35(15): 1800-1818.
34	KANNO H, OZAWA H, SEKIGUCHI A, et al. The role of mTOR signaling pathway in spinal cord injury[J]. Cell Cycle, 2012, 11(17): 3175-3179.
35	ZHANG D, XUAN J, ZHENG B B, et al. Metformin improves functional recovery after spinal cord injury via autophagy flux stimulation[J]. Mol Neurobiol, 2017, 54(5): 3327-3341.
36	WU Y Q, XIONG J, HE Z L, et al. Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury[J]. Acta Pharmacol Sin, 2022, 43(6): 1360-1371.
37	HETZ C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond[J]. Nat Rev Mol Cell Biol, 2012, 13(2): 89-102.
38	BISICCHIA E, MASTRANTONIO R, NOBILI A, et al. Restoration of ER proteostasis attenuates remote apoptotic cell death after spinal cord injury by reducing autophagosome overload[J]. Cell Death Dis, 2022, 13(4): 381.
39	ZHOU Z J, HU B W, LYU Q N, et al. MiR-384-5p promotes spinal cord injury recovery in rats through suppressing of autophagy and endoplasmic reticulum stress[J]. Neurosci Lett, 2020, 727: 134937.
40	HE M, DING Y T, CHU C, et al. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury[J]. Proc Natl Acad Sci USA, 2016, 113(40): 11324-11329.
41	WANG S, WU J, ZENG Y Z, et al. Necrostatin-1 mitigates endoplasmic reticulum stress after spinal cord injury[J]. Neurochem Res, 2017, 42(12): 3548-3558.
42	LI Y, ZHANG J, ZHOU K L, et al. Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury[J]. Cell Biol Toxicol, 2021, 37(3): 401-419.
43	FU H T, HU D, CHEN J L, et al. Repair of the injured spinal cord by schwann cell transplantation[J]. Front Neurosci, 2022, 16: 800513.
44	ZHAO Y Z, JIANG X, XIAO J, et al. Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury[J]. Acta Biomater, 2016, 29: 71-80.
45	LI H T, ZHANG X R, QI X, et al. Icariin inhibits endoplasmic reticulum stress-induced neuronal apoptosis after spinal cord injury through modulating the PI3K/AKT signaling pathway[J]. Int J Biol Sci, 2019, 15(2): 277-286.
46	LIU X H, YANG J, LI Z, et al. Hyperbaric oxygen treatment protects against spinal cord injury by inhibiting endoplasmic reticulum stress in rats[J]. Spine, 2015, 40(24): E1276-E1283.
47	WU Q, ZHANG Y J, GAO J Y, et al. Aquaporin-4 mitigates retrograde degeneration of rubrospinal neurons by facilitating edema clearance and glial scar formation after spinal cord injury in mice[J]. Mol Neurobiol, 2014, 49(3): 1327-1337.
48	ZHENG B B, ZHOU Y L, ZHANG H Y, et al. Dl-3-n-butylphthalide prevents the disruption of blood-spinal cord barrier via inhibiting endoplasmic reticulum stress following spinal cord injury[J]. Int J Biol Sci, 2017, 13(12): 1520-1531.
49	WANG H L, WU Y Q, HAN W, et al. Hydrogen sulfide ameliorates blood-spinal cord barrier disruption and improves functional recovery by inhibiting endoplasmic reticulum stress-dependent autophagy[J]. Front Pharmacol, 2018, 9: 858.
50	KOBAYASHI H, ETOH K, FUKUDA M. Rab35 is translocated from Arf6-positive perinuclear recycling endosomes to neurite tips during neurite outgrowth[J]. Small GTPases, 2014, 5(3): e983874.
51	WU C S, CUI Z M, LIU Y H, et al. The importance of EHD1 in neurite outgrowth contributing to the functional recovery after spinal cord injury[J]. Int J Dev Neurosci, 2016, 52: 24-32.
52	GALLON M, CLAIRFEUILLE T, STEINBERG F, et al. A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer[J]. Proc Natl Acad Sci USA, 2014, 111(35): E3604-E3613.
53	ZENG Y Z, WANG N W, GUO T T, et al. Snx27 deletion promotes recovery from spinal cord injury by neuroprotection and reduces macrophage/microglia proliferation[J]. Front Neurol, 2018, 9: 1059.
54	SPITZBARTH I, MOORE S A, STEIN V M, et al. Current insights into the pathology of canine intervertebral disc extrusion-induced spinal cord injury[J]. Front Vet Sci, 2020, 7: 595796.
55	MYEKU N, WANG H, FIGUEIREDO-PEREIRA M E. cAMP stimulates the ubiquitin/proteasome pathway in rat spinal cord neurons[J]. Neurosci Lett, 2012, 527(2): 126-131.
56	MORIWAKI K, CHAN F K M. RIP3: a molecular switch for necrosis and inflammation[J]. Genes Dev, 2013, 27(15): 1640-1649.
57	WU C S, CHEN J J, LIU Y H, et al. Upregulation of PSMB4 is associated with the necroptosis after spinal cord injury[J]. Neurochem Res, 2016, 41(11): 3103-3112.
58	TICA J R, BRADBURY E J, DIDANGELOS A. Combined transcriptomics, proteomics and bioinformatics identify drug targets in spinal cord injury[J]. Int J Mol Sci, 2018, 19(5): 1461.

[1]	HAN Yongqi, HAN Da, XIA Qian, JI Dingkun, TAN Weihong. Aptamer-drug conjugates (ApDCs): new trend for cancer precision therapy [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1176-1181.
[2]	Jiyu HAN, Yanhong WANG, Daqian WAN. Research progress and development trend of lower extremity exoskeleton rehabilitation robot [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(2): 241-246.
[3]	LI Ruonan, CHEN Xiaoke, XU Yuanyuan, TAN Qiang. Advances in postoperative adjuvant targeted therapy for patients with stage ⅠB-ⅢA non-small cell lung cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1612-1619.
[4]	Jia-ling ZHANG, Feng-chun ZHANG, Ying-chun XU. Research progress in the systemic treatment for breast cancer with brain metastasis [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(5): 671-677.
[5]	LI Chao, MI Jian-qing, WANG Jin. Advances in Philadelphia chromosome-like acute lymphoblastic leukemia [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(9): 1294-1301.
[6]	WEI Xiao-mei1, HU San-lian2, QIAN Hui-juan2, WEI Wei-ping1, WANG Fei-yan1. Study on the clinical application of the intervention program of bowel dysfunction in patients with spinal cord injury [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(6): 828-834.
[7]	LIN Jun-qing, ZHENG Xian-you, BAO Bing-bo, LI Xing-wei, GAO Tao, HUANG Teng-li. Research progress of the mechanism and treatment of macrophage in spinal cord injury repair [J]. , 2020, 40(1): 118-.
[8]	GAO Tao, ZHU Xiao-zhong, BAO Bing-bo, LI Xing-wei, LIN Jun-qing, HUANG Teng-li, CHAI Yi-min, ZHANG Chang-qing, ZHENG Xian-you. Structural changes of rectal smooth muscle after spinal cord injury in rats [J]. , 2019, 39(9): 963-.
[9]	RUAN Xin1, ZHANG Ying-ting1, HAN Ke-qi1, LIN Long-shuai2, CHEN Chen1, YUE Ming1, WANG Chu-qiao1, SUN Ying-gang3, ZHAO Qing-hua2, HE Ming1. SIRT7 protecting hepatocytes LPS or D-GalN/LPS-induced apoptosisattenuating endoplasmic reticulum stress via inactivation of GRP78 [J]. , 2019, 39(8): 812-.
[10]	LI Qi1, ZHOU Xiang-dong1, ZENG Man1, Victor P. KOLOSOV2, Juliy M. PERELMAN2. Role of inositol-requiring kinase 1α/X-box binding protein 1 in airway mucus secretion inducedneutrophil elastase [J]. , 2019, 39(1): 21-.
[11]	GAO Tao, ZHU Xiao-zhong, BAO Bing-bo, LI Xing-wei, ZHENG Xian-you. Research progress of neurogenic bowel dysfunction in spinal cord injury [J]. , 2018, 38(9): 1116-.
[12]	JIAN Chao-hui, BAO Yu-qian. Research progress of autophagy in non-alcoholic fatty liver disease [J]. , 2018, 38(6): 690-.
[13]	LIU Yang, GAO Yu-ting, MIAO Yu-chuan. Effect of Danshen injection on expression of brain-derived neurotrophic factor and insulin-like growth factor-1 in rats with spinal cord injury [J]. , 2018, 38(3): 272-.
[14]	ZHU Xiao-zhong, ZHU Hong-yi, BAO Bing-bo, LI Xing-wei, GAO Tao, ZHENG Xian-you . Effectiveness of defecation reconstruction following nerve transfer in rats by PRV retrograde tracing [J]. , 2017, 37(9): 1196-.
[15]	TANG Wei, XIA Yong-zhi, LIU Jing-xian, LIU Lu, YAN Yi . Effects of sodium houttuyfonate on spinal cord injured neurons in rats [J]. , 2017, 37(12): 1594-.