Minocycline Alleviates Death of Oligodendrocytes by Inhibiting Pro-nerve Growth Factor Production in Microglia After Spinal Cord Injury

Overview

Journal J Neurosci

Specialty Neurology

Date 2007 Jul 20

PMID 17634369

Citations 111

Authors

Tae Y Yune

Jee Y Lee

Gil Y Jung

Sun J Kim

Mei H Jiang

Young C Kim

Young J Oh

George J Markelonis

Tae H Oh

Affiliations

Soon will be listed here.

Abstract

Spinal cord injury (SCI) causes a permanent neurological disability, and no satisfactory treatment is currently available. After SCI, pro-nerve growth factor (proNGF) is known to play a pivotal role in apoptosis of oligodendrocytes, but the cell types producing proNGF and the signaling pathways involved in proNGF production are primarily unknown. Here, we show that minocycline improves functional recovery after SCI in part by reducing apoptosis of oligodendrocytes via inhibition of proNGF production in microglia. After SCI, the stress-responsive p38 mitogen-activated protein kinase (p38MAPK) was activated only in microglia, and proNGF was produced by microglia via the p38MAPK-mediated pathway. Minocycline treatment significantly reduced proNGF production in microglia in vitro and in vivo by inhibition of the phosphorylation of p38MAPK. Furthermore, minocycline treatment inhibited p75 neurotrophin receptor expression and RhoA activation after injury. Finally, minocycline treatment inhibited oligodendrocyte death and improved functional recovery after SCI. These results suggest that minocycline may represent a potential therapeutic agent for acute SCI in humans.

Citing Articles

Potential role of ghrelin in neuroprotection and cognitive function: implications for diabetic cognitive impairment.

Zhang Y, Zhang R, Wang X, Shi L, Zhu H, Liu J PeerJ. 2025; 13:e18898.

PMID: 39995985 PMC: 11849504. DOI: 10.7717/peerj.18898.

Targeting Remyelination in Spinal Cord Injury: Insights and Emerging Therapeutic Strategies.

Al Mamun A, Quan Z, Geng P, Wang S, Shao C, Xiao J CNS Neurosci Ther. 2024; 30(12):1-15.

PMID: 39723448 PMC: 11669846. DOI: 10.1111/cns.70193.

Preparation of a minocycline polymer micelle thermosensitive gel and its application in spinal cord injury.

Gu J, Cai X, Raza F, Zafar H, Chu B, Yuan H Nanoscale Adv. 2024; .

PMID: 39355839 PMC: 11440374. DOI: 10.1039/d4na00625a.

Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury.

Liu Y, Zhao C, Zhang R, Pang Y, Li L, Feng S Stem Cell Res Ther. 2024; 15(1):343.

PMID: 39354635 PMC: 11446099. DOI: 10.1186/s13287-024-03914-x.

TRPM7 Mediates Neuropathic Pain by Activating mTOR Signaling in Astrocytes after Spinal Cord Injury in Rats.

Kim I, Park C, Seo K, Lee J, Yune T Mol Neurobiol. 2024; 61(8):5265-5281.

PMID: 38180616 DOI: 10.1007/s12035-023-03888-6.

References

Majdan M, Miller F . Neuronal life and death decisions functional antagonism between the Trk and p75 neurotrophin receptors. Int J Dev Neurosci. 1999; 17(3):153-61. DOI: 10.1016/s0736-5748(99)00016-7. View

Yamashita T, Tucker K, Barde Y . Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron. 1999; 24(3):585-93. DOI: 10.1016/s0896-6273(00)81114-9. View

Krenz N, Weaver L . Nerve growth factor in glia and inflammatory cells of the injured rat spinal cord. J Neurochem. 2000; 74(2):730-9. DOI: 10.1046/j.1471-4159.2000.740730.x. View

Barrett G . The p75 neurotrophin receptor and neuronal apoptosis. Prog Neurobiol. 2000; 61(2):205-29. DOI: 10.1016/s0301-0082(99)00056-8. View

Chen M, Ona V, Li M, Ferrante R, Fink K, Zhu S . Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000; 6(7):797-801. DOI: 10.1038/77528. View

Friedman W . Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci. 2000; 20(17):6340-6. PMC: 6772976. View

Beattie M, Farooqui A, Bresnahan J . Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma. 2000; 17(10):915-25. DOI: 10.1089/neu.2000.17.915. View

Kim G, Ahmed S, Xu J, Yan P, Xu X, Hsu C . Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci. 2001; 21(1):92-7. PMC: 6762457. View

Brandoli C, Shi B, Pflug B, Andrews P, Wrathall J, Mocchetti I . Dexamethasone reduces the expression of p75 neurotrophin receptor and apoptosis in contused spinal cord. Brain Res Mol Brain Res. 2001; 87(1):61-70. DOI: 10.1016/s0169-328x(00)00284-9. View

10.

Warden P, Bamber N, Li H, Esposito A, Ahmad K, Hsu C . Delayed glial cell death following wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats. Exp Neurol. 2001; 168(2):213-24. DOI: 10.1006/exnr.2000.7622. View

11.

Casha S, Yu W, Fehlings M . Oligodendroglial apoptosis occurs along degenerating axons and is associated with FAS and p75 expression following spinal cord injury in the rat. Neuroscience. 2001; 103(1):203-18. DOI: 10.1016/s0306-4522(00)00538-8. View

12.

Widenfalk J, Lundstromer K, Jubran M, Brene S, Olson L . Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci. 2001; 21(10):3457-75. PMC: 6762497. View

13.

Merkler D, Metz G, Raineteau O, Dietz V, Schwab M, Fouad K . Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J Neurosci. 2001; 21(10):3665-73. PMC: 6762500. View

14.

Sanchez Mejia R, Ona V, Li M, Friedlander R . Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery. 2001; 48(6):1393-9; discussion 1399-401. DOI: 10.1097/00006123-200106000-00051. View

15.

Tikka T, Koistinaho J . Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001; 166(12):7527-33. DOI: 10.4049/jimmunol.166.12.7527. View

16.

He Y, Appel S, Le W . Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res. 2001; 909(1-2):187-93. DOI: 10.1016/s0006-8993(01)02681-6. View

17.

Fahnestock M, Michalski B, Xu B, Coughlin M . The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol Cell Neurosci. 2001; 18(2):210-20. DOI: 10.1006/mcne.2001.1016. View

18.

Du Y, Ma Z, Lin S, Dodel R, Gao F, Bales K . Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A. 2001; 98(25):14669-74. PMC: 64739. DOI: 10.1073/pnas.251341998. View

19.

Lee R, Kermani P, Teng K, Hempstead B . Regulation of cell survival by secreted proneurotrophins. Science. 2001; 294(5548):1945-8. DOI: 10.1126/science.1065057. View

20.

Miller F, Kaplan D . On Trk for retrograde signaling. Neuron. 2001; 32(5):767-70. DOI: 10.1016/s0896-6273(01)00529-3. View