Abstract
The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents among young adults is on the rise. SCI contributes to the high disability rate. Presently, evidences detailing the precise pathological mechanisms in SCI are limited, compounding to the unavailability of an effective treatment method. Surgery, though not a complete curative method, is useful in managing some of the associated symptoms of secondary SCI. Autophagy and inflammation are contributive factors to both exacerbation and improvement of SCI. The mammalian target of rapamycin (mTOR) signaling pathway is a key player in the regulation of inflammatory response and autophagy. Valproic acid (VPA), a clinically used antiepileptic drug, has been suggested to improve neurological conditions, including SCI. This report reviewed the correlation between mTOR and autophagy, as well as autophagy’s role and the therapeutic effects of VPA in SCI. VPA regulates autophagy by potentially inhibiting mTORC1, a complex of mTOR, while also hindering inflammatory response. Conclusively, an effective treatment for SCI could lie in the timely regulation of mTOR signaling pathway, and VPA could be the potential drug that improves SCI owing to its propensity to regulate the mTOR signaling pathway.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- SCI:
-
Spinal cord injury
- mTOR:
-
Mammalian target of rapamycin
- BSCB:
-
Blood–spinal cord barrier
- ER:
-
Endoplasmic reticulum
- mTORC1:
-
Mammalian target of rapamycin complex 1
- ATG13:
-
Autophagy-related protein 13
- Ulk1:
-
Unc-51-like kinase 1
- VPA:
-
Valproic acid
- HDACI:
-
Histone deacetylase inhibitor
- HDAC:
-
Histone deacetylase
- mLST8:
-
Mammalian lethal with SEC13 protein 8
- Raptor:
-
Regulatory protein associated with mTOR
- FIP200:
-
Focal adhesion kinase family interacting protein of 200 kDa
- TLR:
-
Toll-like receptors
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- AMPK:
-
5′ Adenosine monophosphate-activated protein kinase
- PTEN:
-
Phosphatase and tensin homolog
- SCG10:
-
Superior cervical ganglia protein 10
- PI3K:
-
Phosphatidylinositol 3 kinase
- PIP2:
-
Phosphatidylinositol 3,4-bisphosphate
- PIP3:
-
Phosphatidylinositol 3,4,5-trisphosphate
- SAHA:
-
Suberoylanilide hydroxamic acid
- ALP:
-
Autophagy–lysosomal pathway
- CNS:
-
Central nervous system
- NSPCs:
-
Neural stem/progenitor cells
- LC3-II:
-
Light chain 3-II
- SOX2:
-
Sex determining region Y-box 2
- Oct4:
-
Octamer-binding transcription factor 4
- BDNF:
-
Brain-derived neurotrophic factor
- TNF-α:
-
Tumor Necrosis Factor alpha
- TGF:
-
Transforming growth factor
- ALS:
-
Amyotrophic lateral sclerosis
- MAP:
-
Mitogen-activated protein
- JNK:
-
C-Jun N-terminal kinase
References
Andary MT, Green DF, Hulce VD, Pysh JJ (1997) Spinal myoclonus complicating spasticity in spinal cord injury: a case study. Arch Phys Med Rehabil 78(9):1007–1009
Avery LB, Bumpus NN (2014) Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. Mol Pharmacol 85(1):1–10. https://doi.org/10.1124/mol.113.089755
Bai L, Mei X, Shen Z, Bi Y, Yuan Y, Guo Z, Wang H, Zhao H, Zhou Z, Wang C, Zhu K, Li G, Lv G (2017) Netrin-1 improves functional recovery through autophagy regulation by activating the AMPK/mTOR signaling pathway in rats with spinal cord injury. Sci Rep 7:42288. https://doi.org/10.1038/srep42288
Bambakidis T, Dekker SE, Sillesen M, Liu B, Johnson CN, Jin G, de Vries HE, Li Y, Alam HB (2016) Resuscitation with valproic acid alters inflammatory genes in a porcine model of combined traumatic brain injury and hemorrhagic shock. J Neuroinflamm 33(16):1514–1521. https://doi.org/10.1089/neu.2015.4163
Bernard M, Dieudé M, Yang B, Hamelin K, Underwood K, Hébert MJ (2014) Autophagy fosters myofibroblast differentiation through MTORC2 activation and downstream upregulation of CTGF. Autophagy 10(12):2193–2207. https://doi.org/10.4161/15548627.2014.981786
Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S, Lagrèze WA (2010) Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Invest Ophthalmol Vis Sci. 51(1):526–534. https://doi.org/10.1167/iovs.09-3903
Boll MC, Bayliss L, Vargas-Cañas S, Burgos J, Montes S, Peñaloza-Solano G, Rios C, Alcaraz-Zubeldia M (2014) Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis. J Neurol Sci 340(1–2):103–108. https://doi.org/10.1016/j.jns.2014.03.005
Chen HC, Fong TH, Lee AW, Chiu WT (2012) Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. Spine (Phila Pa 1976) 37(6):470–475. https://doi.org/10.1097/BRS.0b013e318221e859
Chen S, Ye J, Chen X, Shi J, Wu W, Lin W, Lin W, Li Y, Fu H, Li S (2018a) Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J Neuroinflamm 15(1):150. https://doi.org/10.1186/s12974-018-1193-6
Chen X, Wang H, Zhou M, Li X, Fang Z, Gao H, Li Y, Hu W (2018b) Valproic acid attenuates traumatic brain injury-induced inflammation in vivo: involvement of autophagy and the Nrf2/ARE signaling pathway. Front Mol Neurosci 11:117. https://doi.org/10.3389/fnmol.2018.00117
Chen WJ, Ma L, Li MS, Ma X (2019) Valproic acid’s effects on visual acuity in retinitis pigmentosa: a systemic review and Meta-analysis. Int J Ophthalmol 12(1):129–134. https://doi.org/10.18240/ijo.2019.01.20
Chu T, Zhou H, Lu L, Kong X, Wang T, Pan B, Feng S (2015a) Valproic acid-mediated neuroprotection and neurogenesis after spinal cord injury: from mechanism to clinical potential. Regen Med 10(2):193–209. https://doi.org/10.2217/rme.14.86
Chu W, Yuan J, Huang L, Xiang X, Zhu H, Chen F, Chen Y, Lin J, Feng H (2015b) Valproic acid arrests proliferation but promotes neuronal differentiation of adult spinal nspcs from sci rats. Neurochem Res 40(7):1472–1486. https://doi.org/10.1007/s11064-015-1618-x
Collins-Yoder A, Lowell J (2017) Valproic Acid: special considerations and targeted monitoring. J Neurosci Nurs 49(1):56–61. https://doi.org/10.1097/JNN.0000000000000259
Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP (2012) Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 318(13):1528–1541. https://doi.org/10.1016/j.yexcr.2012.02.040
Cui SS, Yang CP, Bowen RC, Bai O, Li XM, Jiang W, Zhang X (2003) Valproic acid enhances axonal regeneration and recovery of motor function after sciatic nerve axotomy in adult rats. Brain Res 975(1–2):229–236. https://doi.org/10.1016/s0006-8993(03)02699-4
Dai Q, Zhou D, Xu L, Song X (2018) Curcumin alleviates rheumatoid arthritis-induced inflammation and synovial hyperplasia by targeting mTOR pathway in rats. Drug Design Dev Ther 12:4095–4105. https://doi.org/10.2147/DDDT.S175763
Darvishi M, Tiraihi T, Mesbah-Namin SA, Delshad A, Taheri T (2014) Decreased GFAP expression and improved functional recovery in contused spinal cord of rats following valproic acid therapy. Neurochem Res 39(12):2319–2333. https://doi.org/10.1007/s11064-014-1429-5
Drewes AM, Andreasen A, Poulsen LH (1994) Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study. Paraplegia 32(8):565–569
Duan P, Hu C, Quan C, Yu T, Huang W, Chen W, Tang S, Shi Y, Martin FL, Yang K (2017) 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells. Toxicol Lett 267:21–31. https://doi.org/10.1016/j.toxlet.2016.12.015
Eckert MJ, Martin MJ (2017) Trauma: spinal cord injury. Surg Clin North Am 97(5):1031–1045. https://doi.org/10.1016/j.suc.2017.06.008
Fan QW, Weiss WA (2012) Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol 821:349–359. https://doi.org/10.1007/978-1-61779-430-8_22
Fan H, Tang HB, Shan LQ, Liu SC, Huang DG, Chen X, Chen Z, Yang M, Yin XH, Yang H, Hao DJ (2019) Quercetin prevents necroptosis of oligodendrocytes by inhibiting macrophages/microglia polarization to M1 phenotype after spinal cord injury in rats. J Neuroinflammation 16(1):206. https://doi.org/10.1186/s12974-019-1613-2
Georgoff PE, Nikolian VC, Higgins G, Chtraklin K, Eidy H, Ghandour MH, Williams A, Athey B, Alam HB (2018) Valproic acid induces prosurvival transcriptomic changes in swine subjected to traumatic injury and hemorrhagic shock. J Trauma Acute Care Surg 84(4):642–649. https://doi.org/10.1097/TA.0000000000001763
Ghasemi-Kasman M, Hajikaram M, Baharvand H, Javan M (2015) MicroRNA-mediated in vitro and in vivo direct conversion of astrocytes to neuroblasts. PLoS ONE 10(6):e0127878. https://doi.org/10.1371/journal.pone.0127878
Guo L, Lv J, Huang YF, Hao DJ, Liu JJ (2019) Bioinformatics analyses of differentially expressed genes associated with spinal cord injury: a microarray-based analysis in a mouse model. Neural Regen Res 14(7):1262–1270. https://doi.org/10.4103/1673-5374.251335
Hao HH, Wang L, Guo ZJ, Bai L, Zhang RP, Shuang WB, Jia YJ, Wang J, Li XY, Liu Q (2013) Valproic acid reduces autophagy and promotes functional recovery after spinal cord injury in rats. Neurosci Bull 29(4):484–492. https://doi.org/10.1007/s12264-013-1355-6
Hasan MR, Kim JH, Kim YJ, Kwon KJ, Shin CY, Kim HY, Han SH, Choi DH, Lee J (2013) Effect of HDAC inhibitors on neuroprotection and neurite outgrowth in primary rat cortical neurons following ischemic insult. Neurochem Res 38(9):1921–1934. https://doi.org/10.1007/s11064-013-1098-9
He M, Ding Y, Chu C, Tang J, Xiao Q, Luo ZG (2016) Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury. Proc Natl Acad Sci USA 113(40):11324–11329. https://doi.org/10.1073/pnas.1611282113
Huang Z, Filipovic Z, Mp N, Ung C, Troy EL, Colburn RW, Iaci JF, Hackett C, Button DC, Caggiano AO, Parry TJ (2017) AC105 increases extracellular magnesium delivery and reduces excitotoxic glutamate exposure within injured spinal cords in rats. J Neurotrauma 34(3):685–694. https://doi.org/10.1089/neu.2016.4607
Huo W, Zhang Y, Liu Y, Lei Y, Sun R, Zhang W, Huang Y, Mao Y, Wang C, Ma Z, Gu X (2018) Dehydrocorydaline attenuates bone cancer pain by shifting microglial M1/M2 polarization toward the M2 phenotype. Mol Pain 14:1744806918781733. https://doi.org/10.1177/1744806918781733
Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM, Chao MV (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13:1373–1379
Jo EK, Silwal P, Yuk JM (2019) AMPK-targeted Eff ector networks in mycobacterial infection. Front Microbiol 10:520. https://doi.org/10.3389/fmicb.2019.00520
Kalal BS, Pai VR, Behera SK, Somashekarappa HM (2019) HDAC2 inhibitor valproic acid increases radiation sensitivity of drug-resistant melanoma cells. Med Sci 7(3):51. https://doi.org/10.3390/medsci7030051
Kanno H, Ozawa H, Sekiguchi A, Itoi E (2009) Spinal cord injury induces upregulation of Beclin 1 and promotes autophagic cell death. Neurobiol Dis 33(2):143–148. https://doi.org/10.1016/j.nbd.2008.09.009
Kaur A, Sharma S (2017) Mammalian target of rapamycin (mTOR) as a potential therapeutic target in various diseases. Inflammopharmacology 25(3):293–312. https://doi.org/10.1007/s10787-017-0336-1
Kong QJ, Wang Y, Liu Y, Sun JC, Xu XM, Sun XF, Shi JG (2017) Neuroprotective effects of valproic acid in a rat model of cauda equina injury. World Neurosurg 108:128–136. https://doi.org/10.1016/j.wneu.2017.08.150
Kopper TJ, Gensel JC (2018) Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury. J Neurosci Res 96(6):969–977. https://doi.org/10.1002/jnr.24114
Lampada A, Hochhauser D, Salomoni P (2017) Autophagy and receptor tyrosine kinase signalling: A mTORC2 matter. Cell Cycle 16(20):1855–1856. https://doi.org/10.1080/15384101.2017.1372548
Lee JY, Maeng S, Kang SR, Choi HY, Oh TH, Ju BG, Yune TY (2014) Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. J Neurotrauma 31(6):582–594. https://doi.org/10.1089/neu.2013.3146
Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L (2016) PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7(22):33440–33450. https://doi.org/10.18632/oncotarget.7961
Li J, Jia Z, Xu W, Guo W, Zhang M, Bi J, Cao Y, Fan Z, Li G (2019a) TGN-020 alleviates edema and inhibits astrocyte activation and glial scar formation after spinal cord compression injury in rats. Life Sci 222:148–157. https://doi.org/10.1016/j.lfs.2019.03.007
Li R, Qin X, Liang X, Liu M, Zhang X (2019b) Lipidomic characteristics and clinical findings of epileptic patients treated with valproic acid. J Cell Mol Med 23(9):6017–6023. https://doi.org/10.1111/jcmm.14464
Lipinski MM, Wu J, Faden AI, Sarkar C (2015) Function and mechanisms of autophagy in brain and spinal cord trauma. Antioxid Redox Signal 23(6):565–577. https://doi.org/10.1089/ars.2015.6306
Liu S, Chen Z (2019) Employing endogenous NSCs to promote recovery of spinal cord injury. Stem Cells Int 2019:1958631. https://doi.org/10.1155/2019/1958631
Liu Y, Xu H, An M (2017) mTORC1 regulates apoptosis and cell proliferation in pterygium via targeting autophagy and FGFR3. Sci Rep 7(1):7339. https://doi.org/10.1038/s41598-017-07844-y
Liu S, Li Y, Choi HMC, Sarkar C, Koh EY, Wu J, Lipinski MM (2018a) Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis. Cell Death Dis 9(5):476. https://doi.org/10.1038/s41419-018-0469-1
Liu X, Zhang Y, Yang Y, Lin J, Huo X, Du X, Botchway BOA, Fang M (2018b) Therapeutic effect of curcumin and methylprednisolone in the rat spinal cord injury. Anat Rec (Hoboken) 301(4):686–696. https://doi.org/10.1002/ar.23729
Ma L, Tang H, Yin Y, Yu R, Zhao J, Li Y, Mulholland MW, Zhang W (2015) HDAC5-mTORC1 interaction in differential regulation of ghrelin and nucleobindin 2 (NUCB2)/Nesfatin-1. Mol Endocrinol 29(11):1571–1580. https://doi.org/10.1210/me.2015-1184
Meng HY, Shao DC, Li H, Huang XD, Yang G, Xu B, Niu HY (2018) Resveratrol improves neurological outcome and neuroinflammation following spinal cord injury through enhancing autophagy involving the AMPK/mTOR pathway. Mol Med Rep 18(2):2237–2244. https://doi.org/10.3892/mmr.2018.9194
Nikolian VC, Dennahy IS, Higgins GA, Williams AM, Weykamp M, Georgoff PE, Eidy H, Ghandour MH, Chang P, Alam HB (2018) Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury. J Trauma Acute Care Surg 84(3):459–465. https://doi.org/10.1097/TA.0000000000001765
Noda T (2017) Regulation of autophagy through TORC1 and mTORC1. Biomolecules 7(3):52. https://doi.org/10.3390/biom7030052
Okada S, Hara M, Kobayakawa K, Matsumoto Y, Nakashima Y (2018) Astrocyte reactivity and astrogliosis after spinal cord injury. Neurosci Res 126:39–43. https://doi.org/10.1016/j.neures.2017.10.004
Pandamooz S, Salehi MS, Zibaii MI, Safari A, Nabiuni M, Ahmadiani A, Dargahi L (2019) Modeling traumatic injury in organotypic spinal cord slice culture obtained from adult rat. Tissue Cell 56:90–97. https://doi.org/10.1016/j.tice.2019.01.002
Penas C, Verdú E, Asensio-Pinilla E, Guzmán-Lenis MS, Herrando-Grabulosa M, Navarro X, Casas C (2011) Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury. Neuroscience 178:33–44. https://doi.org/10.1016/j.neuroscience.2011.01.012
Piepers S, Veldink JH, de Jong SW, van der Tweel I, van der Pol WL, Uijtendaal EV, Schelhaas HJ, Scheffer H, de Visser M, de Jong JM, Wokke JH, Groeneveld GJ, van den Berg LH (2009) Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol 66(2):227–234. https://doi.org/10.1002/ana.21620
Rabanal-Ruiz Y, Otten EG, Korolchuk VI (2017) mTORC1 as the main gateway to autophagy. Essays Biochem 61(6):565–584. https://doi.org/10.1042/EBC20170027
Rao T, Wu F, Xing D, Peng Z, Ren D, Feng W, Chen Y, Zhao Z, Wang H, Wang J, Kan W, Zhang Q (2014) Effects of valproic Acid on axonal regeneration and recovery of motor function after peripheral nerve injury in the rat. Arch Bone Jt Surg 2(1):17–24
Riva G, Cilibrasi C, Bazzoni R, Cadamuro M, Negroni C, Butta V, Strazzabosco M, Dalprà L, Lavitrano M, Bentivegna A (2018) Valproic acid inhibits proliferation and reduces invasiveness in glioma stem cells through wnt/β catenin signalling activation. Genes 9(11):522. https://doi.org/10.3390/genes9110522
Samano C, Nistri A (2019) Mechanism of neuroprotection against experimental spinal cord injury by riluzole or methylprednisolone. Neurochem Res 44(1):200–213. https://doi.org/10.1007/s11064-017-2459-6
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169(2):361–371. https://doi.org/10.1016/j.cell.2017.03.035
Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E (2012) Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma 29(5):946–956. https://doi.org/10.1089/neu.2011.1919
Su ZD, Niu WZ, Liu ML, Zou YH, Zhang CL (2014) In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun 5:3338. https://doi.org/10.1038/ncomms4338
Tamargo-Gomez I, Marino G (2018) AMPK: regulation of metabolic dynamics in the context of autophagy. Int J Mol Sci 19(12):3812. https://doi.org/10.3390/ijms19123812
Tang YJ, Li K, Yang CL, Huang K, Zhou J, Shi Y, Xie KG, Liu J (2019) Bisperoxovanadium protects against spinal cord injury by regulating autophagy via activation of ERK1/2 signaling. Drug Design Dev Ther 13:513–521. https://doi.org/10.2147/DDDT.S187878
Teng HF, Li PN, Hou DR, Liu SW, Lin CT, Loo MR, Kao CH, Lin KH, Chen SL (2014) Valproic acid enhances Oct4 promoter activity through PI3K/Akt/mTOR pathway activated nuclear receptors. Mol Cell Endocrinol 383(1–2):147–158. https://doi.org/10.1016/j.mce.2013.12.008
Tortoriello G, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D, Keimpema E, Botting CH, Reinecke K, Herdegen T, Courtney M, Hurd YL, Harkany T (2014) Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33(7):668–685. https://doi.org/10.1002/embj.201386035
Walker CL, Wu X, Liu NK, Xu XM (2019) Bisperoxovanadium mediates neuronal protection through inhibition of PTEN and activation of PI3K/AKT-mTOR signaling after traumatic spinal injuries. J Neurotrauma 36(18):2676–2687. https://doi.org/10.1089/neu.2018.6294
Wang J, Davis S, Zhu M, Miller EA, Ferro-Novick S (2017a) Autophagosome formation where the secretory and autophagy pathways meet. Autophagy 13(5):973–974. https://doi.org/10.1080/15548627.2017.1287657
Wang Q, Chen X, Hay N (2017b) Akt as a target for cancer therapy: more is not always better (lessons from studies in mice). Br J Cancer 117(2):159–163. https://doi.org/10.1038/bjc.2017.153
Wang YF, Liu F, Lan J, Bai J, Li XQ (2018) The effect of botulinum neurotoxin serotype a heavy chain on the growth related proteins and neurite outgrowth after spinal cord injury in rats. Toxins (Basel) 10(2):66. https://doi.org/10.3390/toxins10020066
Warner FM, Jutzeler CR, Cragg JJ, Tong B, Grassner L, Bradke F, Geisler F, Kramer JK (2019) The effect of non-gabapentinoid anticonvulsants on sensorimotor recovery after human spinal cord injury. CNS Drugs 33(5):503–511. https://doi.org/10.1007/s40263-019-00622-6
Wei Z, Zhao W, Schachner M (2018) Electroacupuncture restores locomotor functions after mouse spinal cord injury in correlation with reduction of PTEN and p53 expression. Front Mol Neurosci 11:411. https://doi.org/10.3389/fnmol.2018.00411
Wu F, Xing D, Peng Z, Rao T (2008) Enhanced rat sciatic nerve regeneration through silicon tubes implanted with valproic acid. J Reconstr Microsurg 24(4):267–276. https://doi.org/10.1055/s-2008-1078696
Wu X, Won H, Rubinsztein DC (2013) Autophagy and mammalian development. Biochem Soc Trans 41(6):1489–1494. https://doi.org/10.1042/BST20130185
Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP (2013) mTOR kinase structure, mechanism and regulation. Nature 497(7448):217–223. https://doi.org/10.1038/nature12122
Ye B, Fan C, Shen Y, Wang Q, Hu H, Xiang M (2019) The antioxidative role of autophagy in hearing loss. Front Neurosci 12:1010. https://doi.org/10.3389/fnins.2018.01010
Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, Zhang Y, Chuang DM (2013) Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood–brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury. J Neurosurg 119(3):766–773. https://doi.org/10.3171/2013.6.JNS13135
Zachari M, Ganley IG (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61(6):585–596. https://doi.org/10.1042/EBC20170021
Zeng Q, Long Z, Feng M, Zhao Y, Luo S, Wang K, Wang Y, Yang G, He G (2019) Valproic acid stimulates hippocampal neurogenesis via activating the Wnt/beta-catenin signaling pathway in the APP/PS1/Nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Front Aging Neurosci 11:62. https://doi.org/10.3389/fnagi.2019.00062
Zhang HY, Wang ZG, Wu FZ, Kong XX, Yang J, Lin BB, Zhu SP, Lin L, Gan CS, Fu XB, Li XK, Xu HZ, Xiao J (2013) Regulation of autophagy and ubiquitinated protein accumulation by bFGF promotes functional recovery and neural protection in a rat model of spinal cord injury. Mol Neurobiol 48(3):452–464. https://doi.org/10.1007/s12035-013-8432-8
Zhang HY, Wang ZG, Lu XH, Kong XX, Wu FZ, Lin L, Tan X, Ye LB, Xiao J (2015) Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases. Mol Neurobiol 51(3):1343–1352. https://doi.org/10.1007/s12035-014-8813-7
Zhang D, Wang F, Zhai X, Li XH, He XJ (2018a) Lithium promotes recovery of neurological function after spinal cord injury by inducing autophagy. Neural Regen Res 13(12):2191–2199. https://doi.org/10.4103/1673-5374.241473
Zhang L, Fan Z, Han Y, Xu L, Liu W, Bai X, Zhou M, Li J, Wang H (2018b) Valproic acid promotes survival of facial motor neurons in adult rats after facial nerve transection: a pilot study. J Mol Neurosci 64(4):512–522. https://doi.org/10.1007/s12031-018-1051-0
Zhao H, Cheng L, Du X, Hou Y, Liu Y, Cui Z, Nie L (2016) Transplantation of cerebral dopamine neurotrophic factor transducted BMSCs in contusion spinal cord injury of rats: promotion of nerve regeneration by alleviating neuroinflammation. Mol Neurobiol 53(1):187–199. https://doi.org/10.1007/s12035-014-9000-6
Zhao H, Chen S, Gao K, Zhou Z, Wang C, Shen Z, Guo Y, Li Z, Wan Z, Liu C, Mei X (2017) Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience 348:241–251. https://doi.org/10.1016/j.neuroscience.2017.02.027
Zhao X, Li Y, Lin X, Wang J, Zhao X, Xie J, Sun T, Fu Z (2018) Ozone induces autophagy in rat chondrocytes stimulated with IL-1β through the AMPK/mTOR signaling pathway. J Pain Res 11:3003–3017. https://doi.org/10.2147/JPR.S183594
Zheng B, Zhou Y, Zhang H, Yang G, Hong Z, Han D, Wang Q, He Z, Liu Y, Wu F, Zhang X, Tong S, Xu H, Xiao J (2017) Dl-3-n-butylphthalide prevents the disruption of blood-spinal cord barrier via inhibiting endoplasmic reticulum stress following spinal cord injury. Int J Biol Sci 13(12):1520–1531. https://doi.org/10.7150/ijbs.21107
Zhou K, Sansur CA, Xu H, Jia X (2017a) The temporal pattern, flux, and function of autophagy in spinal cord injury. Int J Mol Sci 18(2):466. https://doi.org/10.3390/ijms18020466
Zhou Y, Wu Y, Liu Y, He Z, Zou S, Wang Q, Li J, Zheng Z, Chen J, Wu F, Gong F, Zhang H, Xu H, Xiao J (2017b) The cross-talk between autophagy and endoplasmic reticulum stress in blood-spinal cord barrier disruption after spinal cord injury. Oncotarget 8(1):1688–1702. https://doi.org/10.18632/oncotarget.13777
Zhu S, Zhang Z, Jia LQ, Zhan KX, Wang LJ, Song N, Liu Y, Cheng YY, Yang YJ, Guan L, Min DY, Yang GL (2019) Valproic acid attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-pyroptosis pathways. Neurochem Int 124:141–151. https://doi.org/10.1016/j.neuint.2019.01.003
Funding
This work was supported by the Natural Science Foundation of Zhejiang Province (Grant No. LY19H170001).
Author information
Authors and Affiliations
Contributions
XL designed the study. CZ, SH, BOAB, YZ and XL prepared the first draft and revised the manuscript. All authors approved the final paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare absence of competing interests.
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed Consent
All authors agree to publish this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhou, C., Hu, S., Botchway, B.O.A. et al. Valproic Acid: A Potential Therapeutic for Spinal Cord Injury. Cell Mol Neurobiol 41, 1441–1452 (2021). https://doi.org/10.1007/s10571-020-00929-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-020-00929-9