Abstract
The purpose of this study was to determine the dynamic changes of the Nogo-66 receptor 1 (NgR1) pathway during epileptogenesis and the potential beneficial of leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (Lingo-1) inhibition on epilepsy rats. The hippocampal changes of the NgR1 pathway during epileptogenesis were determined by western blot analysis of multiple proteins, including neurite outgrowth inhibitor protein A (NogoA), myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), Lingo-1, ras homolog family member A (RhoA) and phosphorylated RhoA (p-RhoA). Lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown the hippocampal expression of Lingo-1. Novel object recognition (NOR) test and Morris Water Maze (MWM) test were employed to determine the cognitive functions of rats. Hematoxylin and eosin (H&E) staining, protein expressions of RhoA, p-RhoA, and myelin basic protein (MBP), as well as convulsion susceptibility test were additionally performed. Our results showed that the NgR1 pathway was activated during epileptogenesis, characterized by up-regulation of NogoA, MAG, OMgp, and Lingo-1, which was especially significant at the chronic phase of epilepsy. The cognitive function, convulsion susceptibility and hippocampal neuronal survival of rats were impaired at the chronic phase of epileptogenesis but all improved by Lingo-1 inhibition; besides, the hippocampal protein expressions of p-RhoA and MBP were significantly decreased at the chronic phase of SC rats but increased after Lingo-1 inhibition. Our results demonstrated that Lingo-1 shRNA can improve epilepsy-induced cognitive impairment, which may be related with the pro-myelination and neuroprotection effects of Lingo-1 inhibition.
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References
Avanzini G, Depaulis A, Tassinari A, De Curtis M (2013) Do seizures and epileptic activity worsen epilepsy and deteriorate cognitive function? Epilepsia 54:14–21. https://doi.org/10.1111/epi.12418
Borham LE, Mahfoz AM, Ibrahim IA, Shahzad N, Lrefai AA, Labib AA, Sef BB, Alshareef A, Khan M, Milibary A (2016) The effect of some immunomodulatory and anti-inflammatory drugs on Li-pilocarpine-induced epileptic disorders in Wistar rats. Brain Res 1648:418–424. https://doi.org/10.1016/j.brainres.2016.07.046
Chen D-L, Zhang P, Lin L, Zhang H-M, Deng S-D, Wu Z-Q, Liu S-H, Wang J-Y (2014) Protective effects of bajijiasu in a rat model of Aβ25-35-induced neurotoxicity. J Ethnopharmacol 154:206–217. https://doi.org/10.1016/j.jep.2014.04.004
Collins C, Osborne LD, Guilluy C, Chen Z, O’Brien ET, Reader JS, Burridge K, Superfine R, Tzima E (2014) Haemodynamic and extracellular matrix cues regulate the mechanical phenotype and stiffness of aortic endothelial cells. Nat Commun 5:3984. https://doi.org/10.1038/ncomms4984
Dean DC III, Sojkova J, Hurley S, Kecskemeti S, Okonkwo O, Bendlin BB, Theisen F, Johnson SC, Alexander AL, Gallagher CL (2016) Alterations of myelin content in Parkinson’s disease: a cross-sectional neuroimaging study. PLoS ONE 11:e0163774. https://doi.org/10.1371/journal.pone.0163774
Drenthen GS, Fonseca Wald ELA, Backes WH, Debeij-Van Hall MHJA, Hendriksen JGM, Aldenkamp AP, Vermeulen RJ, Klinkenberg S, Jansen JFA (2019) Lower myelin-water content of the frontal lobe in childhood absence epilepsy. Epilepsia 60:1689–1696. https://doi.org/10.1111/epi.16280
Friefeld Kesselmayer R, McMillan T, Lee B, Almane D, Hermann BP, Jones JE (2020) Psychosocial and functional outcomes in young adults with childhood-onset epilepsy: a 10-year follow-up. Dev Med Child Neurol. https://doi.org/10.1111/dmcn.14477
Gao F, Gao Y, Liu Y-f, Wang L, Li Y-j (2014) Berberine exerts an anticonvulsant effect and ameliorates memory impairment and oxidative stress in a pilocarpine-induced epilepsy model in the rat. Neuropsych Dis Treat 10:2139. https://doi.org/10.2147/NDT.S73210
Hei Y, Chen R, Mao X, Wang J, Long Q, Liu W (2019) Neuregulin1 attenuates cognitive deficits and hippocampal CA1 neuronal apoptosis partly via ErbB4 receptor in a rat model of chronic cerebral hypoperfusion. Behav Brain Res 365:141–149. https://doi.org/10.1016/j.bbr.2019.02.046
Holmes GL (2015) Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17:101–116. https://doi.org/10.1684/epd.2015.0739
Kalemenev S, Zubareva O, Frolova E, Sizov V, Lavrentyeva V, Lukomskaya NY, Kim KK, Zaitsev A, Magazanik L (2015) Impairment of exploratory behavior and spatial memory in adolescent rats in lithium-pilocarpine model of temporal lobe epilepsy. Dokl Biol Sci 463:175–177. https://doi.org/10.1134/S0012496615040055
Kavroulakis E, Simos PG, Kalaitzakis G, Maris TG, Karageorgou D, Zaganas I, Panagiotakis S, Basta M, Vgontzas A, Papadaki E (2018) Myelin content changes in probable Alzheimer’s disease and mild cognitive impairment: associations with age and severity of neuropsychiatric impairment. J Magn Reson Imaging 47:1359–1372. https://doi.org/10.1002/jmri.25849
Legriel S, Azoulay E, Resche-Rigon M, Lemiale V, Mourvillier B, Kouatchet A, Troché G, Wolf M, Galliot R, Dessertaine G (2010) Functional outcome after convulsive status epilepticus. Crit Care Med 38:2295–2303. https://doi.org/10.1097/CCM.0b013e3181f859a6
Li G, Cheng H, Zhang X, Shang X, Xie H, Zhang X, Yu J, Han J (2013) Hippocampal neuron loss is correlated with cognitive deficits in SAMP8 mice. Neurol Sci 34:963–969. https://doi.org/10.1007/s10072-012-1173-z
Lopes MW, Lopes SC, Santos DB, Costa AP, Gonçalves FM, de Mello N, Prediger RD, Farina M, Walz R, Leal RB (2016) Time course evaluation of behavioral impairments in the pilocarpine model of epilepsy. Epilepsy Behav 55:92–100. https://doi.org/10.1016/j.yebeh.2015.12.001
Luo Y, Hu Q, Zhang Q, Hong S, Tang X, Cheng L, Jiang L (2015) Alterations in hippocampal myelin and oligodendrocyte precursor cells during epileptogenesis. Brain Res 1627:154–164. https://doi.org/10.1016/j.brainres.2015.09.027
Ma L, Yang F, Zhao R, Li L, Kang X, Xiao L, Jiang W (2015) Quetiapine attenuates cognitive impairment and decreases seizure susceptibility possibly through promoting myelin development in a rat model of malformations of cortical development. Brain Res 1622:443–451. https://doi.org/10.1016/j.brainres.2015.07.012
Ma T, Li B, Le Y, Xu Y, Wang F, Tian Y, Cai Q, Liu Z, Xiao L, Li H (2019) Demyelination contributes to depression comorbidity in a rat model of chronic epilepsy via dysregulation of Olig2/LINGO-1 and disturbance of calcium homeostasis. Exp Neurol 321:113034. https://doi.org/10.1016/j.expneurol.2019.113034
Marklund N, Morales D, Clausen F, Hånell A, Kiwanuka O, Pitkänen A, Gimbel DA, Philipson O, Lannfelt L, Hillered L, Strittmatter SM, McIntosh TK (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540–551. https://doi.org/10.1016/j.neuroscience.2009.06.042
Mi S, Pepinsky RB, Cadavid D (2013) Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs 27:493–503. https://doi.org/10.1007/s40263-013-0068-8
Niu H-m, Wang M-y, Ma D-l, Chen X-p, Zhang L, Li Y-l, Zhang L, Li L (2020) Epimedium flavonoids improve cognitive impairment and white matter lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/NRG1/PI3K pathway in rats. Brain Res. https://doi.org/10.1016/j.brainres.2020.146902
Song X-J, Han W, He R, Li T-Y, Xie L-L, Cheng L, Chen H-S, Jiang L (2018) Alterations of hippocampal myelin sheath and axon sprouting by status convulsion and regulating Lingo-1 expression with RNA interference in immature and adult rats. Neurochem Res 43:721–735. https://doi.org/10.1007/s11064-018-2474-2
Tan X, Tu Z, Han W, Song X, Cheng L, Chen H, Tu S, Li P, Liu W, Jiang L (2019) Anticonvulsant and neuroprotective effects of dexmedetomidine on pilocarpine-induced status epilepticus in rats using a metabolomics approach. Med Sci Monitor 25:2066. https://doi.org/10.12659/MSM.912283
Tong J, Liu W, Wang X, Han X, Hyrien O, Samadani U, Smith DH, Huang JH (2012) Inhibition of Nogo-66 receptor 1 enhances recovery of cognitive function after traumatic brain injury in mice. J Neurotraum 30(4):247–258. https://doi.org/10.1089/neu.2012.2493
VanGuilder Starkey HD, Sonntag WE, Freeman WM (2013) Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition. Eur J Neurosci 37:1643–1658. https://doi.org/10.1111/ejn.12165
Wu H-F, Cen J-S, Zhong Q, Chen L, Wang J, Deng DY, Wan Y (2013) The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127. Biomaterials 34:1686–1700. https://doi.org/10.1016/j.biomaterials.2012.11.013
Wu D, Tang X, Gu LH (2018) LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice. CNS Neurol Disord Drug Targets 16:51–64. https://doi.org/10.2174/1871527315666160915150754
Zhou W, Li W, Qu L-H, Tang J, Chen S, Rong X (2015) Relationship of plasma S100B and MBP with brain damage in preterm infants. Int J Clin Exp Med 8:16445
Zhu K-J, Li S, Xu G-Z, Liu S-Y, An N, Yang H (2013) Expression of Nogo-A signaling pathway in temporal lobe cortex from mesial temporal lobe epilepsy patients. J Third Military Med Univ 11:1076–1079
Acknowledgements
This work was supported by the grants from the National Natural Science Foundation of China (grant number 81371452) and Chongqing Municipal Planning Commission of science and Research Fund (grant number 2015XMSB000712).
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RH: conceptualization, methodology, investigation, formal analysis, visualization, and writing original draft. WH, XJS, LC, and HSC: methodology, resources, investigation, and validation. LJ: conceptualization, methodology, supervision, funding acquisition, review, and editing manuscript. All the authors have read and agreed to the published version of the manuscript.
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He, R., Han, W., Song, X. et al. Knockdown of Lingo-1 by short hairpin RNA promotes cognitive function recovery in a status convulsion model. 3 Biotech 11, 339 (2021). https://doi.org/10.1007/s13205-021-02876-8
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DOI: https://doi.org/10.1007/s13205-021-02876-8