Abstract
Minocycline, an anti-infective agent of a tetracycline derivative, is reported to improve behavioral functional recovery after cerebral ischemia via enhancing the levels of brain-derived neurotrophic factor (BDNF). However, the precise mechanisms that minocycline targets to enhance the expression of BDNF are not fully defined. In the present study, we observed the neuroprotective effect and its potential mechanisms of minocycline using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated N2a cells. We found that 50 µM minocycline protected against neuronal apoptosis induced by OGD/R injury, with increased expression ratio of Bcl-2/Bax and reduced expression of caspase-3. Interestingly, minocycline resulted in the up-regulation of only BDNF protein, not BDNF mRNA in N2a cells treated with OGD/R. Furthermore, we found that minocycline inhibited OGD/R-induced up-regulation of miR-155 targeted BDNF transcripts. Moreover, miR-155 mimic could partially abolish the neuroprotective effects of minocycline via inhibiting the levels of BDNF protein. These findings suggest that minocycline is neuroprotective against ischemic brain injury through their modulation of miR-155-mediated BDNF repression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258. https://doi.org/10.1124/pr.111.005108
Cai Z, Li S, Li S, Song F, Zhang Z, Qi G, Li T, Qiu J, Wan J, Sui H, Guo H (2016) Antagonist targeting microRNA-155 protects against lithium-pilocarpine-induced status epilepticus in C57BL/6 mice by activating brain-derived neurotrophic factor. Front Pharmacol 7:129. https://doi.org/10.3389/fphar.2016.00129
Chen SD, Yin JH, Hwang CS, Tang CM, Yang DI (2012) Anti-apoptotic and anti-oxidative mechanisms of minocycline against sphingomyelinase/ceramide neurotoxicity: implication in Alzheimer’s disease and cerebral ischemia. Free Radic Res 46(8):940–950. https://doi.org/10.3109/10715762.2012.674640
Chen SD, Wu CL, Hwang WC, Yang DI (2017) More insight into BDNF against neurodegeneration: anti-apoptosis, anti-oxidation, and suppression of autophagy. Int J Mol Sci. https://doi.org/10.3390/ijms18030545
Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Luz AP, Schiavo GL, Andrighetti MS, Scheid MG, Bolfe RP, Budni J (2017) Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid beta (1–42) in mice. Prog Neuropsychopharmacol Biol Psychiatry 77:23–31. https://doi.org/10.1016/j.pnpbp.2017.03.010
Hasan TF, Rabinstein AA, Middlebrooks EH, Haranhalli N, Silliman SL, Meschia JF, Tawk RG (2018) Diagnosis and management of acute ischemic stroke. Mayo Clin Proc 93(4):523–538. https://doi.org/10.1016/j.mayocp.2018.02.013
Jiang Y, Liu Y, Zhu C, Ma X, Ma L, Zhou L, Huang Q, Cen L, Pi R, Chen X (2015) Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice. Neurobiol Learn Mem 121:20–29. https://doi.org/10.1016/j.nlm.2015.03.003
Kim MW, Bang MS, Han TR, Ko YJ, Yoon BW, Kim JH, Kang LM, Lee KM, Kim MH (2005) Exercise increased BDNF and trkB in the contralateral hemisphere of the ischemic rat brain. Brain Res 1052(1):16–21. https://doi.org/10.1016/j.brainres.2005.05.070
Ksiazek-Winiarek D, Szpakowski P, Turniak M, Szemraj J, Glabinski A (2017) IL-17 exerts anti-apoptotic effect via miR-155-5p downregulation in experimental autoimmune encephalomyelitis. J Mol Neurosci 63(3–4):320–332. https://doi.org/10.1007/s12031-017-0981-2
Launay JM, Mouillet-Richard S, Baudry A, Pietri M, Kellermann O (2011) Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. Transl Psychiatry 1:e56. https://doi.org/10.1038/tp.2011.54
Lu Y, Xiao G, Luo W (2016) Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke. Neuroimmunomodulation 23(4):230–238. https://doi.org/10.1159/000452172
Min Y, Li H, Xu K, Huang Y, Xiao J, Wang W, Li L, Yang T, Huang L, Yang L, Jiang H, Wang Q, Zhao M, Hua H, Mei R, Li F (2017) Minocycline-suppression of early peripheral inflammation reduces hypoxia-induced neonatal brain injury. Front Neurosci 11:511. https://doi.org/10.3389/fnins.2017.00511
Moretti A, Ferrari F, Villa RF (2015) Pharmacological therapy of acute ischaemic stroke: achievements and problems. Pharmacol Ther 153:79–89. https://doi.org/10.1016/j.pharmthera.2015.06.004
Moussaddy A, Demchuk AM, Hill MD (2018) Thrombolytic therapies for ischemic stroke: triumphs and future challenges. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2017.11.010
Naderi Y, Sabetkasaei M, Parvardeh S, Zanjani TM (2017) Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat. Brain Res Bull 131:207–213. https://doi.org/10.1016/j.brainresbull.2017.04.010
Oliveira GB, Fontes Ede A Jr, de Carvalho S, da Silva JB, Fernandes LM, Oliveira MC, Prediger RD, Gomes-Leal W, Lima RR, Maia CS (2014) Minocycline mitigates motor impairments and cortical neuronal loss induced by focal ischemia in rats chronically exposed to ethanol during adolescence. Brain Res 1561:23–34. https://doi.org/10.1016/j.brainres.2014.03.005
Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23. https://doi.org/10.1038/nrn3379
Ploughman M, Windle V, MacLellan CL, White N, Dore JJ, Corbett D (2009) Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke 40(4):1490–1495. https://doi.org/10.1161/STROKEAHA.108.531806
Rueger MA, Muesken S, Walberer M, Jantzen SU, Schnakenburg K, Backes H, Graf R, Neumaier B, Hoehn M, Fink GR, Schroeter M (2012) Effects of minocycline on endogenous neural stem cells after experimental stroke. Neuroscience 215:174–183. https://doi.org/10.1016/j.neuroscience.2012.04.036
Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, Liu F, Brown WT, Li X (2010) BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 88(12):2641–2647. https://doi.org/10.1002/jnr.22416
Stonesifer C, Corey S, Ghanekar S, Diamandis Z, Acosta SA, Borlongan CV (2017) Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 158:94–131. https://doi.org/10.1016/j.pneurobio.2017.07.004
Sun YX, Yang J, Wang PY, Li YJ, Xie SY, Sun RP (2013) Cisplatin regulates SH-SY5Y cell growth through downregulation of BDNF via miR-16. Oncol Rep 30(5):2343–2349. https://doi.org/10.3892/or.2013.2731
Vanelderen P, Rouwette T, Kozicz T, Heylen R, Van Zundert J, Roubos EW, Vissers K (2013) Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model. Reg Anesth Pain Med 38(2):124–130. https://doi.org/10.1097/AAP.0b013e31827d611b
Varendi K, Kumar A, Harma MA, Andressoo JO (2014) miR-1, miR-10b, miR-155, and miR-191 are novel regulators of BDNF. Cell Mol Life Sci 71(22):4443–4456. https://doi.org/10.1007/s00018-014-1628-x
Venketasubramanian N, Yoon BW, Pandian J, Navarro JC (2017) Stroke epidemiology in south, east, and south-east Asia: a review. J Stroke 19(3):286–294. https://doi.org/10.5853/jos.2017.00234
Wei H, Sun T, Tian Y, Wang K (2017) Ginkgolide B Modulates BDNF expression in acute ischemic stroke. J Korean Neurosurg Soc 60(4):391–396. https://doi.org/10.3340/jkns.2016.1010.018
Wen Y, Zhang X, Dong L, Zhao J, Zhang C, Zhu C (2015) Acetylbritannilactone modulates microRNA-155-mediated inflammatory response in ischemic cerebral tissues. Mol Med 21:197–209. https://doi.org/10.2119/molmed.2014.00199
Wu Z, Zou X, Zhu W, Mao Y, Chen L, Zhao F (2016) Minocycline is effective in intracerebral hemorrhage by inhibition of apoptosis and autophagy. J Neurol Sci 371:88–95. https://doi.org/10.1016/j.jns.2016.10.025
Xu N, Meng H, Liu T, Feng Y, Qi Y, Zhang D, Wang H (2017) Blueberry phenolics reduce gastrointestinal infection of patients with cerebral venous thrombosis by improving depressant-induced autoimmune disorder via miR-155-mediated brain-derived neurotrophic factor. Front Pharmacol 8:853. https://doi.org/10.3389/fphar.2017.00853
Yan P, Zhu A, Liao F, Xiao Q, Kraft A, Gonzales E, Perez R, Greenberg SM, Holtzman D, Lee JM (2015) Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy. Stroke 46(6):1633–1640. https://doi.org/10.1161/STROKEAHA.115.008582
Yang Y, Salayandia VM, Thompson JF, Yang LY, Estrada EY, Yang Y (2015) Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J Neuroinflammation 12:26. https://doi.org/10.1186/s12974-015-0245-4
Ye X, Yu L, Zuo D, Zhang L, Zu J, Hu J, Tang J, Bao L, Cui C, Zhang R, Jin G, Zan K, Zhang Z, Yang X, Shi H, Zhang Z, Xiao Q, Liu Y, Xiang J, Zhang X, Cui G (2017) Activated mGluR5 protects BV2 cells against OGD/R induced cytotoxicity by modulating BDNF-TrkB pathway. Neurosci Lett 654:70–79. https://doi.org/10.1016/j.neulet.2017.06.029
Yuan L, Liu J, Dong R, Zhu J, Tao C, Zheng R, Zhu S (2016) 14,15-epoxyeicosatrienoic acid promotes production of brain derived neurotrophic factor from astrocytes and exerts neuroprotective effects during ischaemic injury. Neuropathol Appl Neurobiol 42(7):607–620. https://doi.org/10.1111/nan.12291
Zhang ZG, Chopp M (2015) Promoting brain remodeling to aid in stroke recovery. Trends Mol Med 21(9):543–548. https://doi.org/10.1016/j.molmed.2015.07.005
Zhang Y, Yao H (2017) Potential therapeutic mechanisms and tracking of transplanted stem cells: implications for stroke treatment. Stem Cells Int. https://doi.org/10.1155/2017/2707082
Zhao Y, Xiao M, He W, Cai Z (2015) Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits. Neuropsychiatr Dis Treat 11:507–516. https://doi.org/10.2147/NDT.S73836
Author information
Authors and Affiliations
Contributions
LYN and XGD designed research; LYN, HZC, and HY performed research; LYN and HY analyzed data; and LYN and XGD wrote the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Lu, Y., Huang, Z., Hua, Y. et al. Minocycline Promotes BDNF Expression of N2a Cells via Inhibition of miR-155-Mediated Repression After Oxygen-Glucose Deprivation and Reoxygenation. Cell Mol Neurobiol 38, 1305–1313 (2018). https://doi.org/10.1007/s10571-018-0599-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-018-0599-0