Dual HDAC/BRD4 Inhibitors Relieves Neuropathic Pain by Attenuating Inflammatory Response in Microglia After Spared Nerve Injury
Tóm tắt
Despite the effort on developing new treatments, therapy for neuropathic pain is still a clinical challenge and combination therapy regimes of two or more drugs are often needed to improve efficacy. Accumulating evidence shows an altered expression and activity of histone acetylation enzymes in chronic pain conditions and restoration of these aberrant epigenetic modifications promotes pain-relieving activity. Recent studies showed a synergistic activity in neuropathic pain models by combination of histone deacetylases (HDACs) and bromodomain and extra-terminal domain (BET) inhibitors. On these premises, the present study investigated the pharmacological profile of new dual HDAC/BRD4 inhibitors, named SUM52 and SUM35, in the spared nerve injury (SNI) model in mice as innovative strategy to simultaneously inhibit HDACs and BETs. Intranasal administration of SUM52 and SUM35 attenuated thermal and mechanical hypersensitivity in the absence of locomotor side effects. Both dual inhibitors showed a preferential interaction with BRD4-BD2 domain, and SUM52 resulted the most active compound. SUM52 reduced microglia-mediated spinal neuroinflammation in spinal cord sections of SNI mice as showed by reduction of IBA1 immunostaining, inducible nitric oxide synthase (iNOS) expression, p65 nuclear factor-κB (NF-κB) and p38 MAPK over-phosphorylation. A robust decrease of the spinal proinflammatory cytokines content (IL-6, IL-1ß) was also observed after SUM52 treatment. Present results, showing the pain-relieving activity of HDAC/BRD4 dual inhibitors, indicate that the simultaneous modulation of BET and HDAC activity by a single molecule acting as multi-target agent might represent a promise for neuropathic pain relief.
Tài liệu tham khảo
Van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155:654–62.
Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73.
Alles SRA, Smith PA. Etiology and pharmacology of neuropathic pain. Pharmacol Rev. 2018;70(2):315–47.
Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259–301.
Mathieson S, Kasch R, Maher CG, Zambelli Pinto R, McLachlan AJ, Koes BW, et al. Combination Drug therapy for the management of low back pain and sciatica: systematic review and meta-analysis. J Pain. 2019;20:1–15.
Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012;2017:CD008943.
Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015;38(4):237–46.
Polli A, Godderis L, Ghosh M, Ickmans K, Nijs J. Epigenetic and miRNA expression changes in people with pain: a systematic review. J Pain. 2020;21:763–80.
Ligon CO, Moloney RD, Greenwood-Van MB. Targeting epigenetic mechanisms for chronic pain: a valid approach for the development of novel therapeutics. J Pharmacol Exp Ther. 2016;357(1):84–93.
Odell DW. Epigenetics of pain mediators. Curr Opin Anaesthesiol. 2018;31:402–6.
Marmorstein R, Zhou MM. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol. 2014;6(7): a018762.
Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713.
Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012;149(1):214–31.
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–73.
Cui SS, Lu R, Zhang H, Wang W, Ke JJ. Suberoylanilide hydroxamic acid prevents downregulation of spinal glutamate transporter-1 and attenuates spinal nerve ligation-induced neuropathic pain behavior. NeuroReport. 2016;27(6):427–34.
Danaher RJ, Zhang L, Donley CJ, Laungani NA, Hui SE, Miller CS, et al. Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model. Mol Pain. 2018;1(14):1744806918796763.
Denk F, Huang W, Sidders B, Bithell A, Crow M, Grist J, et al. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain. 2013;154(9):1668–79.
Sanna MD, Guandalini L, Romanelli MN, Galeotti N. The new HDAC1 inhibitor LG325 ameliorates neuropathic pain in a mouse model. Pharmacol Biochem Behav. 2017;160:70–5.
Niesvizky R, Ely S, Mark T, Aggarwal S, Gabrilove JL, Wright JJ, et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer. 2011;117(2):336–42.
Vojinovic J, Damjanov N. HDAC Inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol Med. 2011;17(5–6):397–403.
He XT, Hu XF, Zhu C, Zhou KX, Zhao WJ, Zhang C, et al. Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia. J Neuroinflammation. 2020;17(1):125.
Palomés-Borrajo G, Badia J, Navarro X, Penas C. Nerve excitability and neuropathic pain is reduced by bet protein inhibition after spared nerve injury. J Pain [Internet]. 2021;22(12):1617–30. Available from: https://www.sciencedirect.com/science/article/pii/S152659002100242X. https://doi.org/10.1016/j.jpain.2021.05.005.
Sánchez-Ventura J, Amo-Aparicio J, Navarro X, Penas C. BET protein inhibition regulates cytokine production and promotes neuroprotection after spinal cord injury. J Neuroinflammation [Internet]. 2019;16(1):124. Available from: https://doi.org/10.1186/s12974-019-1511-7.
Borgonetti V, Galeotti N. Combined inhibition of histone deacetylases and BET family proteins as epigenetic therapy for nerve injury-induced neuropathic pain. Pharmacol Res [Internet]. 2021;165:105431. Available from: https://www.sciencedirect.com/science/article/pii/S1043661821000141. https://doi.org/10.1016/j.phrs.2021.105431.
Romanelli MN, Borgonetti V, Galeotti N. Dual BET/HDAC inhibition to relieve neuropathic pain: recent advances, perspectives, and future opportunities. Pharmacol Res. 2021;1:173.
Zhang S, Chen Y, Tian C, He Y, Tian Z, Wan Y, et al. Dual-target inhibitors based on BRD4: novel therapeutic approaches for cancer. Curr Med Chem. 2021;28(9):1775–95. https://doi.org/10.2174/0929867327666200610174453.
Sanna MD, Ghelardini C, Galeotti N. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia. Pain. 2015;156(7):1265–75.
McGrath JC, Lilley E. Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol. 2015;172:3189–93.
Charan J, Kantharia N. How to calculate sample size in animal studies? J Pharmacol Pharmacother. 2013;4(4):303–6.
Bortolozzi A, Castãé A, Semakova J, Santana N, Alvarado G, Cortés R, et al. Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry. 2012;17(6):612–23.
Bourquin AF, Süveges M, Pertin M, Gilliard N, Sardy S, Davison AC, et al. Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse. Pain. 2006;122(1–2):14.e1-14.e14.
Sanna MD, Les F, Lopez V, Galeotti N. Lavender (Lavandula angustifolia Mill.) essential oil alleviates neuropathic pain in mice with spared nerve injury. Front Pharmacol. 2019;10(10):472.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77–88.
Sanna MD, Borgonetti V, Galeotti N. μ opioid receptor-triggered notch-1 activation contributes to morphine tolerance: role of neuron–glia communication. Mol Neurobiol. 2019.
Borgonetti V, Governa P, Biagi M, Galeotti N. Novel therapeutic approach for the management of mood disorders: in vivo and in vitro effect of a combination of L-theanine, Melissa officinalis L. and Magnolia officinalis Rehder & E.H. Wilson. Nutrients. 2020;12(6):1803.
Sanna MD, Mello T, Masini E, Galeotti N. Activation of ERK/CREB pathway in noradrenergic neurons contributes to hypernociceptive phenotype in H4 receptor knockout mice after nerve injury. Neuropharmacology. 2018;1(128):340–50.
Mishra M, Tiwari S, Gomes AV. Protein purification and analysis: next generation western blotting techniques. Expert Rev Proteomics. 2017;14:1037–53.
Borgonetti V, Galeotti N. Fluorescence colocalization analysis of cellular distribution of MOR-1. In: Spampinato SM, editor. Opioid Receptors: Methods and Protocols [Internet]. New York, NY: Springer US; 2021. p. 27–34. Available from: https://doi.org/10.1007/978-1-0716-0884-5_3.
Sanna MD, Lucarini L, Durante M, Ghelardini C, Masini E, Galeotti N. Histamine H4 receptor agonist-induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress. Br J Pharmacol. 2017;174(1):28–40.
Borgonetti V, Governa P, Biagi M, Pellati F, Galeotti N. Zingiber officinale Roscoe rhizome extract alleviates neuropathic pain by inhibiting neuroinflammation in mice. Phytomedicine. 2020;1:78.
Maiarù M, Morgan OB, Tochiki KK, Hobbiger EJ, Rajani K, Overington DWU, et al. Complex regulation of the regulator of synaptic plasticity histone deacetylase 2 in the rodent dorsal horn after peripheral injury. J Neurochem. 2016;138(2):222–32.
Sanna MD, Galeotti N. The HDAC1/c-JUN complex is essential in the promotion of nerve injury-induced neuropathic pain through JNK signaling. Eur J Pharmacol. 2018;825:99–106.
Huang M, Zeng S, Zou Y, Shi M, Qiu Q, Xiao Y, et al. The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation. Br J Pharmacol. 2017;174(1):101–15.
Sanchez R, Meslamani J, Zhou MM. The bromodomain: from epigenome reader to druggable target. Biochim Biophys Acta Gene Regul Mech. 2014;1839:676–85.
Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci. 2018;19(3):138–52.
Guida F, de Gregorio D, Palazzo E, Ricciardi F, Boccella S, Belardo C, et al. Behavioral, biochemical and electrophysiological changes in spared nerve injury model of neuropathic pain. Int J Mol Sci [Internet]. 2020;21(9). Available from: https://www.mdpi.com/1422-0067/21/9/3396.
Wang X, Shen X, Xu Y, Xu S, Xia F, Zhu B, et al. The etiological changes of acetylation in peripheral nerve injury–induced neuropathic hypersensitivity. Mol Pain. 2018;14.
Fiskus W, Sharma S, Qi J, Valenta JA, Schaub LJ, Shah B, et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014;13(5):1142–54.
Heinemann A, Cullinane C, De Paoli-Iseppi R, Wilmott JS, Gunatilake D, Madore J, et al. Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling. Oncotarget. 2015;6(25):21507–21.
Zhao L, Okhovat JP, Hong EK, Kim YH, Wood GS. Preclinical studies support combined inhibition of BET family proteins and histone deacetylases as epigenetic therapy for cutaneous T-cell lymphoma. Neoplasia (United States). 2019;21(1):82–92.
Borgonetti V, Galeotti N. Combined inhibition of histone deacetylases and BET family proteins as epigenetic therapy for nerve injury-induced neuropathic pain. Pharmacol Res. 2021;1(165): 105431.
Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017;28:1776–87.
Proschak E, Stark H, Merk D. Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J Med Chem. 2019;62:420–44.
Borgonetti V, Governa P, Biagi M, Pellati F, Galeotti N. Zingiber officinale Roscoe rhizome extract alleviates neuropathic pain by inhibiting neuroinflammation in mice. Phytomedicine. 2020;1(78):153307.
Faivre EJ, McDaniel KF, Albert DH, Mantena SR, Plotnik JP, Wilcox D, et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature. 2020;578(7794):306–10.
Gilan O, Rioja I, Knezevic K, Bell MJ, Yeung MM, Harker NR, et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020;368(6489):387–94.
Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: symphony of glial cells. Glia. 2019;67:1017–35.
Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159(3):595–602.
Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol. 2019;94:112–20.
Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;26(9):90.
Kannan V, Brouwer N, Hanisch UK, Regen T, Eggen BJL, Boddeke HWGM, et al. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res. 2013;91(9):1133–42.
Patel AR, Patra F, Shah NP, Shukla D. Biological control of mycotoxins by probiotic lactic acid bacteria. Dynamism dairy Ind Consum demands. 2017;2015:2–4.
Patnala R, Arumugam TV, Gupta N, Dheen ST. HDAC inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke. Mol Neurobiol. 2017;54(8):6391–411.
Suh HS, Choi S, Khattar P, Choi N, Lee SC, et al. Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes. J Neuroimmune Pharmacol. 2010;5(4):521–32.
Kaminska B, Mota M, Pizzi M. Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochim Biophys Acta Mol Basis Dis. 2016;1862(3):339–51.
DeMars KM, Yang C, Castro-Rivera CI, Candelario-Jalil E. Selective degradation of BET proteins with dBET1, a proteolysis-targeting chimera, potently reduces pro-inflammatory responses in lipopolysaccharide-activated microglia. Biochem Biophys Res Commun. 2018;497(1):410–5.
Baek M, Yoo E, Choi HI, An GY, Chai JC, Lee YS, et al. The BET inhibitor attenuates the inflammatory response and cell migration in human microglial HMC3 cell line. Sci Rep. 2021;11(1):8828.
Wang H, Huang W, Liang M, Shi Y, Zhang C, Li Q, et al. (+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling. Cell Biosci. 2018;8(1):60.
Hajmirza A, Emadali A, Gauthier A, Casasnovas O, Gressin R, Callanan MB. BET family protein BRD4: an emerging actor in NFκB signaling in inflammation and cancer. Biomedicines. 2018;6:16.
Guo S, Perets N, Betzer O, Ben-Shaul S, Sheinin A, Michaelevski I, et al. Intranasal delivery of mesenchymal stem cell derived exosomes loaded with phosphatase and tensin homolog siRNA repairs complete spinal cord injury. ACS Nano. 2019;13(9):10015–28.
Borgonetti V, Galeotti N. Intranasal delivery of an antisense oligonucleotide to the RNA-binding protein HuR relieves nerve injury-induced neuropathic pain. Pain. 2021;162(5):1500–10.