RARβ Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms

Alt, 2018, DNA double-strand breaks as drivers of neural genomic change, function, and disease, DNA Repair (Amst.), 71, 158, 10.1016/j.dnarep.2018.08.019 Amaya, 2013, Tissue injury and related mediators of pain exacerbation, Curr. Neuropharmacol., 11, 592, 10.2174/1570159X11311060003 Bajpe, 2013, The corepressor CTBP2 is a coactivator of retinoic acid receptor/retinoid X receptor in retinoic acid signaling, Mol. Cell. Biol., 33, 3343, 10.1128/MCB.01213-12 Bar-Shira, 2002, ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage, Oncogene, 21, 849, 10.1038/sj.onc.1205127 Beggs, 2012, P2X4R+ microglia drive neuropathic pain, Nat. Neurosci., 15, 1068, 10.1038/nn.3155 Borsook, 2014, Lost but making progress–Where will new analgesic drugs come from?, Sci. Transl. Med., 6, 249sr243, 10.1126/scitranslmed.3008320 Calvo, 2011, Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway, Glia, 59, 554, 10.1002/glia.21124 Chang, 1998, Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx, Science, 281, 1860, 10.1126/science.281.5384.1860 de Jager, 2011, Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial, Int. J. Geriatr. Psychiatry, 27, 592, 10.1002/gps.2758 Denk, 2016, Persistent alterations in microglial enhancers in a model of chronic pain, Cell Rep., 15, 1771, 10.1016/j.celrep.2016.04.063 Descalzi, 2015, Epigenetic mechanisms of chronic pain, Trends Neurosci., 38, 237, 10.1016/j.tins.2015.02.001 Dheen, 2005, Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia, Glia, 50, 21, 10.1002/glia.20153 Di, 2010, Transcriptional regulation of BRCA1 expression by a metabolic switch, Nat. Struct. Mol. Biol., 17, 1406, 10.1038/nsmb.1941 Dina, 2004, Integrin signaling in inflammatory and neuropathic pain in the rat, Eur. J. Neurosci., 19, 634, 10.1111/j.1460-9568.2004.03169.x Edelmayer, 2014, Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics, Biochem. Pharmacol., 87, 390, 10.1016/j.bcp.2013.11.019 Ellis, 2013, Neuroinflammation and the generation of neuropathic pain, Br. J. Anaesth., 111, 26, 10.1093/bja/aet128 Fernandes, 2007, Activation of the kinase activity of ATM by retinoic acid is required for CREB-dependent differentiation of neuroblastoma cells, J. Biol. Chem., 282, 16577, 10.1074/jbc.M609628200 Fong, 2013, The intertwined roles of transcription and repair proteins, Mol. Cell, 52, 291, 10.1016/j.molcel.2013.10.018 Gardini, 2014, Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation, EMBO J., 33, 890, 10.1002/embj.201385567 Gereau, 2014, A pain research agenda for the 21st century, J. Pain, 15, 1203 Goncalves, 2015, Neuronal RARbeta signaling modulates pten activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration, J. Neurosci., 35, 15731, 10.1523/JNEUROSCI.1339-15.2015 Goncalves, 2019, Discovery and lead optimisation of a potent, selective and orally bioavailable RARbeta agonist for the potential treatment of nerve injury, Bioorg. Med. Chem. Lett., 29, 995, 10.1016/j.bmcl.2019.02.011 Goncalves, 2019, Regulation of myelination by exosome associated retinoic acid release from NG2-positive cells, J. Neurosci., 39, 3013, 10.1523/JNEUROSCI.2922-18.2019 Goncalves, 2018, Retinoic acid synthesis by NG2 expressing cells promotes a permissive environment for axonal outgrowth, Neurobiol. Dis., 111, 70, 10.1016/j.nbd.2017.12.016 Han, 2008, Targeted mutation of EphB1 receptor prevents development of neuropathic hyperalgesia and physical dependence on morphine in mice, Mol. Pain, 4, 60, 10.1186/1744-8069-4-60 Hu, 2009, A useful transgenic mouse line for studying the development of spinal nociceptive circuits, Neurosci. Lett., 450, 211, 10.1016/j.neulet.2008.11.054 Hur, 2012, Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration, Trends Neurosci., 35, 164, 10.1016/j.tins.2011.11.002 Ichijo, 1997, Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways, Science, 275, 90, 10.1126/science.275.5296.90 Iyengar, 2017, The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine, Pain, 158, 543, 10.1097/j.pain.0000000000000831 Jensen, 2014, Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms, Lancet Neurol., 13, 924, 10.1016/S1474-4422(14)70102-4 Ji, 1999, Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity, Nat. Neurosci., 2, 1114, 10.1038/16040 Ji, 2009, MAP kinase and pain, Brain Res. Rev., 60, 135, 10.1016/j.brainresrev.2008.12.011 Jiang, 2008, ApoE promotes the proteolytic degradation of Abeta, Neuron, 58, 681, 10.1016/j.neuron.2008.04.010 Jin, 2003, p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain, J. Neurosci., 23, 4017, 10.1523/JNEUROSCI.23-10-04017.2003 Kawasaki, 2004, Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization, J. Neurosci., 24, 8310, 10.1523/JNEUROSCI.2396-04.2004 Kelley, 2017, Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage, Neural Regen. Res., 12, 72, 10.4103/1673-5374.198986 Kim, 1992, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50, 355, 10.1016/0304-3959(92)90041-9 Lefebvre, 2010, Retinoid X receptors: common heterodimerization partners with distinct functions, Trends Endocrinol. Metab., 21, 676, 10.1016/j.tem.2010.06.009 Lindsay, 2008, PML NBs (ND10) and Daxx: from nuclear structure to protein function, Front. Biosci., 13, 7132, 10.2741/3216 Madabhushi, 2015, Activity-induced DNA breaks govern the expression of neuronal early-response genes, Cell, 161, 1592, 10.1016/j.cell.2015.05.032 Maden, 2007, Retinoic acid in the development, regeneration and maintenance of the nervous system, Nat. Rev. Neurosci., 8, 755, 10.1038/nrn2212 Mano, 2017, Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease, Proc. Natl. Acad. Sci. U S A, 114, E9645, 10.1073/pnas.1707151114 Mapplebeck, 2018, Microglial P2X4R-evoked pain hypersensitivity is sexually dimorphic in rats, Pain, 159, 1752, 10.1097/j.pain.0000000000001265 Marnef, 2017, Transcription-coupled DNA double-strand break repair: active genes need special care, J. Mol. Biol., 429, 1277, 10.1016/j.jmb.2017.03.024 McDonald, 2014, Functional significance of macrophage-derived exosomes in inflammation and pain, Pain, 155, 1527, 10.1016/j.pain.2014.04.029 Meacham, 2017, Neuropathic pain: central vs. peripheral mechanisms, Curr. Pain Headache Rep., 21, 28, 10.1007/s11916-017-0629-5 Moran, 2018, Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field, Br. J. Pharmacol., 175, 2185, 10.1111/bph.14044 Noristani, 2017, RNA-seq analysis of microglia reveals time-dependent activation of specific genetic programs following spinal cord injury, Front. Mol. Neurosci., 10, 90, 10.3389/fnmol.2017.00090 Obata, 2004, MAPK activation in nociceptive neurons and pain hypersensitivity, Life Sci., 74, 2643, 10.1016/j.lfs.2004.01.007 Patil, 2011, Neuropathic pain- and glial derived neurotrophic factor-associated regulation of cadherins in spinal circuits of the dorsal horn, Pain, 152, 924, 10.1016/j.pain.2011.01.017 Puc, 2017, Physiological functions of programmed DNA breaks in signal-induced transcription, Nat. Rev. Mol. Cell Biol., 18, 471, 10.1038/nrm.2017.43 Rhinn, 2012, Retinoic acid signalling during development, Development, 139, 843, 10.1242/dev.065938 Roubert, 2017, The influence of tumor necrosis factor-alpha on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women, Oncotarget, 8, 36127, 10.18632/oncotarget.16632 Ruscheweyh, 2011, Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy, Mol. Pain, 7, 20, 10.1186/1744-8069-7-20 Sharma, 2012, Histone H2AX phosphorylation: a marker for DNA damage, Methods Mol. Biol., 920, 613, 10.1007/978-1-61779-998-3_40 Sharma, 2015, A shortcut to activity-dependent transcription, Cell, 161, 1496, 10.1016/j.cell.2015.06.009 Shiue, 2019, Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury-induced pain in rats, Pain, 160, 210, 10.1097/j.pain.0000000000001395 Song, 2008, Upregulation and redistribution of ephrinB and EphB receptor in dorsal root ganglion and spinal dorsal horn neurons after peripheral nerve injury and dorsal rhizotomy, Eur. J. Pain, 12, 1031, 10.1016/j.ejpain.2008.01.011 Song, 2005, Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats, Acta Pharmacol. Sin., 26, 789, 10.1111/j.1745-7254.2005.00123.x Su, 2015, DNA damage and repair regulate neuronal gene expression, Cell Res., 25, 993, 10.1038/cr.2015.85 Suberbielle, 2015, DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice, Nat. Commun., 6, 8897, 10.1038/ncomms9897 Takahashi, 2004, PML nuclear bodies and apoptosis, Oncogene, 23, 2819, 10.1038/sj.onc.1207533 Tang, 2014, Synaptic activity-regulated Wnt signaling in synaptic plasticity, glial function and chronic pain, CNS Neurol. Disord. Drug Targets, 13, 737, 10.2174/1871527312666131223114457 Ulmann, 2013, Involvement of P2X4 receptors in hippocampal microglial activation after status epilepticus, Glia, 61, 1306, 10.1002/glia.22516 Wahezi, 2015, Pain relief with percutaneous trochanteroplasty in a patient with bilateral trochanteric myelomatous lytic lesions, Pain Physician, 18, E57, 10.36076/ppj/2015.18.E57 Wu, 2012, Role of gap junctions in chronic pain, J. Neurosci. Res., 90, 337, 10.1002/jnr.22764 Zhang, 2017, Bioinformatics genes and pathway analysis for chronic neuropathic pain after spinal cord injury, Biomed. Res. Int., 2017, 6423021, 10.1155/2017/6423021 Zhang, 2013, WNT signaling underlies the pathogenesis of neuropathic pain in rodents, J. Clin. Invest., 123, 2268, 10.1172/JCI65364 Zhao, 2018, Effect of Wnt signaling pathway on pathogenesis and intervention of neuropathic pain, Exp. Ther. Med., 16, 3082