Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats

Obata, Norihiko; Mizobuchi, Satoshi; Itano, Yoshitaro; Matsuoka, Yoshikazu; Kaku, Ryuji; Tomotsuka, Naoto; Morita, Kiyoshi; Kanzaki, Hirotaka; Ouchida, Mamoru; Yokoyama, Masataka

doi:10.1016/j.bbrc.2011.03.137

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…The requirement for P2X4 receptors in the release of BDNF is consistent with observations that P2X4 receptor-deficient mice have impaired microglial BDNF release, possess altered BDNF signaling in the spinal cord, and they are protected from developing mechanical allodynia following peripheral nerve injury (Ulmann et al, 2008). Indeed, there is overwhelming evidence for BDNF involvement in the initiation of central sensitization associated with neuropathic pain (Biggs et al, 2010;Lever et al, 2003;Lu et al, 2007;Obata et al, 2011). However, the previous conclusions that BDNF derived from primary afferent neurons is entirely responsible for spinal nociceptive hypersensitivity has been brought into question by evidence indicating that there is a lack of primary afferent evoked BDNF release in the spinal cord after nerve injury (Lever et al, 2003), and that eliminating BDNF from primary afferents suppresses inflammatory pain but has no effect on nerve injury-induced mechanical allodynia .…”

Section: P2x4r Activation Drives Release Of Brain-derived Neurotrophisupporting

confidence: 78%

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

2011

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One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies, to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia express several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signalling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptormediated signaling and regulation of BDNF in microglia, as well as the implications for microglianeuron interactions in the pathobiology of neuropathic pain.

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Section: P2x4r Activation Drives Release Of Brain-derived Neurotrophisupporting

confidence: 78%

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

2011

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“…Furthermore, mutation of 2GR within the TAC1prom reporter showed that, despite being able to bind GR, neither SNPGR-G nor SNPGR-T is able to contribute to the response of TAC1prom to Dex. Clues as to how this polymorphism affects TAC1 promoter GR response come from experiments that have used “decoy” oligonucleotides to manipulate the activity of promoter elements in cells (Obata et al, 2011). Using this approach activated transcription factors are sequestered away from promoter regions following transfection of “decoy” oligonucleotides.…”

Section: Discussionmentioning

confidence: 99%

Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

Hay

Shanley

Davidson

et al. 2014

Psychoneuroendocrinology

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SummaryExpression or introduction of the neuropeptide substance-P (SP; encoded by the TAC1 gene in humans and Tac1 in rodents) in the amygdala induces anxiety related behaviour in rodents. In addition, pharmacological antagonism of the main receptor of SP in humans; NK1, is anxiolytic. In the current study, we show that the Tac1 locus is up-regulated in primary rat amygdala neurones in response to activation of the glucocorticoid receptor (GR); a classic component of the stress response. Using a combination of bioinformatics, electrophoretic mobility shift assays (EMSA) and reporter plasmid magnetofection into rat primary amygdala neurones we identified a highly conserved GR response sequence (2GR) in the human TAC1 promoter that binds GR in response to dexamethasone (Dex) or forskolin. We also identified a second GR binding site in the human promoter that was polymorphic and whose T-allele is only found in Japanese and Chinese populations. We present evidence that the T-allele of SNPGR increases the activity of the TAC1 promoter through de-sequestration or de-repression of 2GR. The identification of Dex/forskolin response elements in the TAC1 promoter in amygdala neurones suggests a possible link in the chain of molecular events connecting GR activation and anxiety. In addition, the discovery of a SNP which can alter this response may have implications for our understanding of the role of regulatory variation in susceptibility to stress in specific populations.

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“…Furthermore, dysregulation of BDNF is indicated in the pathogenesis of various neurological and psychiatric diseases [1], [2]. Transcription of BDNF can be initiated from at least eight different promoters in mammals [3], [4], which underlies distinct responses to various stimulation cues [3], [5], [6]. Besides the sophisticated transcriptional regulation, alternative polyadenylation of the BDNF transcripts results in two pools of BDNF mRNAs that carry either a short or a long 3′untranslated region (UTR), regardless of which promoter drives BDNF transcription [3], [7].…”

Section: Introductionmentioning

confidence: 99%

HuD Promotes BDNF Expression in Brain Neurons via Selective Stabilization of the BDNF Long 3′UTR mRNA

et al. 2013

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Complex regulation of brain-derived neurotrophic factor (BDNF) governs its intricate functions in brain development and neuronal plasticity. Besides tight transcriptional control from multiple distinct promoters, alternative 3′end processing of the BDNF transcripts generates either a long or a short 3′untranslated region (3′UTR). Previous reports indicate that distinct RNA sequence in the BDNF 3′UTRs differentially regulates BDNF production in the brain to accommodate neuronal activity changes, conceivably through differential interactions with undefined trans-acting factors that regulate stability and translation of these BDNF mRNA isoforms. In this study, we report that the neuronal RNA-binding protein (RBP) HuD interacts with a highly conserved AU-rich element (ARE) specifically located in the BDNF long 3′UTR. Such interaction is necessary and sufficient for selective stabilization of mRNAs that contain the BDNF long 3′UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model, the BDNF long 3′UTR mRNA is increased in the hippocampal dentate granule cells (DGCs), leading to elevated expression of BDNF protein that is transported and stored in the mossy fiber (MF) terminals. Our results identify HuD as the first trans-acting factor that enhances BDNF expression specifically through the long 3′UTR and a novel mechanism that regulates BDNF protein production in selected neuronal populations by HuD abundance.

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Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats

Cited by 16 publications

References 24 publications

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

HuD Promotes BDNF Expression in Brain Neurons via Selective Stabilization of the BDNF Long 3′UTR mRNA

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