CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary
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ORIGINAL ARTICLE
CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons Yong Yang 1 & Jing Wen 1 & Bixin Zheng 1 & Shaogen Wu 1 & Qingxiang Mao 1 & Lingli Liang 1 & Zhisong Li 1 & Thomas Bachmann 1 & Alex Bekker 1 & Yuan-Xiang Tao 1,2,3 Accepted: 4 September 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and timedependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder. Key Words Neuropathic pain . paclitaxel . CREB . DNMT3a.
Chemotherapeutic drug–induced peripheral neuropathic pain (CIPNP) is a common adverse effect in patients treated with anticancer drugs. Paclitaxel, a frontline chemotherapeutic agent used to treat many solid tumors, causes about 40 to 60% of CIPNP cases [1]. Its painful and distressing symptoms Yong Yang, Jing Wen and Bixin Zheng contributed equally to this work. * Yuan-Xiang Tao [email protected] 1
Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 S. Orange Ave., MSB, F-661, Newark, NJ 07103, USA
2
Department of Physiology, Pharmacology & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
3
Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
often lead to a discontinuation of antineoplastic therapy, resulting in a reduction in survival rates. Moreover, these symptoms significantly affect the quality of life of cancer survivors. Unfortunately, current treatments for CIPN
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