Hypomethylation of nerve growth factor (NGF) promotes binding of C/EBPα and contributes to inflammatory hyperalgesia in rats

Yuan, Haiqing; Du, Shibin; Chen, Liping; Xu, Xiaoqing; Wang, Yufeng; Ji, Fuhai

doi:10.1186/s12974-020-1711-1

Cited by 21 publications

(13 citation statements)

References 36 publications

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“…In the search for new therapeutics, targeting the receptor tyrosine kinase (RTK) family has shown promise for persistent pain conditions ( 6 – 11 ). Two members of the RTK family are the leukocyte tyrosine kinase (LTK) and the anaplastic lymphoma kinase (ALK), which belong to the insulin receptor family ( 12 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

Defaye¹,

Iftinca²,

Gadotti³

et al. 2022

Journal of Clinical Investigation

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The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1 + sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non–small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.

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Section: Introductionmentioning

confidence: 99%

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

Defaye¹,

Iftinca²,

Gadotti³

et al. 2022

Journal of Clinical Investigation

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“…Recently, several studies showed that the expression of neurotrophic factors is regulated by epigenetic modifications, such as DNA methylation [11,32,33]. DNA methylation plays an important role in a variety of biological processes.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of excess high-fructose corn syrup on the DNA methylation of hippocampal neurotrophic factor in childhood and adolescence

et al. 2022

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Consumption of fructose-containing beverages such as high-fructose corn syrup (HFCS) is increasing, raising concerns about the negative effects of excessive fructose intake. A recent report indicated that excess HFCS intake impairs hippocampal function. In this study, we focused on neurotrophic factors (NFs) in the hippocampus from the viewpoint of epigenetics to clarify the adverse effects of fructose. We analyzed the effects of HFCS intake on hippocampal function in three age categories: childhood and adolescence (postnatal day (PD) 21–60), young adulthood (PD60-100), and late adulthood (PD100-140). For the experiments, male Sprague-Dawley rats were divided into three age categories, the control group was received distilled water and the HFCS group was received 20% HFCS solution for 40 days in each period. We analyzed mRNA and protein levels for qPCR and western blotting, respectively, of a hippocampal NF, brain-derived neurotrophic factor (Bdnf). HFCS consumption reduced hippocampal Bdnf mRNA and protein expressions in childhood and adolescence. Moreover, pyrosequencing assays revealed increased DNA methylation at the Bdnf promoter in childhood and adolescence. This Bdnf levels reduction may be due to hypermethylation of the promoter regions. It should be noted that this phenomenon was observed only in childhood and adolescence fructose consumption. Our results indicate that the sensitivity of the hippocampus to fructose may vary with age. This study provides insight into the adverse effects of excessive HFCS consumption on the hippocampus in children.

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“…In fact, our previous work has demonstrated that dysregulation of DNA methylation is involved in the CFA-induced in ammation model [14]. A recent study also described that hypomethylation of nerve growth factors affects In ammatory hyperalgesia in rats [39]. These studies suggested that epigenetic regulation, especially DNA methylation could contribute to in ammatory pain.…”

Section: Introductionmentioning

confidence: 93%

Integrated analysis of Transcriptomic Data Reveal AP-1 as a Potential Regulation Hub in Inflammation Induced Hyperalgesia Rat

Zhu

Wang

et al. 2020

Preprint

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Inflammation associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanism of inflammation associated chronic pain remains unclear. Complete Freund's adjuvant (CFA) induced cutaneous inflammation rat has been widely used as an inflammation-induced pain hypersensitivity model. Herein, we presented a transcriptomic profile of CFA-induced rat dorsal root ganglion via an approach targeting gene expression, DNA methylation and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs and 2670 differentially methylated regions, which are all highly associated with multiple inflammation related pathways, including NF-κB signaling pathways and IFN signaling pathways. Integrated analysis further demonstrated that AP-1 network, which may work as a regulator of inflammation response, is sophisticatedly regulated at both transcriptomic and epigenetic level. We believe our data will not only provide drug screening targets for treating chronic pain and inflammation, but also shed a light on the molecular network inflammation induced hyperalgesia.

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Hypomethylation of nerve growth factor (NGF) promotes binding of C/EBPα and contributes to inflammatory hyperalgesia in rats

Cited by 21 publications

References 36 publications

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

Differential effects of excess high-fructose corn syrup on the DNA methylation of hippocampal neurotrophic factor in childhood and adolescence

Integrated analysis of Transcriptomic Data Reveal AP-1 as a Potential Regulation Hub in Inflammation Induced Hyperalgesia Rat

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