Newly Published
Pain Medicine  |   March 2017
Oral Application of Magnesium-l-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling
Author Notes
  • From the Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yet-Sen University, Guangzhou, China (T.X., X.Z., L.-J.Z., X.-H.W., X.-G.L.); Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China (D.L.); Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (H.-D.O.); Department of Anesthesiology, NYU Langone Medical Center, New York University School of Medicine, New York, New York (H.Z.); Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.-M.Z.); Department of Research and Development, NEUROCENTRIA, Fremont, California (G.L.); and Department of Pain Medicine, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China (X.-G.L.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • T.X. and D.L. contributed equally to this article.
    T.X. and D.L. contributed equally to this article.×
  • Submitted for publication July 21, 2016. Accepted for publication February 1, 2017.
    Submitted for publication July 21, 2016. Accepted for publication February 1, 2017.×
  • Research Support: Supported by grants from the National Natural Science Foundation of China, Guangdong Province, China (nos. U1201223, U8137119, and 81600955), from the Natural Science Foundation of Guangdong Province, China (no. Yq2013008), and from the Scientific Research Foundation of Guangdong Province, China (no. 2016A020215035).
    Research Support: Supported by grants from the National Natural Science Foundation of China, Guangdong Province, China (nos. U1201223, U8137119, and 81600955), from the Natural Science Foundation of Guangdong Province, China (no. Yq2013008), and from the Scientific Research Foundation of Guangdong Province, China (no. 2016A020215035).×
  • Competing Interests: Dr. G. Liu declares that he is a co-founder of NEUROCENTRIA, Fremont, California, a company whose goal is to develop drugs to treat age-dependent memory decline and Alzheimer disease. He also reports his United States patent application on magnesium-l-threonate. The other authors declare no competing interests.
    Competing Interests: Dr. G. Liu declares that he is a co-founder of NEUROCENTRIA, Fremont, California, a company whose goal is to develop drugs to treat age-dependent memory decline and Alzheimer disease. He also reports his United States patent application on magnesium-l-threonate. The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. X.-G. Liu: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yet-Sen University, Guangzhou, 510080, China. liuxg@mail.sysu.edu.cn. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   March 2017
Oral Application of Magnesium-l-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling
Anesthesiology Newly Published on March 23, 2017. doi:10.1097/ALN.0000000000001601
Anesthesiology Newly Published on March 23, 2017. doi:10.1097/ALN.0000000000001601
Abstract

Background: Antineoplastic agents, including vincristine, often induce neuropathic pain and magnesium deficiency clinically, but the causal link between them has not been determined. No drug is available for treating this form of neuropathic pain.

Methods: Injection of vincristine (0.1 mg · kg-1 · day-1, intraperitoneally, for 10 days) was used to induce nociceptive sensitization, which was accessed with von Frey hairs and the plantar tester in adult male Sprague–Dawley rats. Magnesium-l-threonate was administered through drinking water (604 mg · kg-1 · day-1). Extracellular and intracellular free Mg2+ were measured by Calmagite chromometry and flow cytometry. Molecular biologic and electrophysiologic experiments were performed to expose the underlying mechanisms.

Results: Vincristine injection induced allodynia and hyperalgesia (n = 12), activated tumor necrosis factor-α/nuclear factor-κB signaling, and reduced free Mg2+ in cerebrospinal fluid by 21.7 ± 6.3% (mean ± SD; n = 13) and in dorsal root ganglion neurons by 27 ± 6% (n = 11). Reducing Mg2+ activated tumor necrosis factor-α/nuclear factor-κB signaling in cultured dorsal root ganglion neurons. Oral application of magnesium-l-threonate prevented magnesium deficiency and attenuated both activation of tumor necrosis factor-α/nuclear factor-κB signaling and nociceptive sensitization (n = 12). Mechanistically, vincristine induced long-term potentiation at C-fiber synapses, up-regulated N-methyl-D-aspartate receptor type 2B subunit of N-methyl-d-aspartate receptor, and led to peptidergic C-fiber sprouting in spinal dorsal horn (n = 6 each). The vincristine-induced pathologic plasticity was blocked by intrathecal injection of nuclear factor-κB inhibitor (n = 6), mimicked by tumor necrosis factor-α, and substantially prevented by oral magnesium-l-threonate (n = 5).

Conclusions: Vincristine may activate tumor necrosis factor-α/nuclear factor-κB pathway by reduction of intracellular magnesium, leading to spinal pathologic plasticity and nociceptive sensitization. Oral magnesium-l-threonate that prevents the magnesium deficiency is a novel approach to prevent neuropathic pain induced by chemotherapy.