Oral Application of Magnesium-l-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling

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.

Normalization of magnesium deficiency attenuated mechanical allodynia, depressive-like behaviors, and memory deficits associated with cyclophosphamide-induced cystitis by inhibiting TNF-α/NF-κB signaling in female rats

“…Previous studies showed that magnesium deficiency in rats, induced by a Mg-depleted diet, showed hyperalgesia, which could be attenuated by supplementation with MgSO 4 [11,12]. Moreover, magnesium deficiency is also associated with the neuropathic pain produced by diabetes [10,45] and chemotherapy agents [24,46]. Although visceral pain differs a lot from neuropathic pain, our present study showed magnesium deficiency in both the serum and CSF of cystitis rats.…”

“…A previous study indicated that L-TAMS attenuated vincristine-induced allodynia via inhibition of TNF-α/ NF-κB signaling [38] in the SDH, and could restore memory deficits in spare nerve injury (SNI) rats through inhibition of TNF-α at a hippocampal level [14]. Combined with the upregulation of TNF-α/NF-κB signaling and IL-1β found in both the SDH and hippocampus of cystitis model rats, we hypothesized that oral application of L-TAMS could attenuate mechanical allodynia, memory deficits, and depressive-like behaviors through inhibition of TNF-α/NF-κB signaling and IL-1β in the SDH and hippocampus of cystitis rats.…”

“…Oral application of L-TAMS (Neurocentria Inc., USA) was used as a method of supplementing magnesium. L-TAMS was administered in drinking water (604 mg [22,24] along with 50 mg•kg −1 •day −1 of elemental magnesium over the course of the study. L-TAMS was applied over two different time periods as shown in Fig.…”

“…Previous research showed that L-TAMS could improve memory function in Alzheimer's disease (AD) through inhibition of neuroinflammation [23]. Additionally, L-TAMS was able to inhibit neuroinflammation, leading to attenuation of neuropathic pain as well as neuropathic pain-associated memory deficits [14,24]. However, no study has shown whether and how L-TAMS influences bladder-related pain and the accompanying depressive symptoms and memory deficits in BPS/IC.…”

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

“…The present work provides evidence supporting the hypothesis that induction of LTP at synapses between afferent C-fibers and dorsal horn neurons by 10 V HFS is associated with mechanical allodynia lasting for 50 days in rats (Figure S2B) and more than 35 days in mice ( Figure 4E) as well as thermal hyperalgesia for around 14 days ( Figure 1H). A microglial BDNF-dependent increase in (or sprouting of) CGRP terminals, which is found in a variety of chronic pain conditions (Christensen and Hulsebosch, 1997;Xu et al, 2017;Zheng et al, 2008), serves as a structural basis of the chronic pain. Our finding is also clinically important because chronic pain, unlike acute pain, rarely has an identifiable temporal and causal relationship with injury or disease in the body.…”