The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice

Abstract

Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood, and effective treatment is still lacking. Methods: Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aged female mice. The pain hypersensitivity, memory function and depression-like behaviors were measured with a set of behavioral tests. Western blots, immunochemistry and in situ hybridization were used to assess molecular changes. Results: Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain and memory/emotional deficits in both ovariectomized and aged female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factoralpha and interleukin-1 beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aged mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. Calcitonin gene-related peptide, a marker for peptidergic C-fibers, was upregulated in dorsal horn, which is associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg 2+ levels in plasma, cerebrospinal fluid and in dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg 2+ deficiency, but did not affect the estrogen decline in ovariectomized and aged mice. Furthermore, in cultured dorsal root ganglion neurons, estrogen at physiological concentration elevated intracellular Mg 2+ , and downregulated phospho-p65, tumor necrosis factor-alpha and interleukin-1 beta exclusively in the presence of extracellular Mg 2+ . Conclusion: Estrogen decline in menopause may cause neuroinflammation by reducing intracellular Mg 2+ in neurons, leading to chronic pain, memory/emotional deficits. Supplement Mg 2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

“… 78 Thus, both TNF-α and IL-1β may be needed for full expression of neuropathic pain. Upregulation of TNF-α in DRG neurons is also reported in vincristine- and bortezomib-induced chemical neuropathy, 29 , 79 diabetic neuropathy 80 and menopausal-induced chronic pain, 27 while blockage of TNF-α synthesis or genetic deletion of TNF receptor 1 (TNFR1) substantially prevents neuropathic pain. 75 , 81 Importantly, local application of TNF-α 70 , 82 or IL-1β 83 onto sciatic nerve at physiological concentrations in naive rats reliably induces the behavioral signs of neuropathic pain.…”

“…(1) Afferent C-fiber conducts nociceptive signals and makes synapses with second order neurons in the superficial spinal dorsal horn. 198 , 199 (2) Pathogenic factors that cause persistent pain can reliably induce the spinal LTP, such as activation of afferent C-fibers by electrical high frequency stimulation (HFS), 200 low frequency stimulation 201 or natural stimuli, 202 peripheral nerve injury, 203 , 204 tissue inflammation, 201 opioid withdrawal, 205 estrogen deficit produced by ovariotomy or aging 27 and antineoplastic agent vincristine. 29 (3) LTP-inducible HFS produces long-lasting behavioral signs of pathological pain in rodent 24 and human subjects.…”

“… 249 In consistence with the enhancement of excitatory synapses in spinal dorsal horn in neuropathic pain, we show that CGRP (a marker for peptidergic C-fiber) in spinal dorsal horn is increased in several animal models of chronic pain, including chemotherapy-induced neuropathy, 29 high frequency noxious stimulation of peripheral nerve 24 and estrogen decline produced ovariectomy and aging. 27 Importantly, the CGRP increase is paralleled with LTP at C-fiber synapses and neuropathic pain behaviors. As CGRP is colocalized with p -p65, TNF-α and IL-1β in DRG neurons, 27 the increased CGRP + C-fibers may be also resulting from neuroinflammation.…”

“… 27 Importantly, the CGRP increase is paralleled with LTP at C-fiber synapses and neuropathic pain behaviors. As CGRP is colocalized with p -p65, TNF-α and IL-1β in DRG neurons, 27 the increased CGRP + C-fibers may be also resulting from neuroinflammation.…”

“…The nociplastic pain is believed to be caused by alteration of nociceptive processing in central nervous system (CNS), 23 such as changes in cerebral activation, synaptic connectivity and even neuronal structures. However, it is worth noting note that compelling experimental and clinical evidence has demonstrated that the functional and structural plastic changes in both peripheral nerves and CNS can be produced by many pathogenic causes of chronic pain, such as activation of nociceptors by intensive noxious stimuli, 24 nerve injury, 25 , 26 internal biochemical change, including overproduction of proinflammatory cytokines, 27 , 28 and external chemical stimuli including anti-cancer agents 29 , 30 and opioids. 31 Thus, the neuroplastic change is probably a common mechanism of chronic pain ( Figure 1 ).…”