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

PURPOSE: 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 factor-alpha 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 Mg2+ levels in plasma, cerebrospinal fluid and in dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg2+ 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 Mg2+, and downregulated phospho-p65, tumor necrosis factor-alpha and interleukin-1 beta exclusively in the presence of extracellular Mg2+. CONCLUSION: Estrogen decline in menopause may cause neuroinflammation by reducing intracellular Mg2+ in neurons, leading to chronic pain, memory/emotional deficits. Supplement Mg2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.

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.

BACKGROUND: Bladder-related pain symptoms in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) are often accompanied by depression and memory deficits. Magnesium deficiency contributes to neuroinflammation and is associated with pain, depression, and memory deficits. Neuroinflammation is involved in the mechanical allodynia of cyclophosphamide (CYP)-induced cystitis. Magnesium-L-Threonate (L-TAMS) supplementation can attenuate neuroinflammation. This study aimed to determine whether and how L-TAMS influences mechanical allodynia and accompanying depressive symptoms and memory deficits in CYP-induced cystitis. METHODS: Injection of CYP (50 mg/kg, intraperitoneally, every 3 days for 3 doses) was used to establish a rat model of BPS/IC. L-TAMS was administered in drinking water (604 mg·kg-1·day-1). Mechanical allodynia in the lower abdomen was assessed with von Frey filaments using the up-down method. Forced swim test (FST) and sucrose preference test (SPT) were used to measure depressive-like behaviors. Novel object recognition test (NORT) was used to detect short-term memory function. Concentrations of Mg2+ in serum and cerebrospinal fluid (CSF) were measured by calmagite chronometry. Western blot and immunofluorescence staining measured the expression of tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB), interleukin-1ß (IL-1ß), and N-methyl-D-aspartate receptor type 2B subunit (NR2B) of the N-methyl-D-aspartate receptor in the L6-S1 spinal dorsal horn (SDH) and hippocampus. RESULTS: Free Mg2+ was reduced in the serum and CSF of the CYP-induced cystitis rats on days 8, 12, and 20 after the first CYP injection. Magnesium deficiency in the serum and CSF correlated with the mechanical withdrawal threshold, depressive-like behaviors, and short-term memory deficits (STMD). Oral application of L-TAMS prevented magnesium deficiency and attenuated mechanical allodynia (n = 14) and normalized depressive-like behaviors (n = 10) and STMD (n = 10). The upregulation of TNF-α/NF-κB signaling and IL-1ß in the L6-S1 SDH or hippocampus was reversed by L-TAMS. The change in NR2B expression in the SDH and hippocampus in the cystitis model was normalized by L-TAMS. CONCLUSIONS: Normalization of magnesium deficiency by L-TAMS attenuated mechanical allodynia, depressive-like behaviors, and STMD in the CYP-induced cystitis model via inhibition of TNF-α/NF-κВ signaling and normalization of NR2B expression. Our study provides evidence that L-TAMS may have therapeutic value for treating pain and comorbid depression or memory deficits in BPS/IC patients.