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

Abstract

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 shortterm memory function. Concentrations of Mg 2+ 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-1β (IL-1β), 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.

The causal role of magnesium deficiency in the neuroinflammation, pain hypersensitivity and memory/emotional deficits in ovariectomized and aging mice

“…Oral L-TAMS depresses the neuroin ammation in dorsal root ganglion and in spinal dorsal horn in ovariectomized and aging mice Previous works show that neuroin ammation in pain pathway, characterized by activation of TNF-α/NF-κB pathway and glial activation, play key roles in development of persistent pain induced by peripheral nerve injury [38,39], chemotherapy [18,19] and high frequency noxious stimulation [6]. We, therefore, tested if oral L-TAMS is capable of depressing the neuroin ammation in dorsal root ganglion (DRG) and spinal dorsal horn in ovariectomized and aging mice.…”

“…Previous works including ours show that chronic oral administration of magnesium-L-threonate (L-TAMS, also called MgT), which can elevate brain Mg 2+ , improves spatial learning in both naïve rats [20] and in a mouse model of Alzheimer's disease [21]. Oral L-TAMS also prevents and restores the memory de cits induced by peripheral nerve injury [22], and the chronic pain [17] and memory/emotional de cits [18,19] induced by the antineoplastic agents. A clinical trial indicates that the global cognitive ability of older adults can be improved by oral L-TAMS [23].…”

“…It has been shown that Mg 2+ de ciency contribute to many in ammation-related chronic diseases, such as hypertension, ischemic heart disease, stroke, metabolic syndrome, diabetes and colorectal cancer [60]. Our previous works show that antineoplastic agents (vincristine oxaliplatin and cyclophosphamide) induce neuroin ammation, and chronic pain, memory decline and depression-like behaviors via producing Mg 2+ de ciency [17][18][19]. In this present work we further showed that Mg 2+ de ciency did the same in animal models of menopause.…”

“…As neuroin ammation plays a key role in memory and emotional de cits in a variety of disease models, such as peripheral nerve injury [8], chemotherapy [18,19], Alzheimer disease [40], and mood depression [41,42], we next investigated if the neuroin ammation also exists in hippocampi of OVX and aging mice. We found that the p-p65, TNF-α and IL-1β in the hippocampi were signi cantly higher in both OVX and aging female mice than those in sham mice in vehicle-treated groups, and the changes were signi cantly attenuated by oral L-TAMS (Figs.…”

“…Mg 2+ de ciency also results in anxiety and depression in animals and humans [16]. Likewise, our recent works shown that Mg 2+ de ciency causes chronic pain [17] and memory/emotional de cits [18,19] by activation of tumor necrosis factor-alpha (TNF-α)/ nuclear factor-kappaB (NF-κB) pathway in the rats treated with antineoplastic agents, including vincristine and cyclophosphamide. Previous works including ours show that chronic oral administration of magnesium-L-threonate (L-TAMS, also called MgT), which can elevate brain Mg 2+ , improves spatial learning in both naïve rats [20] and in a mouse model of Alzheimer's disease [21].…”