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
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
复制标题
镁缺乏正常化可通过抑制雌性大鼠的 TNF-α/NF-κB 信号传导来减轻与环磷酰胺诱发的膀胱炎相关的机械性异常性疼痛、抑郁样行为和记忆缺陷
DOI：
10.1186/s12974-020-01786-5
复制
发表时间：
2020-04-02
影响因子：
9.3
通讯作者：
Zhou, Xiang-Fu
中科院分区：
文献类型：
--
作者：
Chen, Jia-Liang;Zhou, Xin;Zhou, Xiang-Fu
膀胱疼痛综合征/间质性膀胱炎（BPS/IC）患者的膀胱相关疼痛症状常伴有抑郁和记忆障碍。镁缺乏会导致神经炎症，并与疼痛，抑郁和记忆缺陷有关。神经炎症参与环磷酰胺（CTX）诱导的膀胱炎的机械性异常性疼痛。补充L-苏糖酸镁（L-TAMS）可以减轻神经炎症。本研究旨在确定L-TAMS是否以及如何影响CYP诱导的膀胱炎中的机械性异常性疼痛和伴随的抑郁症状和记忆缺陷。方法采用腹腔注射环磷酰胺（50 mg/kg，隔日1次，连续3次）建立BPS/IC大鼠模型。L-TAMS在饮用水中给药（604 mg中心点kg（-1）中心点天（-1））。采用上下法，用von Frey细丝评估下腹部的机械性异常性疼痛。采用强迫游泳试验（FST）和蔗糖偏好试验（SPT）检测抑郁样行为。采用新型物体再认测验（NORT）检测短时记忆功能。用钙镁计时法测定血清和脑脊液中Mg ~（2+）浓度。免疫印迹和免疫荧光染色测量L 6-S1脊髓背角（SDH）和海马中肿瘤坏死因子-α/核因子-κ B（TNF-α/NF-κ B）、白细胞介素-1 β（IL-1 β）和N-甲基-d-天冬氨酸受体2型B亚单位（NR 2 B）的表达。结果CYP诱导的大鼠膀胱炎模型在第1次给药后第8、12、20天血清和脑脊液中游离Mg 2+含量明显降低。血清和脑脊液中镁缺乏与机械性退缩阈值、抑郁样行为和短期记忆缺陷（STMD）相关。口服L-TAMS可预防镁缺乏，减轻机械性异常性疼痛（n = 14），并使抑郁样行为（n = 10）和STMD（n = 10）正常化。L-TAMS可逆转L 6-S1 SDH或海马中TNF-α/NF-κ B信号和IL-1 β的上调。膀胱炎模型中SDH和海马中NR 2B表达的变化通过L-TAMS标准化。结论：L-TAMS通过抑制TNF-α/NF-κ B信号传导和NR 2 B表达正常化，减轻CYP诱导的膀胱炎模型中的机械性异常性疼痛、抑郁样行为和STMD。我们的研究提供了证据表明，L-TAMS可能对治疗BPS/IC患者的疼痛和共病抑郁或记忆缺陷具有治疗价值。
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 center dot kg(-1)center dot 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-alpha/nuclear factor-kappa B (TNF-alpha/NF-kappa B), interleukin-1 beta (IL-1 beta), 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-alpha/NF-kappa B signaling and IL-1 beta 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-alpha/NF-kappa B 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.