Marcinko Katarina, Parsons Tiffany, Lerch Jason P, Sled John G, Sakic Boris
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton.
Clin Exp Neuroimmunol. 2012 Sep;3(3):116-128. doi: 10.1111/j.1759-1961.2012.00032.x.
Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease.
A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE.
Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups.
Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.
病因不明的神经精神症状和脑萎缩是系统性红斑狼疮（SLE）常见且严重的并发症。一种与N-甲基-D-天冬氨酸（NMDA）受体NR2结合的自身抗体被认为是中枢神经系统（CNS）SLE病因中的关键因素。这一假说得到了以下证据的支持：美金刚（MEM）是一种非竞争性NMDA受体拮抗剂，在用与NR2受体上一个表位相似的肽免疫的健康小鼠中，它可预防行为功能障碍和脑病理改变。鉴于SLE是一种慢性疾病，我们目前研究了MEM对MRL/lpr小鼠的影响，该小鼠在患SLE样疾病的同时会出现行为缺陷。
使用一套广泛的行为测试和7特斯拉磁共振成像（MRI）来检查MEM（饮用水中约25毫克/千克体重）的长期治疗是否能预防这种SLE自发模型中的CNS受累情况。
尽管MEM增加了MRL/lpr小鼠对新物体的探索，但未显示出其他有益的、亚品系特异性的作用。相反，MEM对对照MRL +/+小鼠的自发活动有不利影响，并对体重增加有负面影响。同样，MRI显示MEM治疗组脑室周围结构的体积有类似增加。
持续接触MEM主要通过药理学而非自身免疫依赖机制影响身体生长、脑形态和行为。MEM治疗的MRL/lpr小鼠探索行为的亚品系特异性改善可能表明NMDA系统仅仅是复杂致病级联反应的一个组成部分。然而，很明显，长期给予MEM无法完全预防CNS SLE样综合征的发展。
