Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation. Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS. EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS. This low-dose model avoided motor impairments that would confound learning and memory measurements. Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study. Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function. With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared. This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models. Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects. These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4. This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits.

多发性硬化症 (MS) 与沉重的记忆障碍相关，临床前文献表明这些障碍与神经炎症有关。以前，我们已经表明，toll​​ 样受体 4 (TLR4) 拮抗剂，如 (+)-纳曲酮 [(+)-NTX]，可阻断大鼠的神经性疼痛和相关的脊柱炎症。在这里，我们扩展了这些发现，首先证明 (+)-NTX 除 TLR4 外还阻断 TLR2。此外，我们使用 MS 的低剂量实验性自身免疫性脑脊髓炎 (EAE) 模型在两种大鼠品系中检查了 (+)-NTX 是否可以减轻学习和记忆障碍以及相关的神经炎症。EAE 是人类炎性脱髓鞘疾病 MS 最常用的实验模型。这种低剂量模型避免了会混淆学习和记忆测量的运动障碍。十四天后，开始每日皮下 (+)-NTX 或生理盐水注射，并在整个研究过程中继续进行。在第 21 天进行情境和听觉恐惧条件反射以评估海马和杏仁核功能。使用这种低剂量模型，EAE 会损害长期而非短期的情境恐惧记忆；长期和短期听觉提示的恐惧记忆都没有受到影响。这与海马白细胞介素-1β (IL-1β)、TLR2、TLR4、NLRP3 和 IL-17 的 mRNA 增加以及海马 CA1 和 DG 区小胶质细胞标记物 Iba1 的表达升高有关，证实了在高-dose EAE 模型。重要的是，(+)-NTX 完全防止了 EAE 引起的记忆障碍，并有力地减弱了相关的促炎作用。这些发现表明，(+)-NTX 可能通过阻断 TLR2/TLR4 来抑制海马中的神经炎症反应，从而对记忆功能发挥治疗作用。这项研究表明 TLR2 和 TLR4 拮抗剂可能有效治疗 MS 相关的记忆缺陷。