Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Physiology, China Medical University, Shenyang, China.
Behav Brain Funct. 2023 Jun 15;19(1):11. doi: 10.1186/s12993-023-00213-y.
Neuroinflammation has been identified as one of the primary pathogenic factors of neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no dedicated treatments available in clinics to alleviate neuroinflammation in NPSLE. It has been proposed that stimulating basal forebrain (BF) cholinergic neurons may provide potent anti-inflammatory effects in several inflammatory diseases, but its potential role in NPSLE remains unexplored. This study aims to investigate whether and how stimulating BF cholinergic neurons has a protective effect on NPSLE.
Optogenetic stimulation of BF cholinergic neurons significantly ameliorated olfactory dysfunction and anxiety- and depression-like phenotype in pristane induced lupus (PIL) mice. The increased expression of adhesion molecules (P-selectin and vascular cell adhesion molecule-1 (VCAM-1)), leukocyte recruitment, blood-brain barrier (BBB) leakage were significantly decreased. Notably, the brain histopathological changes, including the elevated levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), IgG deposition in the choroid plexus and lateral ventricle wall and lipofuscin accumulation in the cortical and hippocampal neurons, were also significantly attenuated. Furthermore, we confirmed the colocalization between the BF cholinergic projections and the cerebral vessels, and the expression of α7-nicotinic acetylcholine receptor (α7nAChR) on the cerebral vessels.
Our data indicate that stimulation of BF cholinergic neurons could play a neuroprotective role in the brain through its cholinergic anti-inflammatory effects on cerebral vessels. Therefore, this may be a promising preventive target for NPSLE.
神经炎症已被确定为神经精神性系统性红斑狼疮（NPSLE）的主要致病因素之一。然而，临床上尚无专门的治疗方法来缓解 NPSLE 的神经炎症。有研究提出，刺激基底前脑（BF）胆碱能神经元可能对几种炎症性疾病具有强大的抗炎作用，但它在 NPSLE 中的潜在作用仍未被探索。本研究旨在探讨刺激 BF 胆碱能神经元是否以及如何对 NPSLE 具有保护作用。
光遗传学刺激 BF 胆碱能神经元可显著改善匹鲁卡品诱导狼疮（PIL）小鼠的嗅觉功能障碍以及焦虑和抑郁样表型。黏附分子（P-选择素和血管细胞黏附分子-1（VCAM-1））的表达增加、白细胞募集、血脑屏障（BBB）渗漏明显减少。值得注意的是，脑组织病理学变化，包括促炎细胞因子（TNF-α、IL-6 和 IL-1β）水平升高、脉络丛和侧脑室壁 IgG 沉积以及皮质和海马神经元脂褐素积累，也明显减轻。此外，我们还证实了 BF 胆碱能投射与脑血管之间的共定位，以及脑血管上 α7 型烟碱型乙酰胆碱受体（α7nAChR）的表达。
我们的数据表明，刺激 BF 胆碱能神经元可能通过其对脑血管的胆碱能抗炎作用在大脑中发挥神经保护作用。因此，这可能是 NPSLE 的一个有前途的预防靶点。
