补体系统在围术期神经认知障碍中的研究进展

围术期神经认知障碍（PND）是一种常见的围术期神经系统并发症,表现为注意力不集中,学习能力下降和记忆受损,可影响患者术后短期功能恢复及预后,延长患者的住院时间。目前PND的发生机制仍存在争议。补体系统是一种生物级联反应体系,已被证实在多种神经退行性疾病的发生发展过程中起着重要作用。麻醉及手术刺激可激活中枢神经系统中的补体系统,影响神经炎症反应、突触功能、血脑屏障、血脑脊液屏障,引起或加重PND。本文章就补体系统对围术期神经认知功能的影响做一系统综述,以期为PND的潜在药物靶点和治疗提供参考。     

术后谵妄病理生理机制的研究现状

术后谵妄是各类外科术后常见的一种严重并发症。然而,关于术后谵妄的病理生理机制尚未清楚。多种机制共同参与了术后谵妄的发生发展。目前,可能涉及的机制包括缺血性脑损伤、神经递质失调和神经炎症。理解其病理生理机制有助于积极预防和治疗该并发症。本文对术后谵妄的最新机制研究进行综述,以期为临床实践和研究提供必要的参考依据。关键词:术后谵妄;缺血性脑损伤;神经递质失调;神经炎症     

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6‐hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH‐positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.     

Reducing age-dependent monocyte-derived macrophage activation contributes to the therapeutic efficacy of NADPH oxidase inhibition in spinal cord injury

ObjectiveThe average age at the time of spinal cord injury (SCI) has increased to 43 years old. Middle-aged mice (14 months old, MO) exhibit impaired recovery after SCI with age-dependent increases in reactive oxygen species (ROS) production through NADPH oxidase (NOX) along with pro-inflammatory macrophage activation. Despite these aging differences, clinical therapies are being examined in individuals regardless of age based upon preclinical data generated primarily using young animals (∼4 MO). Our objective is to test the extent to which age affects SCI treatment efficacy. Specifically, we hypothesize that the effectiveness of apocynin, a NOX inhibitor, is age-dependent in SCI.MethodsApocynin treatment (5 mg/kg) or vehicle was administered 1 and 6 h after moderate T9 contusion SCI (50kdyn IH) and then daily for 1 week to 4 and 14 MO mice. Locomotor and anatomical recovery was evaluated for 28 days. Monocyte-derived macrophage (MDM) and microglial activation and ROS production were evaluated at 3 and 28 days post-injury.ResultsApocynin improved functional and anatomical recovery in 14 but not 4 MO SCI mice. Apocynin-mediated recovery was coincident with significant reductions in MDM infiltration and MDM-ROS production in 14 MO SCI mice. Importantly, microglial activation was unaffected by treatment.ConclusionThese results indicate that apocynin exhibits age-dependent neuroprotective effects by blocking excessive neuroinflammation through NOX-mediated ROS production in MDMs. Further, these data identify age as a critical regulator for SCI treatment efficacy and indicate that pharmacologically reduced macrophage, but not microglia, activation and ROS production reverses age-associated neurological impairments.     

Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) exhibit microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Here, we report that fluoxetine, one of the most commonly prescribed antidepressants, prevents MPTP-induced degeneration of nigrostriatal DA neurons and increases striatal dopamine levels with the partial motor recovery. This was accompanied by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase; and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. Interestingly, fluoxetine was found to protect DA neuronal damage from 1-methyl-4-phenyl-pyridinium (MPP⁺) neurotoxicity in co-cultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present in vivo and in vitro findings show that fluoxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress. Therefore, we carefully propose that neuroprotection of fluoxetine might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation and microglia-derived oxidative damage.     

木樨草素对脂多糖诱导的小胶质细胞炎性反应的抑制作用

目的:以脂多糖(LPS)刺激小胶质细胞BV-2,体外模拟神经退行性疾病的炎症模型,探讨木樨草素的抗炎作用和机制。方法:采用LPS(0.1μg/mL)刺激小胶质细胞建立炎症模型,MTT法检测木樨草素对BV-2细胞的毒性作用;硝酸还原酶法检测木樨草素对LPS刺激BV-2细胞一氧化氮(NO)表达量的影响;一氧化氮合酶分型法检测木樨草素对LPS刺激BV-2细胞一氧化氮合酶(iNOS)活性的影响;Western Blot法检测木樨草素对LPS刺激BV-2细胞TLR4蛋白表达影响。结果:木樨草素低、中、高剂量及阳性药物能抑制LPS诱导的BV-2炎性反应。结论:木樨草素能够抑制小胶质细胞活化产生的炎症反应,其抗炎作用的机制可能是通过抑制TLR4信号通路而发挥效用。     

Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation

Increasing evidence suggests a role for the immune system in amyotrophic lateral sclerosis (ALS). To determine the extent of the immune activation in ALS we analyzed the expression and cellular distribution of components of innate and adaptive immunity in spinal cord (SC) and motor cortex (MCx) from patients with rapid and slow sporadic ALS and controls. High levels of mRNA and protein of classical complement pathway, C1q and C4, as well as the downstream complement components C3 and C5b-9 were found in all ALS samples. Furthermore, we found higher numbers of activated microglia, reactive astrocytes, dendritic cells (DCs) and CD8(+) T-cells in ALS than in control tissue. Rapid ALS cases had more dendritic cells than slow ALS cases, whereas slow ALS cases had more activated microglia than rapid cases. Our findings demonstrate a persistent and prominent activation of both innate and adaptive immunity in ALS. We propose a complement-driven immune response which may contribute to the progression of the inflammation and ultimately lead to even more motor neuron injury.     

Regulation of kindling epileptogenesis by hippocampal Toll‐like receptors 2

This study examined whether Toll‐like receptors 2 (TLR2) contribute to rapid kindling epileptogenesis. A TLR2 agonist, lipoteichoic acid (LTA), LTA antibody (LTA‐A), or normal saline (control) was administered daily over 3 consecutive days, unilaterally into ventral hippocampus of adult male Wistar rats. Thirty minutes after the last injection, the animals were subjected to a rapid kindling procedure. The ictogenesis was gauged by comparing afterdischarge threshold (ADT) and afterdischarge duration (ADD) before the treatments, after the treatments prior to kindling, and 24 h after kindling. Kindling progression and retention were analyzed using video recording. The results showed that before kindling, LTA produced an ADT reduction. Neither LTA nor LTA‐A affected baseline ADD. On kindling progression, LTA accelerated occurrence of generalized seizures, whereas LTA‐A delayed this effect. Treatment with LTA‐A reduced the number of secondary generalized complex partial seizures. Twenty‐four hours after kindling, the rats of both the saline and LTA groups showed increased hippocampal excitability as compared with prekindling parameters. Administration of LTA‐A prevented kindling‐induced increase of hippocampal excitability. Immunostaining revealed that LTA‐A attenuated the inflammatory response produced by seizures. These findings suggest that the activation of TLR2 in the hippocampus may facilitate limbic epileptogenesis.