Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches

For several decades, the treatment of central nervous system (CNS) disorders such as, for instance, Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) represented an important challenge due to the difficulty in delivering drug molecules and imaging agents to the brain. Two strategies have been developed aimed at achieving the efficient delivery of drugs to the brain: invasive (e.g., temporary osmotic Blood Brain Barrier (BBB) opening, direct local delivery of nanoparticles with encapsulated CNS drugs etc.) and noninvasive approaches. As a part of the noninvasive approach among systemic delivery of drug molecules across BBB using nanocarriers, dendrimers represent promising therapeutics agents per se or nanocarriers of CNS drugs and for gene therapies. This original review emphasizes and analyzes the use of dendrimers as promising systems in the treatment of AD and PD, ischemia/reperfusion injury, neuroinflammation including cerebral palsy, neurological injury after cardiac surgery and particularly after hypothermic circulatory arrest, and for retinal degeneration purposes.     

壳寡糖通过调控SOCS3/STAT3信号通路改善LPS诱导的小鼠神经炎症

目的 探讨壳寡糖(Chitosan oligosaccharide ,COS)对脂多糖(Lipopolysaccharide ,LPS)诱导小鼠神经炎症的改善作用及机制。方法 通过对10周龄C57BL/6N小鼠腹腔注射LPS建立神经炎症模型。动物随机分为5组,分别是：对照(CON)组、LPS组、LPS+COS低剂量(LPS+COS 50 mg/kg)组、LPS+COS中剂量(LPS+COS 100 mg/kg)组、LPS+COS高剂量(LPS+COS 200 mg/kg)组。LPS注射完毕后进行旷场实验、新物体识别、Morris水迷宫等行为学实验。处死动物后,收集脑组织,ELISA分析脑内促炎因子白细胞介素-2(IL-2)、IL-6、IL-1β、肿瘤坏死因子(TNF-α)和抗炎因子IL-4、IL-10的表达;Western blot分析脑内信号传导及转录激活蛋白(STAT3)、细胞因子信号抑制物(SOCS3)蛋白的表达水平。结果 行为学实验结果表明,COS可以改善LPS诱发的小鼠认知障碍下降等表现。ELISA结果表明,LPS组小鼠的促炎细胞因子的释放量显著增加,抗炎细胞因子的释放量显著降低;而COS灌胃可逆转这一变化趋势。Western blot结果提示,与CON组相比,LPS的STAT3磷酸化水平显著升高,同时也促进SOCS3的蛋白表达升高;而COS则显著下调这两个蛋白的表达。结论 COS可能通过抑制SOCS3/STAT3信号通路改善LPS引起的小鼠神经炎症。     

小胶质细胞对阿尔兹海默病发生发展的影响作用

阿尔兹海默病(老年性痴呆,AD)是由β淀粉样蛋白(Aβ)和微管相关蛋白(Tau)聚集形成的具有毒性作用的寡聚物而引起的老年人主要以记忆力下降和脑部形成老年斑、神经纤维缠绕为特征的神经退行性疾病. 小胶质细胞作为中枢神经系统中的固有免疫细胞,是脑内免疫监视的关键成分,发挥内源性免疫防御作用. 正常生理状态的小胶质细胞能有效吞噬和清除毒性Aβ寡聚体,阻止AD发生. 在AD病理过程中,过度激活的小胶质细胞通过补体依赖途径过度吞噬突触,导致突触丧失,同时大量释放炎症因子,促进Tau相关病理变化,对神经元造成直接损伤,导致认知功能下降. 由此可见,小胶质细胞在AD发生发展过程中起着双刃剑的作用,探明小胶质细胞的极化状态及其在AD疾病机理中的作用将为攻克AD的药物研发提供突破性思路.     

Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long‐chain polyunsaturated fatty acids (LCPUFAs) of the n‐6 and n‐3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long‐chain n‐3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) are the most widely studied endocannabinoids and are both derived from phospholipid‐bound ARA. The endocannabinoid system also has well‐established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n‐3 and n‐6 LCPUFA and the endocannabinoid system. For example, long‐term DHA and EPA supplementation reduces AEA and 2‐AG levels, with reciprocal increases in levels of the analogous endocannabinoid‐like DHA and EPA‐derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.     

Gallic acid, a histone acetyltransferase inhibitor, suppresses β-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammation

Scope: We examined the biological effect of gallic acid (GA) as a nuclear factor (NF)‐κB acetyltransferase inhibitor on microglial‐mediated β‐amyloid neurotoxicity and restorative effects on the Aβ‐induced cognitive dysfunction. Methods and results: The protective effects of GA on the survival of neuronal cells were assessed with an MTT assay and a co‐culture system. For the co‐culture experiments, both BV‐2 and primary microglia cells were treated with GA prior to Aβ stimulation, and conditioned media were transferred to Neuro‐2A cells. The mRNA and protein levels of inflammatory cytokines in both microglia and Neuro‐2A cells were assessed with real‐time polymerase chain reaction and western blotting. Inhibition of nuclear factor kappa B (NF‐κB) acetylation with GA treatment resulted in reduced cytokine production in microglia cells and protection of neuronal cells from Aβ‐induced neurotoxicity. Furthermore, we observed a restorative effect of GA on Aβ‐induced cognitive dysfunction in mice with Y‐maze and passive avoidance tests. Finally, we found that GA treatment efficiently blocked neuronal cell death by downregulating the expression of cytokines and the in vivo levels of NF‐κB acetylation. Conclusion: These results suggest that selective inhibition of NF‐κB acetylation by the histone acetyltransferase inhibitor GA is a possible therapeutic approach for alleviating the inflammatory progression of Alzheimer disease.     

Inhibition of neuroinflammation by cinnamon and its main components

Uncontrolled activation of microglia contributes to neuroinflammation, which is highly involved in the development of neurodegenerative diseases. Although cinnamon has neuro-protective properties, its capacity to inhibit neuroinflammation has not been investigated and its active compounds remain unclear. Therefore, the composition of cinnamon extract was analysed by LC–MS and the ability of cinnamon and its main constituents to inhibit neuroinflammation was evaluated using a lipopolysaccharide (LPS)-activated BV2 microglia culture system. In total, 50 μg/mL cinnamon extract decreased significantly the production and expression of nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in LPS-activated BV2 microglia. Blocking of nuclear factor-κB (NF-κB) activation was the most likely mechanism responsible for inhibition by cinnamon of neuroinflammation. Among the eight tested compounds, cinnamaldehyde had the greatest anti-neuroinflammatory capacity. Experimental results suggest that cinnamon may have a potential therapeutic effect against neurodegenerative diseases and its potent anti-neuroinflammatory capacity was primarily attributed to cinnamaldehyde.     

Aromatic‐Turmerone Attenuates LPS‐Induced Neuroinflammation and Consequent Memory Impairment by Targeting TLR4‐Dependent Signaling Pathway

Scope : Curcuma longa (turmeric) is a folk medicine in South and Southeast Asia, which has been widely used to alleviate chronic inflammation. Aromatic‐turmerone is one of the main components abundant in turmeric essential oil. However, little information is available from controlled studies regarding its biological activities and underlying molecular mechanisms against chronic inflammation in the brain. In the current study, we employed a classical LPS model to study the effect and mechanism of aromatic‐turmerone on neuroinflammation. Methods and results : The effects of aromatic‐turmerone were studied in LPS‐treated mice and BV2 cells. The cognitive function assays, protein analyses, and histological examination were performed. Oral administration of aromatic‐turmerone could reverse LPS‐induced memory disturbance and normalize glucose intake and metabolism in the brains of mice. Moreover, aromatic‐turmerone significantly limited brain damage, through inhibiting the activation of microglia and generation of inflammatory cytokines. Further study in vitro revealed that aromatic‐turmerone targeted Toll‐like receptor 4 mediated downstream signaling, and lowered the release of inflammatory mediators. Conclusion : These observations indicate that aromatic‐turmerone is effective in preventing brain damage caused by neuroinflammation and may be useful in the treatment of neuronal inflammatory diseases.