l-Theanine attenuates cadmium-induced neurotoxicity through the inhibition of oxidative damage and tau hyperphosphorylation

Cadmium (Cd) has long been known to induce neurological degenerative disorders. We studied effects of l-theanine, one of the major amino acid components in green tea, on Cd-induced brain injury in mice. Male ICR mice were intraperitoneally injected with l-theanine (100 or 200 mg/kg/day) or saline and after one hour these mice were orally administrated with CdCl₂ (3.75–6 mg/kg). The treatment was conducted for 8 weeks. l-Theanine significantly reduced Cd level in the mouse brain and plasma. Cd-induced neuronal cell death in the mouse cortex and hippocampus were apparently inhibited by l-theanine treatment. l-Theanine also decreased the levels of malondialdehyde (MDA) and ROS, and obviously elevated the levels of glutathione (GSH) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the mouse brain. Hyperphosphorylation of tau protein is proposed to be an early event for the evolution of tau pathology, and may play an important role in Cd-induced neurodegeneration. Our results showed that l-theanine significantly suppressed Cd-induced tau protein hyperphosphorylation at Ser199, Ser202, and Ser396. Mechanism study showed that l-theanine inhibited the activation of glycogen synthase kinase-3β (GSK-3β) which contributed to the hyperphosphorylation of tau and Cd-induced cytotoxicity. Furthermore, l-theanine reduced Cd-induced cytotoxicity possibly by interfering with the Akt/mTOR signaling pathway. In conclusion, our study indicated that l-theanine protected mice against Cd-induced neurotoxicity through reducing brain Cd level and relieved oxidative damage and tau hyperphosphorylation. Our foundings provide a novel insight into the potential use of l-theanine as prophylactic and therapeutic agents for Cd-induced neurodegenerative diseases.     

Long-term effects of corticosterone on behavior,oxidative and energy metabolism of parietotemporal cerebral cortex and hippocampus of rats: comparison to intracerebroventricular streptozotocin

We studied the effect of long-term application of corticosterone (CORT) s.c. the equivalent of cortisol in rats, on behavior, oxidative and energy metabolism in brain parietotemporal cortex and hippocampus of 1-year-old male Wistar rats. The data were compared with results derived from long-term and low dose intracerebroventricular application of the diabetogenic drug streptozotocin (STZ) known to inhibit the function of the neuronal insulin receptor and generating an insulin resistant brain state. CORT reduced both working and reference memory increasingly with time and running parallel to the STZ-induced deficit. The effect of CORT on the activities of the glycolytic enzymes hexokinase, phosphofructokinase, pyruvate kinase, glyceraldehyde-3-phosphodehydrogenase, lactate dehydrogenase and, in tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase equaled in both experimental conditions and in both regions studied: significant decreases of all enzyme activities except lactate dehydrogenase which increased between three and fourfold of normal. The CORT- and STZ-induced marked fall in ATP was in the same range in the regions studied. Differences became obvious in the concentration of creatine phosphate in parietotemporal cerebral cortex showing no decrease after CORT obviously due to a different susceptibility of the CORT-receptor. It is discussed that both CORT and STZ may act on the neuronal insulin receptor in a similar way. However, further studies are needed on the gene expression of insulin and the insulin receptor and its protein levels to clarify the exact action of CORT on the neuronal insulin receptor function.     

Nrf2激活对AGEs诱导大鼠海马损伤的抗炎、抗氧化保护作用

目的 探讨核因子红系2相关因子2(nuclear factor erythroid derived 2-related factor 2,Nrf2)激活剂莱菔硫烷(sulforaphane,SFP)对糖基化终末产物(advanced glycation products,AGEs)诱导大鼠海马氧化应激损伤和炎症反应的保护作用及其机制。方法 40只Wistar大鼠被随机分为4组:生理盐水组(Control组)、SFP对照组、AGEs组和SFP组,给予AGEs组及SFP组大鼠双侧海马立体定向注射AGEs 5 μL,造成AGEs组大鼠海马损伤,Control组及SFP对照组注射等量的生理盐水作为对照; 造模前1周给予SFP组和SFP对照组大鼠5 mg· kg^-1·d^-1 SFP腹腔注射,连续4周,AGEs组及Control组则同时给予同体积的生理盐水,造模结束后3周进行Morris水迷宫实验,测定大鼠逃避潜伏期及穿越平台次数; 生化试剂盒检测大鼠海马超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)活性及丙二醛(MDA)水平; ELISA和Western blot法测定肿瘤坏死因子(TNF-α)以及白介素-1β(IL-1β)的表达水平。结果 与Control组比较,AGEs组大鼠逃避潜伏期明显延长,穿越平台次数减少; 海马氧化应激及炎症反应水平明显升高。SFP组较AGEs组逃避潜伏期显著降低、穿越平台次数明显增加; 海马组织抗氧化系统水平升高; 炎症因子表达减少。结论 SFP作为Nrf2激动剂,能改善AGEs引起的氧化应激和炎症反应,具有神经保护作用。     

Chronic mild stress in mice promotes cognitive impairment and CDK5-dependent tau hyperphosphorylation

This study was undertaken to know whether cognition deficits produced by chronic mild stress (CMS) were associated with pathological markers of Alzheimer's disease (AD). The results show that the impairment in the Morris water maze test induced by CMS correlated with an increase in CDK5-dependent phospho-tau levels and with an increase in APP processing. Mice exposed to CMS may then constitute a non-transgenic model for sporadic forms of AD.     

Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress,inflammation and apoptosis in rats

Isoniazid (INH) is among the most important anti-tuberculosis agents widely prescribed. However, its clinical use is restricted due to its severe side effects associated with neurotoxicity. The aim of the present study was to investigate the neuroprotective effects of chrysin (CR), a natural antioxidant, against INH-induced neurotoxicity in rats. The rats were treated orally with INH (400 mg/kg body weight) alone or with CR (25 and 50 mg/kg body weight) for 7 consecutive days. INH administration significantly increased brain lipid peroxidation and resulted in a significant decrease in antioxidant biomarkers including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH). INH treatment also increased levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activities of p38α mitogen-activated protein kinase (p38α MAPK) while decreasing levels of neural cell adhesion molecule (NCAM). Double immunofluorescence expressions of c-Jun N-terminal kinase (JNK) and Bcl-2 associated X protein (Bax) in brain tissues were increased after INH administration. Furthermore, INH increased mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier subunit (Gclm), glutamate cysteine ligase catalytic subunit (Gclc), NF-κB, TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6) and GFAP in rat brain tissues. Co-treatment with CR increased anti-oxidant capacity as well as regulated inflammation and apoptosis in brain. Additionally, molecular docking results showed that CR had the potential to interact with the active sites of TNF-α and NFκ-B. In conclusion, CR improved INH-induced brain oxidative damage, inflammation and apoptosis, possibly through their antioxidant properties.     

依达拉奉联合尿激酶溶栓治疗轻型急性脑梗死的疗效与安全性及对氧化应激水平的影响

目的 探讨依达拉奉联合尿激酶(UK)静脉溶栓对急性脑梗死患者的疗效、安全性以及对机体氧化应激水平的影响。方法 120例急性脑梗死患者随机分为对照组60例与观察组60例; 对照采取尿激酶溶栓治疗,观察组给予依达拉奉联合尿激酶溶栓治疗; 比较2组神经功能缺损(NIHSS)评分、日常生活(Barthel)指数、mRS评分,观察急性脑梗死溶栓效果,评价2组临床疗效和症状性颅内出血(SICH)发生率,并比较2组治疗前后血清氧化应激指标GSH-Px和ROS水平。结果 治疗24 h与7 d后对照组与观察组NHISS评分和Barthel评分无明显差异(P>0.05); 治疗7 d与14 d后对照组与观察组mRS评分无明显差异(P>0.05); 治疗24 h后对照组与观察组血管再通率无明显差异(P>0.05); 治疗28 d后观察组总有效率为85.00%,高于对照组的78.33%(P>0.05); 观察组SICH发生率为1.67%,低于对照组的6.67%(P>0.05); 治疗后2组GSH-Px水平均显著升高(P<0.05),而ROS均明显下降(P<0.05); 治疗后观察组GSH-Px水平显著高于对照组(P<0.05),而ROS显著低于对照组(P<0.05)。结论 依达拉奉联合UK治疗急性脑梗死(发病6～12 h)能取得良好疗效,能更好地改善机体氧化应激水平,较单用尿激酶溶栓的安全性更高。     

Aminoguanidine alleviated MMA-induced impairment of cognitive ability in rats by downregulating oxidative stress and inflammatory reaction

Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many “treated” patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment.     

大鼠海马注射溶血磷脂酸诱导tau蛋白高度磷酸化和凋亡研究

目的研究溶血磷脂酸(LPA)在大鼠体内对海马神经细胞tau蛋白磷酸化水平的影响和诱导神经细胞凋亡的细胞毒性作用.方法将72只SD大鼠分为实验组(n=32)、实验对照组(n=32)和对照组(n=8),利用脑立体定位技术在大鼠双侧海马微量注射溶血磷脂酸、溶剂,于注射后12、24、48和72 h各不同时间点采用免疫组化方法测定该区域神经细胞中ser202位点磷酸化tau蛋白(PS202-tau)的表达,TUNEL技术检测细胞凋亡.结果实验组LPA注射后24 h海马CA4区神经细胞中PS202-tau阳性表达到达高峰,阳性表达高于对照组和实验对照组(P＜0.05).LPA注射后48 h TUNEL阳性细胞数达高峰,每个视野中阳性细胞数多于对照组和实验对照组(P＜0.05).结论LPA在动物整体水平可诱导大鼠海马神经细胞tau蛋白高度磷酸化,并导致神经细胞发生凋亡.     

依达拉奉对癫痫大鼠脑内谷氨酸的影响

目的 探讨依达拉奉对戊四氮致痫大鼠脑中谷氨酸的影响.方法 30只成年SD大鼠随机分为对照组、癫痫组和治疗组,癫痫组和治疗组大鼠腹腔注射戊四氮60mg/kg,诱导癫痫发作.治疗组于注射戊四氮之前1h经腹腔注射依达拉奉30mg,并观察1h.然后处死大鼠取脑,应用柱前衍生HPLC-荧光法测定大鼠脑皮质谷氨酸(Glu)的含量.结果 治疗组痫性发作潜伏期、平均痫性发作等级及脑内谷氨酸含量与癫痫组相比差异均有显著性(P<0.01).结论 依达拉奉可以通过拮抗氧自由基并抑制谷氨酸的释放,在癫痫发作中发挥保护作用.     

侧脑室注射链脲佐菌素对大鼠脑内能量代谢及线粒体功能影响的研究

目的探讨侧脑室注射链脲佐菌素(streptozotocin,STZ)对大鼠脑内能量代谢及线粒体功能的影响。方法 12只SD大鼠随机分为STZ组及生理盐水组。30天后电镜下观察两组大鼠海马及额顶颞皮层,并检测线粒体呼吸链复合物Ⅱ和Ⅳ、Na+ -K+ -ATP酶、活性,及三磷酸腺苷(adenosine triphosphate,ATP)、二磷酸腺苷(adeno- sine diphosphate,ADP)的浓度。结果 STZ组海马及额顶颢皮层电镜下有明显改变,ATP浓度、ATP/ADP比值及线粒体功能降低明显(P>0．05),ADP浓度升高明显(P>0．05)。结论侧脑室注射STZ引起能量代谢明显异常及线粒体活性的下降并有神经细胞受损。     

The effect of Zn(II) and streptozotocin administration in the mouse brain

Streptozotocin is a natural antibiotic produced by Streptomyces achromogenes able to induce diabetes in experimental animals. Among various toxic properties, streptozotocin is a potent source for reactive oxygen species. In this paper, we report the biological response of brain, upon treatment with streptozotocin in terms of metal ions dismetabolism and metallothionein expression. In addition, important information on the preventive effect of zinc in eliciting the pharmacological effect of the drug are reported, in relation to the effective role of the metal ions in inducing metallothionein synthesis. In the brain, streptozotocin treatment affects mostly the hippocampus and cerebellum as shown by a high GAFP and MT-I-II immunopositivity of glial cells. The Zn pre-treatment reduces significantly, as a general effect, the occurrence of hyperglycaemic status. At the brain level, the observed astrocytosis is strongly reduced. The high inducibility of MT represents a rapid and convenient response able to prevent the deleterious effects consequent to the oxidative stress. All together these results support the efficacy of the Zn treatment in order to prevent streptozotocin effects, including brain tissues.     

氧化应激及黑色素对神经细胞铁蛋白mRNA表达的影响

目的 探讨神经黑色素(NM)对神经元和神经胶质细胞在氧化应激状态下铁蛋白mRNA表达的影响. 方法 采用人类神经母细胞瘤细胞株(SK-N-SH)和人类胶质母细胞瘤细胞株(U373)作为神经元和神经胶质细胞模型,以Fenton试剂(FR)诱导氧化应激后分别加入NM或多巴胺黑色素(DAM),同时将铁螯合剂去铁胺(DFO)处理过的细胞作为对照,Q-PCR检测各组铁蛋白mRNA的表达. 结果 FR、FR+DAM处理后SK-N-SH细胞铁蛋白mRNA的表达高于空白对照组,FR+DAM组铁蛋白mRNA表达高于FR+NM组,差异均有统计学意义(P＜0.05);与DFO未处理组比较,FR、NM、FR+NM、DAM组中相对应的DFO处理组铁蛋白mRNA的表达均明显降低,差异有统计学意义(P＜0.05); FR、NM、DAM、FR+NM和FR+DAM处理后U373细胞铁蛋白mRNA的表达无明显变化,DFO处理组与相应的DFO未处理组比较铁蛋白mRNA的表达也无明显变化,差异无统计学意义(P＞0.05). 结论 铁蛋白对细胞有保护作用,DAM不能模拟NM制作PD模型.     

氧化应激与认知功能障碍的研究进展

氧化应激（Oxidative Stress）不仅在糖尿病、高血压病等身心疾病中起着重要作用,而且对阿尔茨海默病（AlzheimerDisease,AD）、帕金森病（Parkin-son Disease,PD）等神经精神障碍的认知功能也有一定影响。强烈或持续性的氧化应激可通过诱导细胞凋亡和炎性反应导致细胞、组织损害。流行病学及动物研究均表明,母孕期遭受应激可能会影响胎儿的神经心理发育过程,造成胎儿大脑某区域的缺陷,引起持续性认知改变、神经内分泌和行为反应,增加后代精神疾病的患病风险。现对氧化应激与认知功能障碍的机制进行综述。     

慢性不可预见性温和应激后大鼠行为及微管相关蛋白tau磷酸化的改变

目的研究慢性不可预见性温和应激所致的动物行为学改变及微管相关蛋白tau磷酸化的改变。方法将大鼠随机分为慢性不可预见性温和应激抑郁（CUMS）组和对照组,对模型组大鼠进行连续21d的慢性不可预见性应激。进行行为学观察,使用western blotting检测总tau,tau磷酸化（Ser356,Thr231）水平的改变。结果CUMS组大鼠慢性应激后糖水偏好及自主活动显著减低,与对照组比较差异有统计学意义（P〈0．05）;CUMS组大鼠慢性应激后海马tau磷酸化表达升高,与对照组比较差异有统计学意义（P〈0．05）。结论慢性应激后微管相关蛋白tau磷酸化水平升高,神经可塑性受损,提示了新的抑郁症和阿尔茨海默病联系的生化机制。     

Arbutin reduces cognitive deficit and oxidative stress in animal model of Alzheimer's disease

Abstract

Objectives: Recent evidences have shown the beneficial effects of natural products for treating of Alzheimer's disease (AD). Arbutin is derived from Pyrus biossieriana and exerts a wide range of pharmacological activities including anti-inflammatory and anti-oxidant effects. The present study was designed to examine the protective effects of arbutin on streptozotocin (STZ)-induced neurotoxicity in rats.

Materials and methods: The spatial memory impairment was induced by intracerebroventricular (i.c.v) microinjection of STZ (3?mg/kg, 10?μL). Animals received the pretreatment of arbutin (50?mg/kg) for 21?days before STZ injection. The Morris Water maze (MWM) task was used to study the spatial learning and memory. The levels of oxidative stress markers including malondialdehyde (MDA), nitrite and carbonyl were measured in serum and hippocampus samples. In addition, antioxidant level was assessed by ferric reducing antioxidant power (FRAP) test.

Results: The obtained result indicated that administration of STZ is led to memory impairment and increases the levels of oxidative stress markers in the hippocampus tissues. Conversely, arbutin improves spatial memory and reduces oxidative and nitrosative stress, as evidenced by a significant decrease in the amount of MDA and nitrite in the serum and hippocampus. In addition, an increase in FRAP levels of hippocampus was observed in arbutin receiving animals. The protein carbonyl content was not reduced in arbutin receiving animals.

Conclusion: It could be concluded that arbutin protects the brain against STZ-induced memory impairment and oxidative damage in the hippocampus. The neuroprotective effect of arbutin might be mediated through its antioxidant and free radical scavenging effects.     

Edaravone attenuates intracerebroventricular streptozotocin‐induced cognitive impairment in rats

Alzheimer's disease is a major cause of dementia worldwide. Edaravone, a potent free radical scavenger, is reported to be neuroprotective. The present study was designed to investigate the effect of chronic edaravone administration on intracerebroventricular‐streptozotocin (ICV‐STZ) induced cognitive impairment in male Wistar rats. Cognitive impairment was developed by single ICV‐STZ (3 mg/kg) injection bilaterally on day 1. Edaravone (1, 3 and 10 mg/kg, orally, once daily) was administered for 28 days. Morris water maze and passive avoidance tests were used to assess cognitive functions at baseline and on days 14 and 28. ICV‐STZ caused cognitive impairment as evidenced by increased escape latency and decreased time spent in target quadrant in the Morris water maze test and reduced retention latency in the passive avoidance test. STZ caused increase in oxidative stress, cholinesterases, inflammatory cytokines and protein expression of ROCK‐II and decrease in protein expression of ChAT. Edaravone ameliorated the STZ‐induced cognitive impairment. STZ‐induced increase in oxidative stress and increased levels of pro‐inflammatory cytokines (TNF‐α, IL‐1β) were mitigated by edaravone. Edaravone also prevented STZ‐induced increased protein expression of ROCK‐II. Moreover, edaravone significantly prevented STZ‐induced increased activity of cholinesterases in the cortex and hippocampus. The decreased expression of ChAT caused by STZ was brought towards normal by edaravone in the hippocampus. The results thus show that edaravone is protective against STZ‐induced cognitive impairment, oxidative stress, cholinergic dysfunction and altered protein expressions. This study thus suggests the potential of edaravone as an adjuvant in the treatment of Alzheimer's disease.     

Puerarin attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice

Puerarin (PUE), an isoflavone purified from the root of Pueraria lobata (Chinese herb), has been reported to attenuate learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). In the present study, we tested PUE in a sporadic AD (SAD) mouse model which was induced by the intracerebroventricular injection of streptozotocin (STZ). The mice were administrated PUE (25, 50, or 100 mg/kg/d) for 28 days. Learning and memory abilities were assessed by the Morris water maze test. After behavioral test, the biochemical parameters of oxidative stress (glutathione peroxidase (GSH-Px), superoxide dismutases (SOD), and malondialdehyde (MDA)) were measured in the cerebral cortex and hippocampus. The SAD mice exhibited significantly decreased learning and memory ability, while PUE attenuated these impairments. The activities of GSH-Px and SOD were decreased while MDA was increased in the SAD animals. After PUE treatment, the activities of GSH-Px and SOD were elevated, and the level of MDA was decreased. The middle dose PUE was more effective than others. These results indicate that PUE attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. PUE may be a promising therapeutic agent for SAD.     

依达拉奉对脂多糖诱导的PD大鼠模型神经保护作用的实验研究

目的 研究依达拉奉对脂多糖(LPS)诱导的帕金森病(PD)大鼠模型的保护作用及机制.方法 大鼠黑质内立体定向注射14μg LPS建立PD大鼠模型.选取造模成功PD大鼠24只,随机分成大、小剂量组和未治疗组.3组大鼠分别接受不同剂量的依达拉奉注射液(5.0mg/kg,1.0mg/kg)或生理盐水;另外选取正常大鼠5只,作为正常对照组.注射4w后观察各组大鼠黑质酪氨酸羟化酶(TH)阳性细胞的数量以及超氧化物歧化酶(SOD)及丙二醛(MDA)表达变化.结果 与未治疗组相比,依达拉奉大、小剂量组TH阳性细胞数显著增多,SOD表达也明显增多(P＜0.05),MDA表达明显减少(P＜0.05).结论 依达拉奉可能通过减少LPS诱导的自由基产生而对PD大鼠发挥神经保护作用.     

The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis

The cognitive impairment caused by Alzheimer’s disease (AD) is associated with beta-amyloid (Aβ) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1β, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38α MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3β and p38α MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1β secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.