Parallel relationship between microglial activation and substantia nigra damage in a rotenone-induced Parkinson's disease rat model

BACKGROUND： Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson＇s disease （PD）. However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD.OBJECTIVE： To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced PD.DESIGN, TIME AND SETTING： The neuropathological experiment was performed at the School of Traditional Chinese Medicine, Capital Medical University, China, from July 2007 to July 2008. MATERIALS： Rotenone was purchased from Sigma, USA. METHODS： The Parkinson＇s model was induced by injection of a rotenone oily-emulsion （2 mg/kg daily） subcutaneously into the back of 58 male adult Wistar rats for 3-6 weeks. Another three rats served as normal controls.MAIN OUTCOME MEASURES： Neurobehavioral changes were observed and recorded following rotenone treatment. Tyrosine hydroxylase and complement receptor OX42 were separately analyzed by immunohistochemical staining within 4 weeks following stopping rotenone treatment. Rotenone content was measured using high performance liquid chromatography in the cerebellum of rats that scored 2.4-6.RESULTS： Rotenone induced a loss of dopaminergic neurons in the substantia nigra as well as microglial activation, with increased behavior scores. Dopaminergic loss was still ongoing even when rotenone was stopped. Dopaminergic neuronal degeneration in the substantia nigra was initially 6%, but was 85% at 2 weeks after scoring, and degeneration depended on activated microglia. Rotenone was detected in the cerebellum at concentrations between 78.9 μg/L and 309.6 μg/L. CONCLUSION： Nigrostriatal dopaminergic degeneration paralleled the microglial activation. Rotenone absorbed into the brain in its original form initiated pathological injury in the substantia niara of PD rats.

Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson’s disease and neuronal damage through inhibition of microglia

Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

Objective To evaluate the role of thrombin-activated microglia in the neurodegeneration of nigral dopaminergic neurons in the rat substantia nigra （SN） in vivo. Methods After stereotaxic thrombin injection into unilateral SN of rats, immunostaining, reverse transcription polymerase chain reaction （RT-PCR） and biochemical methods were used to observe tyrosine hydroxylase （TH） irnmunoreactive positive cells, microglia activation, nitric oxide （NO） amount and inducible nitricoxide synthase （iNOS） expression. Results （1） Selective damage to dopaminergic neurons was produced after thrombin injection, which was evidenced by loss of TH imrnunostaining in time-dependent manner; （2） Strong microglial activation was observed in the SN; （3） RT-PCR demonstrated the early and transient expression of neurotoxic factors iNOS mRNA in the SN. Immunofluorescence results found that thrombin induced expression of iNOS in microglia. The NO production in the thrombininjected rats was significantly higher than that of controls （P 〈 0.05）. Conclusion Thrombin intranigral injection can injure the dopaminergic neurons in the SN. Thrombin-induced microglia activation precedes dopaminergic neuron degeneration, which suggest that activation of microglia and release of NO may play important roles in dopaminergic neuronal death in the SN.

Scorpion venom heat-resistant protein decreases immunoreactivity of OX-42-positive microglia cells in MPTP-treated mice

BACKGROUND： Microglia function as the immune surveyors of the brain under normal physiologica conditions. However, microglia become activated in response to brain injuries and immunological OBJECTIVE： To explore the influence of scorpion venom （SV） heat-resistant protein on frontal cortex and hippocampal microglia cells in a mice model of Parkinson＇s disease. DESIGN, TIME AND SETTING： Randomized, controlled, cellular immunity study. The experiment was performed at the Physiology Department Laboratory in Dalian Medical University between June 2005 and July 2008. MATERIALS： Ninety-six healthy, C57B1/6 mice; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine （MPTP） from Sigma, USA; SV heat-resistant protein （Experimental Base Institute in Dalian Medical University）. The mice were randomly divided into four groups （n = 24）： normal control, negative control, model, and SV heat-resistant protein. METHODS： Mice in the model and SV heat-resistant protein groups were subcutaneously injected with MPTP （20 mg/kg） to model Parkinson＇s disease, while the normal control and negative control groups were injected with physiological saline in the neck for 8 successive days. In addition, mice in the model and normal control groups were intraperitoneally injected with physiological saline 2 hours following administration, while SV heat-resistant protein and negative control groups were injected SV heat-resistant protein （0.01 mg/kg）. MAIN OUTCOME MEASURES： lmmunoreactivity of microglia cells in MPTP-treated mice. RESULTS： Compared with normal control mice, MPTP-treated mice displayed increased OX-42 expression in the brain. However, in the SV heat-resistant protein-treated mice, OX-42 expression was decreased, compared to the model group. In the model mouse group, the number of OX-42-positive microglia was increased in the frontal cortex, caudatum, and hippocampal hilus, compared to the normal control mice （P 〈 0.01）. However, in the SV heat-resistant protein-treated mice, the number of OX-42-positive microglia significantly decreased in the frontal cortex, caudatum, and hippocampal hilus, compared to the model group （P 〈 0.01）. CONCLUSION： SV heat-resistant protein inhibited MPTP-induced microglial activation in the mouse frontal cortex and hippocampus, resulting in reduced microglial activation in the brain.

Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats:Implication for immunosuppressive therapy in Parkinson’s disease

Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium （MPP^＋）-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP^＋. Methods The rat model of PD was established by intranigral microinjection of MPP^＋. At baseline and on day 1, 3, 7, 14, 21 following MPP^＋ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 （microglia marker） in the substantia nigra （SN）. The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase （TH） positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP^＋ resulted in robust activa- tion of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP^＋ induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP^＋-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.

A STIR nucleic acid drug delivery system for stirring phenotypic switch of microglia in Parkinson’s disease treatments

Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease(PD).The regulation of neuroinflammation can reduce the severity of neurological damage to alleviate diseases.Numerous studies have shown that the phenotype switch of microglia is tightly associated with the nuclear factorκB(NF-κB)-mediated inflammatory pathway.Therefore,the small interfering RNA(siRNA)therapy for downregulating the expression of NF-κB,provides a promising therapeutic strategy for Parkinson’s disease treatments.Considering the brain delivery challenges of siRNA,a sequential targeting inflammation regulation(STIR)delivery system based on poly(amino acid)s is developed to improve the therapeutic effects of Parkinson’s disease treatments.The STIR system sequentially targets the blood–brain barrier and the microglia to enhance the effective concentration of siRNA in the targeted microglia.The results demonstrate that the STIR nanoparticles can transform microglial phenotypes and regulate brain inflammation,thus achieving neuronal recovery and abnormal aggregation ofα-synuclein protein(α-syn)reduction in the treatment of Parkinson’s disease.Herein,this STIR delivery system provides a promising therapeutic platform in PD treatments and has great potential for other neurodegenerative diseases’therapies.

Gastrodin inhibits neuroinflammation in rotenone-induced Parkinson's disease model rats

The present study showed that the latency of rats moving on a vertical grid was significantly prolonged, and the number of rats sliding down from the declined plane was increased remarkably, in rotenone-induced Parkinson＇s disease model rats compared with control rats. The moving latency recovered to normal levels, but the number of slides was significantly increased at 28 days after model establishment. The slope test is a meaningful approach to evaluate the symptoms of Parkinson＇s disease model rats treated with rotenone. In addition, loss of substantia nigral dopaminergic neurons in model rats was observed at 1 day after the model was established, and continued gradually at 14 and 28 days. The expression of tyrosine hydroxylase-positive cells was significantly increased in gastrodin-treated rats at 14 days. Significant numbers of activated microglia cells were observed in model rats at 14 and 28 days; treatment of rats with Madopar at 28 days suppressed microglial activation. Treatment of rats with gastrodin or Madopar at 28 days significantly reduced interleukin-1β expression. The loss of substantia nigral dopaminergic neurons paralleled the microglial activation in Parkinson＇s disease model rats treated with rotenone. The inflammatory factors tumor necrosis factor-a and interleukin-1β are involved in the substantia nigral damage. Gastrodin could protect dopaminergic neurons via inhibition of interteukin-1β expression and neuroinflammation in the substantia nigra.

Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson's disease

Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson＇s disease （PD）, whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflamma- tory mediator production （e.g., tumor necrosis factor-a, interleukin-1β ＆ inducible nitric oxide synthase activity）, thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflamma- tory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to β2-adrenoceptor （β2-AR） stimulation via the production of growth factors （e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor ＆ glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the β2-AR in down-regulating expression levels of the human a-synuclein gene SNCA and relative a-synuclein protein abundance. Given that a-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson＇s disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of a-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via （1） inhibiting nigral microglial activation ＆ pro-inflammatory mediator production, （2） promoting the synthesis of neurotrophic factors from midbrain astrocytes and （3） downregulating a-synuclein gene expression and protein abundance in a β2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease

Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.

The Yin-Yang of osteopontin in nervous system diseases: damage versus repair

Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in the last decade,several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion,but also increasing their survival.The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions(i.e.,multiple sclerosis,Parkinson’s,and Alzheimer’s diseases).Intriguingly,recent findings show that osteopontin is involved not only in promoting tissue damage(the Yin),but also in repair/regenerative mechanisms(the Yang),mostly triggered by the inflammatory response.These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule,which are exposed after thrombin or metalloproteases cleavages.Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions.This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases.Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.

The microglial P2Y_(6)receptor as a therapeutic target for neurodegenerative diseases

Neurodegenerative diseases are associated with chronic neuroinflammation in the brain,which can result in microglial phagocytosis of live synapses and neurons that may contribute to cognitive deficits and neuronal loss.The microglial P2Y_(6) receptor(P2Y_(6)R)is a G-protein coupled receptor,which stimulates microglial phagocytosis when activated by extracellular uridine diphosphate,released by stressed neurons.Knockout or inhibition of P2Y_(6)R can prevent neu-ronal loss in mouse models of Alzheimer’s disease(AD),Parkinson’s disease,epilepsy,neuroinflammation and aging,and prevent cognitive deficits in models of AD,epilepsy and aging.This review summarises the known roles of P2Y_(6)R in the physiology and pathology of the brain,and its potential as a therapeutic target to prevent neurodegeneration and other brain pathologies.

Possible role of microparticles in neuroimmune signaling of microglial cells

Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signaling agents.This study tested the hypothesis that MPs derived from activated microglia,which represent the mononuclear phagocyte system in the brain,could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner.Methods:Human THP-1 monocytic cells were used to model human microglia.MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured.Results:When exposed to lipopolysaccharide(LPS)or mitochondrial transcription factor A in combination with interferon(IFN)-γ,THP-1 cells released MPs.When reapplied to THP-1 cells,MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells,as well as monocyte chemoattractant protein-1.The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γplus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ.The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells.Conclusion:Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses.

蛋白酶抑制剂Lactacystin建立帕金森病大鼠模型的胶质细胞反应

目的：探讨蛋白酶抑制剂造成的蛋白酶功能损伤的帕金森病（PD）动物模型黑质区胶质细胞的病理特点.方法：将SD大鼠随机分成3组：Lactacystin组、生理盐水组及正常对照组.使用立体定向注射方法向黑质区注射Lactacystin制作PD大鼠单侧模型.采用免疫组化方法观察大鼠黑质区酪氨酸羟化酶（TH）、胶质纤维酸性蛋白（GFAP）、植物凝集素（BSI-B4）免疫阳性细胞并对其进行细胞计数及灰度分析,对黑质区的多巴胺神经元、星形胶质细胞及小胶质细胞进行分析.结果：模型组病变侧黑质区TH阳性细胞较正常组和生理盐水组明显减少（P〈0.05）,胞浆染色浅.GFAP免疫组化染色模型组灰度值较正常组及生理盐水组降低（P〈0.05）.BSI-B4免疫组化染色模型组阳性细胞均数较正常组和生理盐水明显增加（P〈0.05）;模型组灰度值较正常组及生理盐水组低（P〈0.05）.结论：泛素蛋白酶抑制剂lactacystin可导致多巴胺能神经元变性死亡,并可导致黑质区小胶质细胞增生活化与星形胶质细胞的活化.

Dopamine: an immune transmitter

The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.

Emerging role of galectin 3 in neuroinflammation and neurodegeneration

Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.

松果菊苷抑制MPTP诱导的帕金森病模型小鼠神经胶质细胞激活及其机制研究

目的探讨松果菊苷对帕金森病(Parkinson’s disease,PD)模型小鼠脑部黑质致密部小胶质细胞活化与多巴胺(dopamine,DA)神经元损伤的作用,及其对多巴胺神经元-小胶质细胞生存微环境的影响。方法①松果菊苷药效实验:采用C57BL/6雄性小鼠,随机分为空白组、模型组、阳性药组(美满霉素,30 mg·kg^-1)、松果菊苷组(20 mg·kg^-1),除空白组、模型组注射等体积生理盐水外,其余组分别腹腔注射相应药物,每日1次,连续给药至取材前停止。给药3 d后,除空白组外,各组腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP,30 mg·kg^-1),每日1次,连续7 d,分别观察各组小鼠运动行为改变,脑部小胶质细胞特异性标志物(OX-42)和酪氨酸羟化酶(TH)阳性细胞数目;②松果菊苷药效机制研究:采用C57BL/6雄性小鼠,随机分为假手术组、模型组(IgG溶液,0.2μg·μL-1)、松果菊苷组(20 mg·kg^-1)、anti-Chemokine receptor组(AntiCX3CR1,0.2μg·μL-1),假手术组脑部注射等体积生理盐水,模型组脑部注射等体积IgG溶液,松果菊苷组腹腔注射松果菊苷溶液,Anti-CX3CR1组则在每次MPTP注射前1 h,侧脑室注射Anti-CX3CR1(5μL),造模方法同①,各组分别观察CX3CR1的表达水平的改变。结果松果菊苷腹腔注射给药后,可明显改善MPTP腹腔注射模型动物运动行为状态(P<0.05,P<0.01),增加TH的表达、降低OX-42免疫荧光表达强度(P<0.05,P<0.01),明显减轻模型小鼠的小胶质细胞激活及多巴胺能神经元的损伤。West Blot结果显示,Anti-CX3CR1组脑内CX3CR1表达水平与松果菊苷组表达一致。结论松果菊苷腹腔注射给药可较明显地降低MPTP造成的多巴胺能神经元损伤,其机制可能与抑制小胶质细胞CX3CR1激活有关。

依达拉奉对脂多糖诱导的大鼠多巴胺能神经元变性保护作用的研究

目的探讨自由基清除剂依达拉奉对脂多糖(LPS)诱导的多巴胺能神经元变性的保护作用。方法18只大鼠随机分成3组:磷酸缓冲液(PBS)对照组、生理盐水+LPS组(生理盐水治疗组)和依达拉奉+LPS组(依达拉奉治疗组)。黑质内立体定向注射15μg(2μl)LPS或PBS,采用免疫组织化学方法观察注射后14d大鼠黑质酪氨酸羟化酶(TH)阳性细胞的数量以及小胶质细胞的形态学变化。结果与对照组相比,生理盐水治疗组TH阳性细胞数减少到对侧的16%(P<0.05),细胞突触也明显减少;依达拉奉治疗组TH阳性细胞数较生理盐水治疗组明显增多,为对侧的59%(P<0.05),部分突触存在。两治疗组小胶质细胞形态无明显差异。结论依达拉奉显著抑制LPS诱导的黑质多巴胺能神经元变性。

帕金森病发病与小胶质细胞老化关系的探讨

帕金森病(PD)是一种中老年常见的神经退行性病变。其发病机制可能与小胶质细胞(MI)的慢性炎症反应有关。老化的MI通过释放炎症介质导致多巴胺(DA)神经元大量死亡,帕金森病临床发病。因此澄清MI老化的原因对于了解PD发病及防治策略具有重要意义。

CX3CR1参与雷公藤内酯对MPP^+帕金森病大鼠多巴胺能神经元的保护作用

目的:探讨雷公藤内酯对1-甲基-4-苯基吡啶(MPP+)帕金森病模型大鼠的保护作用及其可能机制。方法:采用MPP+黑质内注射建立帕金森病大鼠模型。实验分为假手术组、模型组、雷公藤内酯组及其溶剂对照组,利用酪氨酸羟化酶(TH)免疫荧光强度测定多巴胺神经元存活率、小胶质细胞标记物OX-42免疫荧光强度测定小胶质细胞激活程度、Western blotting测定趋化因子受体CX3CR1表达量。结果:免疫组化结果表明,MPP+黑质内注射可使模型组OX-42免疫荧光强度增高,DA神经元进行性变性死亡。雷公藤内酯组OX-42免疫荧光强度较模型组低(P<0.01),TH阳性神经元数量较模型组多(P<0.01)。Western blotting结果提示雷公藤内酯组CX3CR1表达量较模型组低(P<0.05)。结论:雷公藤内酯对MPP+帕金森病大鼠模型具有神经保护作用,其机制可能与抑制小胶质细胞激活有关,抑制CX3CR1可能是其抑制小胶质细胞的途径之一。