Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Evaluating the role of large language models in inflammatory bowel disease patient information

This letter evaluates the article by Gravina et al on ChatGPT’s potential in providing medical information for inflammatory bowel disease patients.While promising,it highlights the need for advanced techniques like reasoning+action and retrieval-augmented generation to improve accuracy and reliability.Emphasizing that simple question and answer testing is insufficient,it calls for more nuanced evaluation methods to truly gauge large language models’capabilities in clinical applications.

Cell reprogramming therapy for Parkinson’s disease

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

May ChatGPT be a tool producing medical information for common inflammatory bowel disease patients’questions?An evidencecontrolled analysis

Artificial intelligence is increasingly entering everyday healthcare.Large language model(LLM)systems such as Chat Generative Pre-trained Transformer(ChatGPT)have become potentially accessible to everyone,including patients with inflammatory bowel diseases(IBD).However,significant ethical issues and pitfalls exist in innovative LLM tools.The hype generated by such systems may lead to unweighted patient trust in these systems.Therefore,it is necessary to understand whether LLMs(trendy ones,such as ChatGPT)can produce plausible medical information(MI)for patients.This review examined ChatGPT’s potential to provide MI regarding questions commonly addressed by patients with IBD to their gastroenterologists.From the review of the outputs provided by ChatGPT,this tool showed some attractive potential while having significant limitations in updating and detailing information and providing inaccurate information in some cases.Further studies and refinement of the ChatGPT,possibly aligning the outputs with the leading medical evidence provided by reliable databases,are needed.

Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer’s disease mice

Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation,leading to brain lesions and cognitive impairment,numerous studies have aimed to reduce Aβaggregation and slow AD progression.The diphenylalanine(FF)sequence is critical for amyloid aggregation,and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings.In this study,we examined the effects of a moderate-intensity rotating magnetic field(RMF)on Aβaggregation and AD pathogenesis.Results indicated that the RMF directly inhibited Aβamyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro.Using the AD mouse model APP/PS1,RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments,including exploration and spatial and non-spatial memory abilities.Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation,attenuated microglial activation,and reduced oxidative stress in the APP/PS1 mouse brain.These findings suggest that RMF holds considerable potential as a non-invasive,high-penetration physical approach for AD treatment.

Exploring the role of N-acetyltransferases in diseases:a focus on N-acetyltransferase 9 in neurodegeneration

Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.

Machine learning as a tool predicting short-term postoperative complications in Crohn’s disease patients undergoing intestinal resection: What frontiers?

The recent study,“Predicting short-term major postoperative complications in intestinal resection for Crohn’s disease:A machine learning-based study”invest-igated the predictive efficacy of a machine learning model for major postoperative complications within 30 days of surgery in Crohn’s disease(CD)patients.Em-ploying a random forest analysis and Shapley Additive Explanations,the study prioritizes factors such as preoperative nutritional status,operative time,and CD activity index.Despite the retrospective design’s limitations,the model’s robu-stness,with area under the curve values surpassing 0.8,highlights its clinical potential.The findings align with literature supporting preoperative nutritional therapy in inflammatory bowel diseases,emphasizing the importance of compre-hensive assessment and optimization.While a significant advancement,further research is crucial for refining preoperative strategies in CD patients.

Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease,with insights into Pink1 knockout models

Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.

Sex modulates the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease

There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease,the effects of sex on treatment outcome are still unclear.The aim of this retrospective observational study,was to examine sex differences in motor symptoms,nonmotor symptoms,and quality of life after subthalamic nucleus deep brain stimulation.Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation aged 63.00±8.01 years(55 men and 35 women).Outcomes of clinical evaluations were compared between sexes via a Student’s t-test and within sex via a paired-sample t-test,and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex.We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation.Restless legs syndrome was alleviated to a greater extent in men than in women.Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation.Furthermore,Hoehn-Yahr stage was positively correlated with the treatment response in men,while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women.In conclusion,women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms,non-motor symptoms,and quality of life.We found sex-specific factors,i.e.,Hoehn-Yahr stage and levodopa equivalent dose,that were related to motor improvements.These findings may help to guide subthalamic nucleus deep brain stimulation patient selection,prognosis,and stimulation programming for optimal therapeutic efficacy in Parkinson’s disease.

Detection of Alzheimer’s disease onset using MRI and PET neuroimaging:longitudinal data analysis and machine learning

The scientists are dedicated to studying the detection of Alzheimer’s disease onset to find a cure, or at the very least, medication that can slow the progression of the disease. This article explores the effectiveness of longitudinal data analysis, artificial intelligence, and machine learning approaches based on magnetic resonance imaging and positron emission tomography neuroimaging modalities for progression estimation and the detection of Alzheimer’s disease onset. The significance of feature extraction in highly complex neuroimaging data, identification of vulnerable brain regions, and the determination of the threshold values for plaques, tangles, and neurodegeneration of these regions will extensively be evaluated. Developing automated methods to improve the aforementioned research areas would enable specialists to determine the progression of the disease and find the link between the biomarkers and more accurate detection of Alzheimer’s disease onset.

Comparison and development of machine learning for thalidomideinduced peripheral neuropathy prediction of refractory Crohn’s disease in Chinese population

BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.

Colliding Bodies Optimization with Machine Learning Based Parkinson’s Disease Diagnosis

Parkinson’s disease(PD)is one of the primary vital degenerative diseases that affect the Central Nervous System among elderly patients.It affect their quality of life drastically and millions of seniors are diagnosed with PD every year worldwide.Several models have been presented earlier to detect the PD using various types of measurement data like speech,gait patterns,etc.Early identification of PD is important owing to the fact that the patient can offer important details which helps in slowing down the progress of PD.The recently-emerging Deep Learning(DL)models can leverage the past data to detect and classify PD.With this motivation,the current study develops a novel Colliding Bodies Optimization Algorithm with Optimal Kernel Extreme Learning Machine(CBO-OKELM)for diagnosis and classification of PD.The goal of the proposed CBO-OKELM technique is to identify whether PD exists or not.CBO-OKELM technique involves the design of Colliding Bodies Optimization-based Feature Selection(CBO-FS)technique for optimal subset of features.In addition,Water Strider Algorithm(WSA)with Kernel Extreme Learning Machine(KELM)model is also developed for the classification of PD.CBO algorithm is used to elect the optimal set of fea-tures whereas WSA is utilized for parameter tuning of KELM model which alto-gether helps in accomplishing the maximum PD diagnostic performance.The experimental analysis was conducted for CBO-OKELM technique against four benchmark datasets and the model portrayed better performance such as 95.68%,96.34%,92.49%,and 92.36%on Speech PD,Voice PD,Hand PD Mean-der,and Hand PD Spiral datasets respectively.

Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer’s disease

Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment.The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer’s disease.Alzheimer’s disease mouse models were established by injection of beta amyloid 1?42 aggregates into dentate gyrus bilaterally.Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration.Afterwards,neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies.Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1?42-induced cognitive impairment,and these effects are similar to those shown in the mesenchymal stem cells.These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer’s disease.All procedures and experiments were approved by Institutional Animal Care and Use Committee(CICUAL)(approval No.CICUAL 2016-011)on April 25,2016.

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.

Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.

Divalent metal transporter 1 expression and iron deposition in the substantia nigra of a rat model of Parkinson's disease

Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.

Melatonin ameliorates microvessel abnormalities in the cerebral cortex and hippocampus in a rat model of Alzheimer’s disease

Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease

The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.

Neuroprotection by immunomodulatory agents in animal models of Parkinson's disease

Parkinson’s disease（PD） is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.