Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

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.

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole organism.Consequently,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.This review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection.Differences among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of COVID-19.To effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities.Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

Neurophysiological, histological, and behavioral characterization of animal models of distraction spinal cord injury: a systematic review

Distraction spinal cord injury is caused by some degree of distraction or longitudinal tension on the spinal cord and commonly occurs in patients who undergo corrective operation for severe spinal deformity.With the increased degree and duration of distraction,spinal cord injuries become more serious in terms of their neurophysiology,histology,and behavior.Very few studies have been published on the specific characteristics of distraction spinal cord injury.In this study,we systematically review 22 related studies involving animal models of distraction spinal cord injury,focusing particularly on the neurophysiological,histological,and behavioral characteristics of this disease.In addition,we summarize the mechanisms underlying primary and secondary injuries caused by distraction spinal cord injury and clarify the effects of different degrees and durations of distraction on the primary injuries associated with spinal cord injury.We provide new concepts for the establishment of a model of distraction spinal cord injury and related basic research,and provide reference guidelines for the clinical diagnosis and treatment of this disease.

Knee osteoarthritis:A review of animal models and intervention of traditional Chinese medicine

Background:Knee osteoarthritis(KOA)characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults.The pathophysiology of KOA remains poorly understood,as it involves complex mechanisms that result in the same outcome.Consequently,researchers are interested in studying KOA and require appropriate animal models for basic research.Chinese herbal compounds,which consist of multiple herbs with diverse pharmacological properties,possess characteristics such as multicomponent,multipathway,and multitarget effects.The potential benefits in the treatment of KOA continue to attract attention.Purpose:This study aims to provide a comprehensive overview of the advantages,limitations,and specific considerations in selecting different species and methods for KOA animal models.This will help researchers make informed decisions when choosing an animal model.Methods:Online academic databases(e.g.,PubMed,Google Scholar,Web of Science,and CNKI)were searched using the search terms“knee osteoarthritis,”“animal models,”“traditional Chinese medicine,”and their combinations,primarily including KOA studies published from 2010 to 2023.Results:Based on literature retrieval,this review provides a comprehensive overview of the methods of establishing KOA animal models;introduces the current status of advantages and disadvantages of various animal models,including mice,rats,rabbits,dogs,and sheep/goats;and presents the current status of methods used to establish KOA animal models.Conclusion:This study provides a review of the animal models used in recent KOA research,discusses the common modeling methods,and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Establishing of the Transplanted Animal Models for Human Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide.Even with the applications of excision, radiotherapy, chemotherapy, and gene therapy, the 5 year survival rate is only 15% in the USA. Clinically relevant laboratory animal models of the disease could greatly facilitate understanding of the pathogenesis of lung cancer, its progression, invasion and metastasis. Transplanted lung cancer models are of special interest and are widely used today. Such models are essential tools in accelerating development of new therapies for lung cancer. In this communication we will present a brief overview of the hosts, sites and pathways used to establish transplanted animal lung tumor models.

Applications and advancements in animal models for antiviral research on mosquito-borne arboviruses

Vector-borne diseases caused by arthropod-borne viruses(arboviruses) are a considerable challenge to public health globally. Mosquito-borne arboviruses, such as Chikungunya, Dengue, and Zika viruses, cause a range of human illnesses and may be fatal. Currently, efforts to control these diseases still face challenges due to growing vector resistance towards insecticides, urbanization, and limited effective antiviral treatments and vaccines. Animal models are crucial in antiviral research on mosquito-borne arboviruses, playing a role in understanding disease mechanisms,vaccine development, and toxicity testing, but the application of animal models still faces the challenges of ethical considerations and animal-to-human translational success. Genetically engineered mouse models, hamster models and non-human primate(NHP) are currently used in arbovirus research, but new models such as tree shrews and novel humanized mice are emerging. In the context of Malaysian research, the use of long-tailed macaques as potential NHP models for arbovirus research is possible;however, it faces the ethical dilemma of using an endangered species for scientific purposes. Overall, animal models play a crucial role in advancing infectious disease research, but a balance between medical research and species conservation must be upheld.

An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus(HIV)infection is strongly associated with a height-ened incidence of lymphomas.To mirror the natural course of human HIV infection,animal models have been developed.These models serve as valuable tools to inves-tigate disease pathobiology,assess antiretroviral and immunomodulatory drugs,ex-plore viral reservoirs,and develop eradication strategies.However,there are currently no validated in vivo models of HIV-associated lymphoma(HAL),hampering progress in this crucial domain,and scant attention has been given to developing animal models dedicated to studying HAL,despite their pivotal role in advancing knowledge.This re-view provides a comprehensive overview of the existing animal models of HAL,which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Preliminary exploration of animal models of congenital choledochal cysts

BACKGROUND Various animal models have been used to explore the pathogenesis of choledochal cysts(CCs),but with little convincing results.Current surgical techniques can achieve satisfactory outcomes for treatment of CCs.Consequently,recent studies have focused more on clinical issues rather than basic research.Therefore,we need appropriate animal models to further basic research.AIM To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs.METHODS Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group,sham surgical group,or control group.A rat model of CC was established by partial ligation of the bile duct.The reliability of the model was confirmed by measurements of serum biochemical indices,morpho-logy of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues.RESULTS Dilation classified as mild(diameter,≥1 mm to<3 mm),moderate(≥3 mm to<10 mm),and severe(≥10 mm)was observed in 17,17,and 2 rats in the surgical group,respectively,while no dilation was observed in the control and sham surgical groups.Serum levels of alanine aminotransferase,aspartate aminotrans-ferase,total bilirubin,direct bilirubin,and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery,while direct bilirubin,total bilirubin,and gamma-glutamyltransferase were further increased 14 d after surgery.Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery.The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues.CONCLUSION The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC,which may contribute to investigating the pathogenesis of CC.

Advances in viral encephalitis:Viral transmission,host immunity,and experimental animal models

Viral infections have led to many public health crises and pandemics in the last few centuries.Neurotropic virus infection-induced viral encephalitis(VE),especially the symptomatic inflammation of the meninges and brain parenchyma,has attracted growing attention due to its high mortality and disability rates.Understanding the infectious routes of neurotropic viruses and the mechanism underlying the host immune response is critical to reduce viral spread and improve antiviral therapy outcomes.In this review,we summarize the common categories of neurotropic viruses,viral transmission routes in the body,host immune responses,and experimental animal models used for VE study to gain a deeper understanding of recent progress in the pathogenic and immunological mechanisms under neurotropic viral infection.This review should provide valuable resources and perspectives on how to cope with pandemic infections.

Protective Effects of Oral Fructose-1, 6-diphosphate on Liver Injury in Animal Models

Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in rats was induced by carbon tetrachloride （ CCl4 ） ; Acute liver injury model in mice was induced by aminogalactose （GAIN） or lipopolysaccharide （LPS）. Results In CCl4-induced chronic liver injury model, FDP （1 , 4 g·kg^-1·d^-1, q.d., for 10 weeks） significantly lowered ALT, AST,γ-glutamyl transpeptidase （γ-GT）, alkaline phosphatase （ALP）, and total bilirubin （T-BIL） in serum compared with vehicle; simultaneously it evidently elevated abnormal total protein （TP）, albumin （ALB） and total cholesterol （ T-CHO ） levels in serum; it also dose-dependently reduced hydroxyproline contents in hepatic tissue. 4 g·kg^-1·d^-1 of FDP apparently decreased incidence of hepatic cirrhosis, and alleviated pathological changes of liver tissue. In GaiN-induced model, 1.0 - 4. 0 g·kg^-1·d^-1 of FDP （ bid, for 3 d ） significantly lowered alanine aminotransferase （ ALT ） and aspartate aminotransferase （ AST ） levels in serum ; it also decreased liver coefficient. 4. 0 g·kg^-1·d^-1 of FDP significantly alleviated pathological changes of cell ultra-structures. In LPS-induced model, only high dose of FDP （4. 0 g·kg^-1·d^-1, bid, for 12 d） significantly decreased ALT level in serum. Conclusion This study first demonstrated the protective effect of oral FDP on chronic liver injury caused by CCl4, and confirmed its effect on acute liver injury at the same time, suggesting that Long-term oral FDP is efficacious against liver injury induced by different factors and can be used as an oral liver protective agent in clinic.

Serotonin controls axon and neuronal regeneration in the nervous system:lessons from regenerating animal models

Traumatic brain injury （TBI） is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which causes denaturation of the white matter and axon retraction, leaving patients with severe brain damage or even in a persistent vegetative state.

Call for papers of the special issue on Animal Models and Infectious Diseases

Primates and animal models are major areas of coverage for Zoological Research （ZR）. Over the past few years, ZR has released a series of special issues/topics addressing various aspects of these areas, e.g., ge- netics, immunology, and physiology neuroscience. A special issue for 2017 focusing on ＂Animal Models of Infectious Diseases＂ is under preparation and, so far, includes original research articles and reviews on filo- viruses and coxsackievirus involving guinea pigs, mice, and other species. Further to this, ZR would like to extend a very warm invitation to all peer researchers in the field to submit outstanding work to the journal on this special issue.

Meeting report:the 4^(th) symposium on animal models of non-human primates in Kunming,Yunnan,China

From 2 to 4 November, 2016, the 4th Symposium on Animal Models of Non-Human Primates （NHP） was held in Kunming, Yunnan, China. This meeting was organized by the Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences （CAS） ＆ Yunnan Province Kunming Primate Research Center （KPRC）, Zoological Research, and Kunming Institute of Zoology （KIZ）, CAS.

Pial iontophoresis of ferric chloride versus cortical ferric chloride injection in establishing iron-induced posttraumatic epilepsy animal models

BACKGROUND： In order to study the pathogenesis of iron-induced posttraumatic epilepsy （PTE）, foreign scholars have established several kinds of PTE animal models, among which, the iron- induced PTE animal models proposed by Willmore is the most famous. The iron-induced PTE animal models can be established by two methods： one is cortical ferric chloride injection （CFCI） and the other one is pial iontophoresis of ferric chloride （PIFC）. Because Willmore did not give out the elaboration of the behaviors and electroencephalograms （EEGs） of the iron induced PTE animal models established by these two methods, so we have known little about these animal models. OBJECTIVE： To observe the behaviors and EEGs of the iron-induced PTE animal models established by PIFC and CFCI, in order to compare the differences and the study value of these two methods. DESIGN： Qualitative controlled observation tria SETTING： Department of Neurosurgery, Urumqi General Hospital, Lanzhou Military Area Command of Chinese PLA. MATERIALS： Forty healthy adult male SD rats, weighing 200 to 250 g, were involved in this experiment. Reagents and instruments： Ferric chloride （FeCl3·6H2O, Sigma USA）, rat stereotaxic apparatus （ASI company, USA）, the wireless blue tooth electroencephlograms recording system （Nuocheng electric Co.Ltd, Shanghai）, a set of air turbine dental drill unit, dental base acrylic resin powder, microinjector （50 μL）, amperemeter （1 mA）, a pair of batteries, electric resistance （200 kΩ） , variable resistance （100 kΩ）, tubule with endo-meridians of 2 mm （used as import tube）, several silver wire segments and several acupuncture needles were employed in this study. METHODS： This study was carried out in the Experimental Animal Center of the Urumqi General Hospital, Lanzhou Military Area Command of Chinese PLA between November 2004 and April 2005. Establishing the PET animal models by CFCI method： Twenty SD rats were taken, intraperitoneally anesthetized with 50 mg/kg barbanylum and fixed on stereotaxic apparatus. A cranial burr hole with the diameter of 2 mm was drilled 3 mm behind the coronal suture and 2 mm lateral to the sagittal line on the left cranium. Another 5 cranial burr holes with diameter of 2 mm were drilled to place electrodes. The positions of holes were set that taking bregma as original point, sagittal line as Y-axis, the line through the original point and vertical to the Y-axis as X-axis. The unit of the coordinate axis was mm. The coordinate value of the electrodes were （4, 0）, （4, -6）, （-4, 0）, （-4, -6）, at last, a hole with the diameter of 2 mm was drilled on the center of the coronale. 5 μL ferric chloride solution （FeCl3, 100 mmol/L, pH 1.5） was injected into the sensorimotor cortex of rats using microinjector within 5 minutes. The needling depth was 3 mm. The needle was retained for 5 minutes so as to prevent the outflow of liquid. Establishing the PTE animal models by PIFC method： Twenty SD rats were chosen and weighed, and the procedures after weighing were as above.A cranial burr hole with the diameter of 4 mm was drilled in the position where needle inserted in animal models established by CFCI method. Cerebral dura mater was cut. Another 5 holes were drilled to place electrodes in the same position as above. The tip of tubule cotton stuffed inside （to prevent the rapid flow of FeCl3 solution, 100 mmol/L, pH 1.5） was gently connected to cerebral pia mater. The positive and negative electrodes of the amperemeter whose output current was 100 μA were connected to acupuncture needles. The acupuncture needle, which was connected to positive electrode, was inserted into ferric chloride solution, and that which was connected to negative electrode was inserted into the right forelimb of rats subcutaneously. The rats were galvanized for 10 minutes. Record of EEG： The silver wire with blunt anterior extremity was placed on the cerebral dura mater. Then, silver wire and cranial bones were firmly fixed with dental base acrylic resin power. The other side was connected to the wireless blue tooth electroencephlograms recording system to monitor EEG changes. Assessment criteria of seizure degree： Grade Ⅰ ： ＂wet dog-like＂ shudder, facial muscle convulsion and chewing;Grade Ⅱ： rhythmical nodding：Grade Ⅲ： forelimb clonus：Grade Ⅳ： forelimb clonus while standing： Grade Ⅴ： lost the balance, vert, limb＇s convulsion and the whole body＇s tic. MAIN OUTCOME MEASURES： Behaviors and EEGs changes of iron-induced PTE animal models established by PTFC and CFCI. RESULTS： All the 40 rats were involved in the result analysis. （1） The changes of the behaviors： The two animal models both had the epileptic seizures. The epileptic seizure of the animal model established by PIFC mainly presented automatic behavior of chewing, and facial muscle convulsion accompanied with chewing. Epileptic seizure reached the peak within 2.5 to 7 hours after model establishing.It was gradually decreased within 24 hours and hardly seen 1 day after model establishing. The epileptic seizure of the rat model established by CFCI mainly presented turnover upspring and limbs＇ convulsion and urinary incontinence accompanied. The epileptic seizure reached the peak within 3 to 8 hours.It was relatively frequent within 1 week and gradually decreased within 2 weeks after model establishing. The PTE animal models established by CFCI were more closed to clinical PTE process. （2） The form of seizures： The epileptic seizures of the rat model established by PIFC mainly presented grade Ⅰ , seldom presented grades Ⅲ, Ⅳ and Ⅴ; The epileptic seizures of rat model established by CFCI mainly presented the head turning to the right, body＇s rotation, then appeared as grades Ⅳ and Ⅴ, and the whole procedure lasted 1 minute. At the interval of big seizures, grade Ⅰ was observed. From the respect of seizure manifestation, the PTE models established by CFCI were more similar to human PTE. （3） EEGs changes： The sharp waves with average frequency of 9.66 Hz and average amplitude of 183.90 μV were observed on the EEGs of the model established by PIFC when the rats were suffering seizures. The spike waves with average frequency of 16.01 Hz and average amplitude of 143.60 μV were observed on the EEGs of the model established by CFCI when the rats were suffering seizures. CONCLUSTON： （1）Iron-induced PTE rat model is stable and credible. （2）Compared with PTE animal model established by PIFC, PTE animal model established by CFCI is a chronic animal model, and its seizure manifestation is more similar to human PTE. so it is worth further studies.

Features of animal models of complex partial epilepsy established through unilateral,bilateral and alternate-side kindling at hippocampus of rats

BACKGROUND： Electrical stimulation kindling model, having epilepsy-inducing and spontaneous seizure and other advantages, is a very ideal experimental animal model. But the kindling effect might be different at different sites. OBJECTIVE： To compare the features of animal models of complex partial epilepsy established through unilateral, bilateral and alternate-side kindling at hippocampus and successful rate of modeling among these 3 different ways. DESIGN： A randomized and controlled animal experiment SETTING： Department of Neurology, Qilu Hospital, Shandong University MATERIALS： Totally 60 healthy adult Wistar rats, weighing 200 to 300 g, of either gender, were used in this experiment. BL-410 biological functional experimental system （Taimeng Science and Technology Co. Ltd, Chengdu） and SE-7102 type electronic stimulator （Guangdian Company, Japan） were used in the experiment. METHODS： This experiment was carried out in the Experimental Animal Center of Shandong University from April to June 2004. After rats were anesthetized, electrode was implanted into the hippocampus. From the first day of measurement of afterdischarge threshold value, rats were given two-square-wave suprathreshold stimulation once per day with 400 μA intensity, 1ms wave length, 60 Hz frequency for 1 s duration. Left hippocampus was stimulated in unilateral kindling group, bilateral hippocampi were stimulated in bilateral kindling group, and left and right hippocampi were stimulated alternately every day in the alternate-side kindling group. Seizure intensity was scored： grade 0： normal, 1： wet dog-like shivering, facial spasm, such as, winking, touching the beard, rhythmic chewing and so on; 2： rhythmic nodding; 3： forelimb spasm;4： standing accompanied by bilateral forelimb spasm;5： tumbling, losing balance, four limbs spasm. Modeling was successful when seizure intensity reached grade 5. t test was used for the comparison of mean value between two samples. MAIN OUTCOME MEASURES： Comparison of the successful rate of modeling, the times of stimulation to reach intensity of grade 5, the lasting time of seizure of grade 3 of rats in each group. RESULTS： Four rats of alternate-side kindling group dropped out due to infection-induced electrode loss, and 56 rats were involved in the result analysis. The successful rate of unilateral kindling group, bilateral kin- dling group and alternate-side kindling group was 55%（11/20）,100%（16/16）and 100%（20/20）, respective- ly. The stimuli to reach the grade 5 spasm were significantly more in the bilateral kindling group than in the unilateral kindling group [（30.63±3.48）, （19.36±3.47）times, t=8.268, P 〈 0.01], and those were significantly fewer in the alternate-side kindling group than in the unilateral kindling group [（ 10.85±1.98）times, t=-8.744, P 〈 0.01]. The duration of grade 3 spasm was significantly longer in the bilateral kindling group than in the unilateral kindling group [（9.75±2.59）, （3.21 ±1.58）days,t=-8.183,P 〈 0.01], Among 20 successful rats of al- ternate-side kindling group, grade 5 spasm was found in the left hippocampi of 11 rats, but grade 3 spasm in their right hippocampi; Grade 5 spasm was found in the right hippocampi of the other 9 rats, grade 4 spasm in the left hippocampus of 1 rat and grade 3 of 8 rats. CONCLUSION ： The speed of establishing epilepsy seizure model by alternate-side kindling is faster than that by unilateral kindling, while that by bilateral kindling is slower than that by unilateral kindling. The successful rate is very high to establish complex partial epilepsy with alternate-side or bilateral kindling. Epilepsy seizure established by alternate-side kindling has antagonistic effect of kindling and the seizure duration of grade 3 spasm is prolonged.

Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models

Multipotent mesenchymal stromal cells [also known as mesenchymal stem cells(MSCs)] are currently being studied as a cell-based treatment for inflammatory disorders. Experimental animal models of human immune-mediated diseases have been instrumental in establishing their immunosuppressive properties. In this review, we summarize recent studies examining the effectiveness of MSCs as immunotherapy in several widely-studied animal models, including type 1 diabetes, experimental autoimmune arthritis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, graft-vs-host disease, and systemic lupus erythematosus. In addition, we discuss mechanisms identified by which MSCs mediate immune suppression in specific disease models, and potential sources of functional variability of MSCs between studies.