CN105878240A - Primates Parkinson's disease model behavior assessment optimal method - Google Patents
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Abstract
The invention belongs to the technical field of bioscience, and particularly relates to a primates Parkinson's disease (PD) model behavior assessment optimal method. The method comprises the steps of establishing a rhesus monkey PD animal model; injecting MPTP into muscle of a rhesus monkey once a day till typical and stable PD clinical symptoms appear, wherein dosage is 0.2-0.5 mg/kg according to individual sensitivity difference; conducting behavior assessment on the rhesus monkey at two fixed time periods each day while MPTP injection is conducted, and taking the average score of one week as the final score of the week. A set of complete primates PD model behavior assessment method is provided and can be used for new drug efficacy assessment and horizontal and vertical comparative study of different new drugs. The assessment method absorbs the advantages and discards the disadvantages of different rating scales, and can reflect individual clinical difference comprehensively and accurately based on practical experience and clinical performance characteristics of rhesus monkeys, and individual clinical difference includes individual sensitivity difference, disease severity difference, disease sequence difference and individual PD feature difference.
Description
Technical field
The invention belongs to technical field of life science, be specifically related to primates Parkinson disease model Behavioral assessment optimization side
Method.
Background technology:
Parkinson disease (Parkinson's disease, PD) are a kind of old neurodegenerative diseases, and sickness rate is only second to
Alzheimer, main clinic symptoms for trembling, muscle rigidity, bradykinesia and postural balance abnormal, main pathology is special
Point is for nigral dopamine (dopamine, DA) serotonergic neuron serious degenerative disappearance and Lewy body (lewy body, LB) occurs.
PD takes place mostly in the older population of more than 60 years old, and sickness rate reaches 1%-2%, and within more than 40 years old, crowd's sickness rate is more than 0.1%, in
Existing a kind of rejuvenation incidence trend.Along with prolongation and the appearance of aging of population average life, rising occurs in the sickness rate of PD
Trend, it is contemplated that to the year two thousand thirty, China's parkinson disease number will account for global half with, which results in the great attention of scholars.
At present PD etiology and pathogenetic research are all relied on animal model.Up to the present, it is known that animal
Model has rat, mice, cat, nonhuman primate models etc., but no matter from hereditism, genetic homology, Physiology and biochemistry feature, disease
From the point of view of the aspects such as reason feature, non-human primate model has the advantage that other animal models are incomparable, it is possible to real mould
Anthropomorphic class PD pathogenesis and process.So far, the method selecting primate making PD model is varied, has acute inclined side
Damage model, acute bilateral damage model (such as abdominal cavity, intramuscular injection modeling reagent) and subacute or chronic systemic damage mould
Types (such as intramuscular injection, Intranasal sprays modeling reagent) etc., every kind of modeling mode pluses and minuses are different, and animal clinical shows also that gap is relatively
Greatly.Due to parkinson disease and model thereof diagnosis rely primarily on Behavioral assessment, but neurological deficit score standard is irregular not at present
Together, emphasis is different, and as Kurlan is more suitable for the evaluation in modeling stage, Canadian marking scales is then more suitable for commenting of drug effect
Valency, does not has a set of perfect, comprehensive, general primates PD model score standard.Based on this, the present invention intends setting up one
On the basis of primates parkinson macaque model, previous karyotype studies being combined with self experiment, induction and conclusion goes out a set of complete
Whole PD primate model comprehensive value model, horizontal to Behavioral assessment, the evaluating drug effect offer for each primate model,
Longitudinal relative analysis basis.
Summary of the invention
Technical scheme provides a kind of primates Parkinson disease model Behavioral assessment optimization method, for modeling
The Behavioral assessment of stage and evaluating drug effect stage primates Parkinson disease model provides a kind of reliable, sensitive evaluation side
Method.
Primates Parkinson disease model Behavioral assessment optimization method, comprises the following steps: set up Rhesus Macacus PD animal mould
Type: to Rhesus Macacus intramuscular injection MPTP, once a day, according to individual sensitivity difference, dosage is 0.2-0.5mg/kg, until going out
Existing typical, stable PD clinical symptoms；During injection MPTP, every day carries out behavioristics in 2 set time sections to Rhesus Macacus
Evaluate, using the scoring average of a week as the final score in this week.
Described Behavioral assessment method, including comprehensive neurological deficit score scale i.e. SLQ marking scales, is shown in Table 4, by dynamic
State monitoring model is in progress, and in conjunction with animal morbidity practical situation, contrasts SLQ marking scales, comprehensively analyzes.
Described Behavioral assessment method, employing whole day images, manually retouches meter, the artificial mode stimulated.
Described during positive evaluating drug effect, every day carries out Behavioral assessment in 2 set time sections to Rhesus Macacus, system
Meter analyzes behavioristics's score average of every 2 days, continuous dynamic evaluation therapeutic effect.
Described Behavioral assessment method, needs 3 people complete independently in the environment of being independent of each other, and three people's evaluation results kiss
Right need 90%.
The primates Parkinson disease model Behavioral assessment optimization method that the present invention provides, applicable object is: primates is
System property PD model, primates inclined side PD model, stable breeding primates PD model, put primates PD model in a suitable place to breed.
The invention provides a set of perfect primates PD model behavior evaluation methodology, can be used for new drug pharmacodynamic assessment,
The comparative study horizontal, longitudinal of each new drug.This evaluation methodology absorbs, has abandoned the pluses and minuses of each marking scales, and combines reality
Trample experience, self macaque clinical manifestation characteristic, it is possible to comprehensive, accurately reflect individual clinical difference, as individual sensitivity is poor
Different, morbidity order of severity difference, morbidity sequencing difference, individual PD feature difference.
Accompanying drawing explanation
Fig. 1 is that the Kurlan scale of embodiment is to all animal comprehensive result figures；
Fig. 2 is that the Papa scale of embodiment is to all animal comprehensive result figures；
Fig. 3 is that the Canadian scale of embodiment is to all animal comprehensive result figures；
Fig. 4 is that the SLQ scale of embodiment is to all animal comprehensive result figures；
Fig. 5 is first animal each marking scales relative analysis figure of embodiment；
Fig. 6 is second animal each marking scales relative analysis figure of embodiment；
Fig. 7 is the 3rd animal each marking scales relative analysis figure of embodiment；
Fig. 8 is the 4th animal each marking scales relative analysis figure of embodiment；
Fig. 9 is the 5th animal each marking scales relative analysis figure of embodiment；
Figure 10 is the 6th animal each marking scales relative analysis figure of embodiment.
Detailed description of the invention
It is described in conjunction with the embodiments the detailed description of the invention of the present invention.
The preparation of animal model of the present invention
One, materials and methods
1. choose experimental animal:
Choose Healthy Youth Rhesus Macacus (river western macaque subspecies) 10, body weight 3.5-5.5kg, in age 3.5-4.5 year, be shown in Table
1, and it is randomly divided into model group (n=6) and matched group (n=4).January, adaptability list cage was fed in advance, was allowed to free drinking-water
Feed.Animal is carried by base, National Laboratory macaque kind source (Ya'an Sichuan province) (animal uses licence: SCXK (river): 2013-105)
Supply.In experiment, the disposal to animal meets Ministry of Science & Technique of PRC's " directiveness meaning about kind treatment laboratory animal
See " regulation.
Table 1: each test macaque basic document
2 animals process:
Model group takes muscle injection mode to use MPTP, and different according to sensitivity, application dosage is from minimum dose
0.2mg/kg starts, and is gradually increased dosage to 0.5mg/kg, after animal activity minimizing, bradykinesia occurs, trembles, often
Within 1-3 days, use a MPTP (depending on interval natural law is according to individual instances), until stable clinical symptoms occurs, within last week, lead to
The intravenous method of transmission from one meridian to another uses MPTP, to consolidate clinical symptoms.Matched group gives Isodose normal saline.
The concrete details that is administered is shown in Table 2.
Table 2. modeling concrete scheme
3. positive drug evaluation of programme: proceed by levodopa positive drug evaluation in the 4th week after MPTP is administered for the last time
Experiment.30min before the meal, oral (being hidden in orange juice) feeds levodopa (levodopa/carbidopa=12/3mg/kg, card
Degrade in periphery as periphery decarboxylase inhibitor, suppression levodopa than DOPA), every day 2 times, totally 4 weeks.
4. animal behavioral study scheme: start to execution animal from quarantine domestication, equal whole day unmanned monitoring camera-shooting animal；
Every day is artificial observation real time record Animal Behavior Science abnormal conditions during feeding, hello water；Every day, artificial stimulating animal, evaluated
Function of nervous system's damage situations: attempt to touch the face of every animal, extremity with obtuse iron staff, and perform record.Modelling phase, every day
Evaluating Animal Behavior Science performance in 2 set time sections, within 7 days, result is as a statistics point；Positive drug evaluation phase, 2 days knots
Fruit is as a statistics point.
The successful decision method of model: when model occur activity minimizing, bradykinesia, tremble, muscle rigidity time, it is determined that
Model success；When static tremor occurs in all animals, and when remaining trembles stable, stop using MPTP.
Optimal Behavioral assessment option screening way: neurological deficit score scale will be commonly used at present, be shown in Table each evaluation index in 3
Be analyzed, and each index is simultaneously used for modeling phase, model stability phase, the evaluation for the treatment of phase, picking out can be sensitive
The evaluation index of reaction animal clinical performance and evaluation methodology, as one of SLQ scale member；Actual according further to animal
Performance, suitable extension evaluation methodology and index, it is used for constituting SLQ scale.
Table 4 primates parkinson disease comprehensive neurological deficit score amount (SLQ marking scales)
Note: available 0.25,0.5 point of evaluation, at utmost reaction animal actual clinical situation.
Two, result
2.1. modeling result smoothly completes the modeling experiment of Rhesus Macacus, and all animals is through various dose, different time note
After penetrating MPTP, becoming mould rate is 100%, all show tremble, be slow in action, motion actuated difficulty, expression minimizing, rigid posture etc.
Typical clinical symptom, also show drowsiness, yawn, constipation, sounding reduce or can not the atypical features such as sounding, and these are non-
Classical symptom is consistent with patient's PD atypia clinical symptoms.
2.2., after positive drug levodopa treatment effect oral Gavage levodopa in 30-60min, test monkey activity is bright
Aobvious increase, irritability strengthens, and occurs that spontaneous activity increases, and climbing such as increases at the symptom that is clearly better.Above-mentioned situation after the treatment 1.5
Hour, fade away, after 2 hours, almost all disappears.
2.3. animal behavioral study result is through tight Comprehensive Comparison, we have concluded that complete set, accurate, clever
The primates parkinson disease comprehensive grading scale of quick reaction clinical practice situation, i.e. SLQ marking scales, detailed score by rules is shown in Table
4, each marking scales evaluation index relative analysis the results are shown in Table 4.From table 3,4 it can be seen that SLQ scale includes motor function and life
Viability two parts, SLQ Scale assessment index almost contains all marking scales, and each index proportion is in each big scale
In the range of；Grading system is brighter and clearer, is more beneficial for distinguishing the small difference between animal.
2.4.SLQ scale benefit analysis Kurlan scale, Papa scale, Canadian scale and the single scale of SLQ scale
Analysis result is shown in that Fig. 1～Fig. 4, single animal each marking scales relative analysis result are shown in Fig. 5～Figure 10.From seeing that Fig. 1～Fig. 4 is permissible
Finding out, the PD score curve overall variation trend of 4 kinds of marking scales is basically identical, and Canadian scale is slightly worse；In the modeling stage,
SLQ scale curve obtained variation tendency is the most consistent with Kurlan scale, but at modeling commitment, SLQ scale is the most sensitive；
In the evaluating drug effect stage, SLQ scale curve obtained variation tendency is the most consistent with Papa scale, but SLQ scale score result is more
Animal practical situation, i.e. animal PD symptom can be reacted by light order being heavily: M6 M4 M1 M5 M3 M2.Fig. 5～Figure 10 shows
Showing, SLQ scale score plots changes and Papa scale, Canadian scale particularly Kurlan scale are consistent, but Papa
Scale, Canadian scale cannot accurately reflect the actual clinical performance of the slightly light animal (M5, M3, M2) of the state of an illness, i.e. scoring with just
The Chang Zuwu significance difference opposite sex.Therefore, the comprehensive grading scale of the present invention is applicable not only to modeling stage, particularly modeling in early days,
And it is applicable to the Behavior evaluation in evaluating drug effect stage.
To sum up, the comprehensive grading system not only content of the present invention is comprehensive, and susceptiveness, accuracy be better than the most each
Marking scales, modeling each stage of evaluating, the behavioristics in evaluating drug effect each stage that can be sensitive change, it is possible to as a kind of behavioristics
Standards of grading are used for primates PD scale-model investigation.
Claims (5)
1. primates Parkinson disease model Behavioral assessment optimization method, it is characterised in that comprise the following steps: set up Rhesus Macacus
PD animal model: to Rhesus Macacus intramuscular injection MPTP, once a day, according to individual sensitivity difference, dosage is 0.2-0.5mg/
, until there is typical, stable PD clinical symptoms in kg；During injection MPTP, Rhesus Macacus is entered by every day in 2 set time sections
Row Behavioral assessment, using the scoring average of a week as the final score in this week.
Primates Parkinson disease model Behavioral assessment optimization method the most according to claim 1, it is characterised in that described
Behavioral assessment method, including comprehensive neurological deficit score scale i.e. SLQ marking scales, be in progress by Dynamic monitoring pattern, knot
Close animal morbidity practical situation, contrast SLQ marking scales, comprehensively analyze.
Primates Parkinson disease model Behavioral assessment optimization method the most according to claim 1, it is characterised in that described
Behavioral assessment method, use whole day shooting, manually retouch meter, the mode of artificial stimulation.
Primates Parkinson disease model Behavioral assessment optimization method the most according to claim 1, it is characterised in that described
During positive evaluating drug effect, every day carries out Behavioral assessment in 2 set time sections to Rhesus Macacus, every 2 days of statistical analysis
Behavioristics's score average, continuous dynamic evaluation therapeutic effect.
Primates Parkinson disease model Behavioral assessment optimization method the most according to claim 1, it is characterised in that described
Behavioral assessment method, need 3 people complete independently in the environment of being independent of each other, and three people's evaluation result goodnesses of fit need
90%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020216069A1 (en) * | 2019-04-23 | 2020-10-29 | 中国科学院脑科学与智能技术卓越创新中心 | Method of preparing model for non-human primates displaying compulsive ritualistic behavior |
| CN113379676A (en) * | 2021-05-01 | 2021-09-10 | 首都医科大学宣武医院 | Method, device, equipment and storage medium for detecting and correcting abnormal gray-white matter volume |
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| CN105662638A (en) * | 2016-01-07 | 2016-06-15 | 四川农业大学 | Method for establishing rhesus monkey model with chronic process Parkinson's disease |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2001084921A2 (en) * | 2000-04-24 | 2001-11-15 | Wyeth | Transgenic animal |
| CN105662638A (en) * | 2016-01-07 | 2016-06-15 | 四川农业大学 | Method for establishing rhesus monkey model with chronic process Parkinson's disease |
Non-Patent Citations (2)
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Cited By (2)
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|---|---|---|---|---|
| WO2020216069A1 (en) * | 2019-04-23 | 2020-10-29 | 中国科学院脑科学与智能技术卓越创新中心 | Method of preparing model for non-human primates displaying compulsive ritualistic behavior |
| CN113379676A (en) * | 2021-05-01 | 2021-09-10 | 首都医科大学宣武医院 | Method, device, equipment and storage medium for detecting and correcting abnormal gray-white matter volume |
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Application publication date: 20160824 |