CN104857014B - Application of the 2 hydroxypropyl beta cyclodextrins in the medicine for preparing the treatment chain adrenal gland white matter of brain degeneration diseases of X - Google Patents
Application of the 2 hydroxypropyl beta cyclodextrins in the medicine for preparing the treatment chain adrenal gland white matter of brain degeneration diseases of X Download PDFInfo
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Abstract
The invention discloses a kind of 2 hydroxypropyl beta cyclodextrins（HPCD）The chain adrenal gland white matter of brain degeneration diseases of X are treated preparing（X‑ALD）Medicine in application, belong to biomedicine field.The present invention is by wild type and X ALD model mices（ABCD1 knock out mice）Inject 2 hydroxypropyl beta cyclodextrins, cell, adrenal gland and cerebellar tissue section are carried out to the cell for injecting HPCD mouse and carries out Filipin dyeing, measure its total plasma cholesterol, very-long-chain fatty acid, body weight, and carry out behaviouristics detection, as a result find, HPCD can be such that blood plasma, cerebellum, adrenal cholesterol levels drop within normal range (NR), and reduce VLCFA levels, and behaviouristics caused by alleviating X ALD mouse Nerve retrogression pathological changes is abnormal.Show that HPCD can treat X ALD based on the result, it can be used for the medicine for preparing treatment X ALD.
Description
Technical field
The invention belongs to biomedicine field, and in particular to 2- hydroxy propyl-Betas-cyclodextrin is preparing the treatment chain kidneys of X-
Application in the medicine of upper gland white matter of brain degeneration disease.
Background technology
The chain adrenal gland white matter of brain degeneration diseases (X-ALD) of X- are a kind of lipid-metabolism class diseases of the chain stealthy heredity of X.Mesh
Before think, because peroxisome is to very-long-chain fatty acid (VLCFA), mainly C23~C30 aliphatic acid in cell, especially
Obstacle occurs for C26 oxidation, so that VLCFA largely assembles in the organs such as blood, white matter of brain, adrenal cortex and tissue, triggers
Central nervous system demyelinate and Adrenal cortex atrophy or depauperation.Every 100,000 people there are about 0.5-1 people and suffer from the disease, wherein
95% is male, and 5% is women heterozygote.X-ALD Disease-causing genes ABCD1 (Sarde et al., 1994) encoding superoxide
Enzyme body memebrane protein ALDP (adrenoleukodystrophy protein), it contains 745 amino acid.ALDP and other 3
Protein binding on peroxisomal membrane, dimer is formed, the VLCFA of saturation can be transported in peroxisome
Aoxidized.Due to ABCD1 gene mutations, cause ALDP dysfunctions so that VLCFA oxidation is obstructed, and then causes VLCFA
Aggregation.VLCFA assembles in nervous system can destroy the stability of myelin and normally forming for myelin, and thin in adrenal cortex
Aggregation can reduce the ACTH receptor function on adrenal cortical cell film surface in born of the same parents, make intracellular steroid synthesis suppressed, and
To hypoadrenalism.
Effective X-ALD disease treatments scheme is there is no at present, and the treatment method treated at present includes cortex hormone of aadrenaline
Alternative medicine and dietetic treatment etc..During generation adrenal insufficiency, HRT can be used, gives steroid hormone
The endocrinosity of patient can be significantly improved, but neurological symptom can not be improved；Low fat diet coordinates Lorenzo ' s oil
(three erucic acid glyceric acid:Olein=4:1) horizontal to VLCFA in some patients blood plasmas may reduce has certain curative effect,
But the demyelinated of brain can not be prevented；Gene therapy have a extensive future but in the recent period it is still infeasible；HSCT can be controlled effectively
The brain type patient of disease early stage is treated, but is unsuitable for the brain type patient in disease rapid progress stage；Drug-induced gene therapy such as Lip river
The use and curative effect for cutting down statin also rest on experimental level at present.
Treatment X-ALD can reduce the VLCFA water in some patientss blood plasma using most wide Lorenzo ' s oil at present
It is flat, but brain lesionses caused by can not improving X-ALD and behaviouristics are abnormal.Another small molecule 4-PBA for being used to test is in patient
In have preferable tolerance, it is horizontal can not but to reduce internal VLCFA.
X-ALD is typically considered the lipid-metabolism class disease that VLCFA assembles initiation in tissue.Present invention discover that HPCD
X-ALD mouse are acted on, blood plasma, cerebellum, adrenal cholesterol levels is dropped within normal range (NR), and is reduced
VLCFA is horizontal, and behaviouristics caused by alleviating X-ALD mouse Nerve retrogression pathological changes is abnormal.
The content of the invention
It is an object of the invention to provide a kind of 2- hydroxy propyl-Betas-cyclodextrin (HPCD) on the treatment chain kidneys of X- are prepared
Application in the medicine of gland white matter of brain degeneration disease (X-ALD).
The purpose of the present invention is achieved through the following technical solutions：
The present invention is by wild type (WT) and X-ALD model mices (ABCD1 knock out mice, ABCD1-/-Mouse)
HPCD is injected, 6 monthly ages to 7 monthly age mouse are injected weekly 4 times, and cell Filipin dyeing, adrenal gland and small are carried out at 7 monthly age
Brain tissue slice Filipin is dyed and the measurement of total plasma cholesterol and very-long-chain fatty acid；7 monthly ages to 12 monthly ages monthly note
Penetrate 5 times, the measurement of body weight is carried out at 12 monthly age；Monthly injected after the monthly age of mouse 12 8 times, behaviouristics inspection is carried out at 20 monthly age
Survey.As a result find, HPCD can make blood plasma, cerebellum, adrenal cholesterol levels drop within normal range (NR), and reduce
VLCFA is horizontal, and behaviouristics caused by alleviating X-ALD mouse Nerve retrogression pathological changes is abnormal.HPCD energy is shown based on the result
X-ALD is enough treated, it can be used for the medicine for preparing treatment X-ALD.
The present invention has the advantages that：Compared to existing medicine Lorenzo ' s oil and 4-PBA, HPCD
It is horizontal to not only reduce VLCFA in X-ALD Mice Bodies, and alleviates the behaviouristics abnormal symptom of X-ALD mouse.HPCD will
It is a kind of compound of new effective treatment X-ALD diseases.
Brief description of the drawings
Fig. 1 is HPCD injection X-ALD mouse programme diagrams.
Fig. 2 is 7 monthly age WT and ABCD1-/-The confocal microscopy view of Mouse Tail-tip fibroblast Filipin dyeing.
Fig. 3 is 7 monthly age WT and ABCD1-/-Mouse adrenal gland and the fluorescence microscope of cerebellar tissue section Filipin dyeing
Figure.
Fig. 4 is 7 monthly age WT and ABCD1-/-The statistical results chart of the plasma total cholesterol levels of mouse；NS：Without significance difference
It is different；*：There were significant differences, P<0.05.
Fig. 5 is 7 monthly age WT and ABCD1-/-The statistical results chart of the VLCFA contents of mouse adrenal gland or brain tissue；NS：Nothing
Significant difference；*：There were significant differences, P<0.05；*：There were significant differences, P<0.01.
Fig. 6 is 12 monthly age WT and ABCD1-/-The body weight figure of mouse；NS：Without significant difference；*：There were significant differences, P<
0.05；*：There were significant differences, P<0.01.
Fig. 7 is 20 monthly age WT and ABCD1-/-The statistical results chart of mouse bull stick experimental result；NS：Without significant difference；*：
There were significant differences, P<0.05；*：There were significant differences, P<0.01.
Fig. 8 is 20 monthly age WT and ABCD1-/-The statistical results chart of the liftoff number of mouse forelimb in the experiment of mouse spacious field；NS：
Without significant difference；*：There were significant differences, P<0.01.
Fig. 9 is 20 monthly age WT and ABCD1-/-Mouse moves the statistical result of total distance in the experiment of mouse spacious field in 15 minutes
Figure；NS：Without significant difference；*：There were significant differences, P<0.05；*：There were significant differences, P<0.01.
Figure 10 is 20 monthly age WT and ABCD1-/-Motion track in the experiment of mouse spacious field in mouse 15 minutes is as schemed.
Embodiment
Further detailed description is done to the present invention with reference to embodiment, but should not be construed as limiting the invention,
Without departing from the spirit and substance of the case in the present invention, the modifications or substitutions made to the inventive method, step or condition belong to
In the scope of the present invention.Unless otherwise specified, technological means used in embodiment be well known to those skilled in the art it is normal
Rule means.
Embodiment 1HPCD injects X-ALD mouse programs
Material used in the present embodiment：2- hydroxy propyl-Betas-cyclodextrin (2-hydroxypropyl- β-
Cyclodextrin) HPCD is purchased from Cyclodextrin Technologies Development, Inc., ABCD1 gene knockouts
Mouse is purchased from Jackson Laboratory.
According to the program shown in Fig. 1 to wild type (WT) and X-ALD model mices (ABCD1 knock out mice,
ABCD1-/-Mouse) nape part injection HPCD, injection dosage is the every kg mouse weights of 4000mg HPCD, specific as follows：With 0.9%
Normal saline 20%HPCD (W/V), 6 monthly ages to 7 monthly age mouse inject weekly 4 20%HPCD, and control group injection is androgynous
Product physiological saline, cell Filipin dyeing, adrenal gland and cerebellar tissue section Filipin dyeing and blood are carried out at 7 monthly age
Starch the measurement of T-CHOL and very-long-chain fatty acid；7 monthly ages to 12 monthly ages are monthly injected 5 times, and body weight is carried out at 12 monthly age
Measurement；Monthly injected after the monthly age of mouse 12 8 times, behaviouristics detection is carried out at 20 monthly age.
Embodiment 2HPCD alleviates the accumulation of X-ALD mouse cells inner cholesterol
Material used in the present embodiment：Filipin is purchased from Sigma.
The symptom of X-ALD mouse cells levels cholesterol accumulation whether can be improved for detection HPCD, distinguished in Example 1
7 monthly age WT, ABCD1 of injecting normal saline and HPCD-/-Mouse, it is separately cultured their tail point fibroblast and carries out
Filipin dyeing observations.
Filipin is dyed：The tail point fibroblast being separately cultured fixes 30min with 4% paraformaldehyde room temperature；PBS is washed
Twice；The Filipin mother liquors (5mg/mL) dissolved with the PBS alcohol,diluteds containing 10% hyclone (FBS) arrive the μ of final concentration 50
G/mL, room temperature lucifuge are incubated 30min；PBS is washed three times, and deionization is washed twice；Mounting, laser co-focusing is micro- after air dried overnight
Sem observation, it is stored in -20 DEG C.
Filipin coloration results are as shown in Fig. 2 compared with WT mouse cells, the ABCD1 of injecting normal saline-/-Mouse is thin
Intracellular has a large amount of accumulation of cholesterol, and in injection HPCD ABCD1-/-In mouse cell, the phenomenon of accumulation of cholesterol is delayed
Solution.
Embodiment 3HPCD alleviates X-ALD mouse tissue accumulation of cholesterol, reduces total plasma cholesterol and very-long-chain fatty acid
(VLCFA)
The symptom of X-ALD mouse tissues levels cholesterol accumulation whether can be improved for detection HPCD, the total courage of blood plasma is reduced and consolidate
Alcohol and very-long-chain fatty acid (VLCFA).Injecting normal saline and HPCD 7 monthly age WT, ABCD1 are distinguished in Example 1-/-It is small
Mouse, separation adrenal gland and cerebellum progress frozen section and Filipin dyeing, progress total plasma cholesterol and very-long-chain fatty acid
Measurement.
(1) tissue section strain：Thoracic cavity will be cut off after mouse anesthesia, the 20mL through left ventricle insertion scalp acupuncture connection is injected
Device, while an osculum is cut at right auricle of heart with scissors, 20mL physiological saline is pushed into, changes 20mL 4% poly first after having pushed away rapidly
Aldehyde；Tissue adrenal gland and cerebellum needed for taking out, fixed stay overnight is put into 4% paraformaldehyde；Tissue after fixation is immersed in
In 30% sucrose (being dissolved in PBS) overnight；With OCT investing tissues, -80 DEG C are stored in；The OCT tissues embedded are fixed on frost
On slicer, slice thickness is 20 μm, and PBS washes away the OCT of histotomy attachment, and section is immersed in containing 100 μ g/mL's
4h is dyed in filipin solution；Histotomy is washed 3 times with PBS, then is washed with deionized water once；Fluorescence microscopy is used after fixation
Sem observation.Frozen tissue section is stored in -20 DEG C after drying.
As a result as shown in figure 3, compared with WT mouse cells, the ABCD1 of injecting normal saline-/-The adrenal cortex of mouse
There are a large amount of accumulation of cholesterol with cerebellum, and inject HPCD ABCD1-/-In the adrenal cortex and cerebellum of mouse, cholesterol
Accumulation is eased.
(2) T-CHOL determines with very-long-chain fatty acid：
Wherein, the measuring method of total plasma cholesterol is：The μ L of mice serum 3 are taken, contain cholesterol esterase with 300 μ L
(200U/L), cholesterol oxidase (100U/L), peroxidase (3KU/L), the courage of 4-AA (0.3mmol/L)
Sterol determines reagent and reacted 5 minutes at 37 DEG C, measurement 500nm or so absorbances, cholesterol level is calculated by standard curve.
The measuring method of very-long-chain fatty acid is：Adrenal gland or brain tissue are through organic solvent (chloroform:Methanol=2:1, v/v)
Homogenate, extracting and N2Dry, prepare fatty acid methyl ester.Fatty acid methyl ester is dissolved with heptane after the drying, by gas chromatograph point
From by peak figure identification and calculating fatty acid concentration.
As a result as shown in Figure 4,5：The ABCD1 of injecting normal saline-/-Mice plasma T-CHOL and VLCFA amounts are small compared with WT
Mouse is significantly raised, but HPCD injections make ABCD1-/-Cholesterol in mice plasma returns to normal level (Fig. 4), improves it
VLCFA accumulation (Fig. 5) in brain tissue and adrenal gland.
Embodiment 4HPCD reduces X-ALD mouse weights
Injecting normal saline and HPCD 12 monthly age WT, ABCD1 are distinguished in Example 1-/-Mouse carries out body weight.As a result
As shown in Figure 6：The ABCD1 of injecting normal saline-/-Mouse weight is significantly raised compared with WT mouse, and injects HPCD ABCD1-/-It is small
Mouse weight recovery is normal.
It is abnormal that embodiment 5HPCD alleviates X-ALD mice behaviors
The exception on X-ALD mice behaviors can be improved for detection HPCD, distinguish injecting normal saline in Example 1
With HPCD 20 monthly age WT, ABCD1-/-Mouse carries out bull stick experiment and spacious field experiment respectively.
(1) bull stick is tested：Mouse is a few days ago undergone training tested.Experimental day, mouse is positioned over balance fatigue and turned
On lever device, device is allowed to start to rotate with 4rpm starting rotating speed, and speed is gradually promoted into 10rpm in two minutes.
After rotation rod speed reaches 10rpm, start to note down the time that mouse drops from rotary bar.
What bull stick experiment detected is the time that mouse adheres to not dropping on the horizontal bull stick ramped up, as a result such as Fig. 7
It is shown, the ABCD1 of injecting normal saline-/-Mouse adheres to that the time drops to the 19% of WT mouse on bull stick, and HPCD injections make
ABCD1-/-Mouse adheres to that the time returns to the 87% of WT mouse.
(2) spacious field is tested：Mouse preceding is placed in experimental place to adapt to environment in advance tested.Experimental day, by mouse
40 × 40cm of length and width, high 40cm plexiglas inframe are placed on, camera device is laid in top, and record mouse is in 15 minutes
Activity.Plexiglas bottom is divided into the square of 9 deciles.Camera device monitors mouse event trace, activity in device
Distance and lift the behaviors such as upper limbs.
The statistical result of mouse forelimb is liftoff number is as shown in figure 8, the ABCD1 of injecting normal saline-/-Mouse lifts forelimb
Number be remarkably decreased to the 32% of WT mouse, and HPCD injection make ABCD1-/-Mouse lifts forelimb number and returns to WT mouse
95%.In mouse 15 minutes mobile total distance statistical result as shown in figure 9, the motion track in spacious field in 15 minutes such as
Shown in Figure 10, likewise, the ABCD1 of injecting normal saline-/-Mouse moved 32% that total distance is WT mouse in 15 minutes,
And HPCD injections make ABCD1-/-The total distance of mouse movement is recovered.
Claims (1)
- Application of the 1.2- hydroxy propyl-Betas-cyclodextrin in the medicine for preparing the treatment chain adrenal gland white matter of brain degeneration diseases of X-.
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| WO2000018394A1 (en) * | 1998-09-28 | 2000-04-06 | The Johns Hopkins University | Adrenoleukodystrophy treatments and drug screening |
| US6664039B1 (en) * | 1998-10-14 | 2003-12-16 | California Institute Of Technology | Methods and compositions for modulating neurodegeneration |
| JP2004277357A (en) * | 2003-03-17 | 2004-10-07 | Tsuneo Imanaka | AGENT FOR ACTIVATING FATTY ACID-beta-OXIDATION SYSTEM OF PEROXISOME, AND METHOD FOR SCREENING MATERIAL FOR ACTIVATING FATTY ACID-beta-OXIDATION SYSTEM OF PEROXISOME |
| CN102539592A (en) * | 2010-12-09 | 2012-07-04 | 北京国立柏林医学科技发展有限公司 | Method for detecting content of VLCFAs (very long chain fatty acids) in body fluid |
| CN103717240A (en) * | 2011-06-10 | 2014-04-09 | 蓝鸟生物公司 | Gene therapy vectors for adrenoleukodystrophy and adrenomyeloneuropathy |
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| US8728824B2 (en) * | 2011-06-22 | 2014-05-20 | Quest Diagnostics Investments Inc. | Mass spectrometric determination of fatty acids |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000018394A1 (en) * | 1998-09-28 | 2000-04-06 | The Johns Hopkins University | Adrenoleukodystrophy treatments and drug screening |
| US6664039B1 (en) * | 1998-10-14 | 2003-12-16 | California Institute Of Technology | Methods and compositions for modulating neurodegeneration |
| JP2004277357A (en) * | 2003-03-17 | 2004-10-07 | Tsuneo Imanaka | AGENT FOR ACTIVATING FATTY ACID-beta-OXIDATION SYSTEM OF PEROXISOME, AND METHOD FOR SCREENING MATERIAL FOR ACTIVATING FATTY ACID-beta-OXIDATION SYSTEM OF PEROXISOME |
| CN102539592A (en) * | 2010-12-09 | 2012-07-04 | 北京国立柏林医学科技发展有限公司 | Method for detecting content of VLCFAs (very long chain fatty acids) in body fluid |
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