CN104906124B - Application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury - Google Patents
Application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury Download PDFInfo
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Abstract
The invention discloses application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury.The drug is using a effective amount of Calcium Dibutyryladenosine Cyclophosph-ate as active constituent, in addition the medicament that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.The Calcium Dibutyryladenosine Cyclophosph-ate of the present invention functional rehabilitation, neuron adenosine cyclophosphate concentration, neuron after Spinal Cord Injury in Rats repair three aspects, are significantly improved effect.Calcium Dibutyryladenosine Cyclophosph-ate has the ability of more powerful activation adenosine cyclophosphate signal pathway, is the drug that excellent promotion spinal cord injury is restored.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to Calcium Dibutyryladenosine Cyclophosph-ate is in the medicine for preparing treatment spinal cord injury
Application in object.
Background technology
Spinal cord injury is that a kind of disability rate is high, and rear poor disease, incidence is annual 10.4~83.0/100 ten thousand, and is had
The trend being gradually increasing.Spinal cord injury leads to the partly or completely death such as nerve cell, Deiter's cells in tissue, together
When tissue in nerve conduction fiber fracture, demyelinate etc. occurs, so as to cause the missing of function of spinal nerves.Spinal cord injury
Feeling below lesion level can not only be led to, the obstacle of motor function is lived and lost, it is also possible to lead to the barrier of multiple organ dysfunctions
Hinder, such as respiratory system, the circulatory system, urinary system and digestive system.Since it causes the forfeiture of labour, prolonged health
The medical expense of a large amount of medical resource and costliness is treated, occupied again, and huge bear is brought to personal, family and the whole society
Load.Although operative treatment and drug therapy (such as glucocorticoid) make to varying degrees impaired spinal cord obtained restore and again
Raw space, but still inevitably cause the serious consequence of patient's paralysis or even death.
Adenosine cyclophosphate is the derivative of nucleotide, in recent years research shows that, adenosine cyclophosphate spinal cord injury recovery in have
Important function.Functional rehabilitation after spinal cord injury is primarily limited to the power of regeneration of Damaged axon.Axon regeneration be unsuccessfully due to
Aixs cylinder own growth Disability causes, and myelin phosphatide mortifier in extracellular environment etc. also can induce Axonal growth cone and collapse
It falls into, inhibit axon regeneration, the glial scar that astroglia is formed becomes the physical barriers of axon elongation.It is more crucial
It is that spinal cord injury can lead to being denaturalized of neuron, necrosis or severe atrophy, reduces the quantity of neuron.Thus, promote aixs cylinder
Regeneration and neuronal survival can improve the reparation after central lesion.Why adult organism neuron loses Regenerated energy
Power, one of the major reasons are that intracellular loops phosphorus adenosine level declines.
Invention content
The technical problems to be solved by the invention are for spinal cord injury disease, provide a kind of Calcium Dibutyryladenosine Cyclophosph-ate
New medicine use.The present inventor by repeatedly experimental studies have found that, Calcium Dibutyryladenosine Cyclophosph-ate can significantly improve ridge
The behavioral functions of cord injury rats restores, increase neuron adenosine cyclophosphate concentration, promote axon growth, especially calcium ion with
Dibutyryl adenosine cyclophosphate has synergistic effect, compared with dibutyryl adenosine cyclophosphate is used alone, the drug effect of Calcium Dibutyryladenosine Cyclophosph-ate
It is more prominent.
The present invention provides application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury.
Those skilled in the art know that Calcium Dibutyryladenosine Cyclophosph-ate of the invention is preferably comprised C18H23N5O8P·1/
2Ca and C18H23N5O8P·1/2Ca·2.3H2O, the preferred C of the present invention18H23N5O8P·1/2Ca·2.3H2O。
Wherein, the spinal cord injury is preferably comprised neuronal cell denaturation, necrosis and aixs cylinder regression.
Wherein, the dosage of the Calcium Dibutyryladenosine Cyclophosph-ate is preferably 0.6~1.0mg/kg body weight/days.
Wherein, the administering mode of the Calcium Dibutyryladenosine Cyclophosph-ate is intravenous injection or intramuscular injection.
Wherein, the drug is preferably using a effective amount of Calcium Dibutyryladenosine Cyclophosph-ate as active constituent, in addition pharmacy
The pharmaceutical preparation that upper acceptable auxiliary material or complementary ingredient are prepared.
Wherein, the pharmaceutical preparation is preferably freeze-dried powder or injection, is most preferably freeze-dried powder.
On the basis of common knowledge of the art, above-mentioned each optimum condition can be combined arbitrarily to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：Present invention research finds that Calcium Dibutyryladenosine Cyclophosph-ate can be used for nervous centralis
The reparation of system function damage, such as the reparation of spinal cord injury.The recovery of BBB detection functions, neural round rings after Spinal Cord Injury in Rats
Phosphorus adenosine concentration, neuron repair three aspects, and the function of Calcium Dibutyryladenosine Cyclophosph-ate is all significantly beyond dibutyryl adenosine cyclophosphate.
Calcium Dibutyryladenosine Cyclophosph-ate can not only inhibit phosphodiesterase, the degradation for preventing adenosine cyclophosphate, moreover it is possible to by calcium ion activated
Adenyl cyclase, the synthesis for increasing adenosine cyclophosphate.Thus Calcium Dibutyryladenosine Cyclophosph-ate has more powerful activation ring phosphorus gland
The ability of glycosides signal pathway is the drug that excellent promotion spinal cord injury is restored.
Description of the drawings
Fig. 1 is the BBB scoring change curves of rat after spinal cord injury.
Fig. 2 is cAMP changes of contents curve graphs in the spinal cord of rat after spinal cord injury.
Fig. 3 is the neuron number variation diagram of rat after spinal cord injury.
Specific embodiment
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.Test method without specific conditions in the following example, according to conventional methods and conditions or according to quotient
Product specification selects.
Experiment material and method
SD male rats are cleaned, weight 200-220g is purchased from Shanghai Experimental Animal Center, is divided into four groups, every group of 30 (its
In be divided into as 0,7,14 day each 10 of group), respectively A groups：Negative control group (amyelia damage modeling processing), B groups：Physiology salt
Water group (being intramuscular injection normal saline after spinal cord injury modeling), C groups：Injecting dibutyryl adenosine cyclophosphate group, (i.e. spinal cord injury is made
After mould it is intramuscular injection dibutyryl adenosine cyclophosphate 0.16mg/ days, 2ml is dissolved in as active constituent using commercially available 20mg dibutyryl adenosine cyclophosphates
Solution is configured in physiological saline), D groups：It (is two butyryl of intramuscular injection i.e. after spinal cord injury modeling to inject Calcium Dibutyryladenosine Cyclophosph-ate group
Adenosine cyclophosphate calcium 0.16mg/ days, with 20mg C18H23N5O8P·1/2Ca·2.3H2O is dissolved in 2ml physiological saline for active constituent
In be configured to solution).
Calcium Dibutyryladenosine Cyclophosph-ate is from first biochemical pharmaceutcal corporation, Ltd's (batch 1306021) of Shanghai medicine-feeding
Spinal cord moderate lesion rat model --- bilateral lamina removal art (T8)
(1) after 1% amobarbital of rats by intraperitoneal injection (50mg/kg) fully anesthesia, prostrate, back is with T10 (centrum)
Center shaving preserved skin；
(2) exposure T8 vertebral plates, back side center line 30-40mm stringer notch cut skin and subcutaneous tissue, exposure T6-11 sections
Vertebral plate；
(3) T9 both sides processus articular superior is cut off, and T8 both sides pedicle of vertebral arch is cut, T8 vertebral plates is made to be detached with vertebra, remove T8
Vertebral plate cleans the spinal cord under exposure endorchis package after debridement.
Spinal cord crushes
(1) it is inwardly at the uniform velocity closed and is kept closed 20 seconds from spinal cord both sides with gap 0.5mm tweezers；
(2) after modeling success, layering suture muscle and skin.
1 BBB detection functions of embodiment restore experiment
Animal is smooth as surface, and in the open environment of all round closure, free movement 4 minutes is taken the photograph with video recorder
Picture.By assessing rat trunk, tail, the motion conditions of hind leg score.Divided according to BBB standards of grading 21, point in the morning, afternoon and evening three
Phase：
0 point：Without visible hind limb motor
1 point：One or two joint light exercises, usually hip and/or knee joint
2 points：One joint is movable extensively or a joint is movable extensively and has another joint light activity
3 points：Two joints are movable extensively
4 points：All three joints can light activity for hind leg
5 points：Two joint light activities, third joint can be movable extensively
6 points：Two joints are movable extensively, and third joint can light activity
7 points：All three joints can be movable extensively for hind leg
8 points：It can be landed in the case of non-bearing with pawl facies palmaris
9 points：Between or pawl facies palmaris load bearing support or the load-bearing of the pawl back side movement, flukeless facies palmaris support movement
10 points：Accidental pawl facies palmaris load-bearing movement；Unmatched hind leg coordination
11 points：Facies palmaris load-bearing of seeing that can be more is moved, but unmatched hind leg coordination
12 points：Facies palmaris load-bearing of seeing that can be more is moved, accidental front and rear limb coordination
13 points：Common facies palmaris load-bearing movement, can common front and rear limb coordination
14 points：There are duration facies palmaris load-bearing movement and front and rear limb coordination；Or there is common facies palmaris movement, sustained
Front and rear limb coordination occasionally has the movement of pawl back side
15 points：Limb coordination before and after the movement of duration facies palmaris and duration, ground is grabbed in nothing or Europe during forelimb advances；
Just driving claw position and body parallel during contact
16 points：Visible duration facies palmaris movement and limb coordination before and after duration, forelimb are normal during advancing in gait
See that pawl grabs ground；Just driving claw position and body parallel during contact rotate after transfer of bearing a heavy burden.
17 points：Visible duration facies palmaris movement and limb coordination before and after duration, forelimb are normal during advancing in gait
See that pawl grabs ground；Just during contact and bear a heavy burden shift after driving claw position and body parallel.
18 points：Visible duration facies palmaris movement and limb coordination before and after duration in gait, forelimb can during advancing
Duration pawl grabs ground；Just driving claw position is rotated with body parallel, heavy burden after shifting during contact.
19 points：Visible duration facies palmaris movement and limb coordination before and after duration in gait, forelimb can during advancing
Duration pawl grabs ground；Just during contact and bear a heavy burden shift after driving claw position and body parallel.Tail is sometimes or always sagging.
20 points：Duration facies palmaris moves, and duration coordinates gait, and toes persistently grab ground, just during contact and after transfer of bearing a heavy burden
And body parallel, trunk is unstable, and tail persistently tilts for driving claw position.
21 points：Duration facies palmaris moves, and duration coordinates gait, and toes persistently grab ground, driving claw position in active procedure
Always with body parallel, trunk is continual and steady, and tail persistently tilts.
| BBB scores | Behaviouristics shows |
| In early days | Nothing or the movement of few hindlimb joints |
| Mid-term | Ataxic gait |
| Late period | Fine movement, such as toe and tail in tow, trunk is unstable and claw alternately rotates |
Fig. 1 is the BBB scoring change curves of rat after spinal cord injury.Take 0 day, 7 days, 14 days three time points were seen
It examines.It can be seen that rat hindlimb is paralysed (0 point) completely when B, C, D group damage (SCI) 0 day.After 7 days, C groups (11.1 ± 0.8)
Recovery is significantly higher than B groups (9.8 ± 0.7), and D groups (12.5 ± 0.6) recovery is significantly higher than C groups；p<0.05, there were significant differences.14
After it, C groups (15.6 ± 0.6) recovery is significantly higher than B groups (12.9 ± 0.9), and D groups (18.6 ± 0.6) recovery is significantly higher than C groups；p
<0.05, significant difference.BBB scoring displays, calcium ion can promote dibutyryl adenosine cyclophosphate to repair impaired exercise early function
It is multiple.Therefore, Calcium Dibutyryladenosine Cyclophosph-ate can be obviously improved the motor function reparation of rat after spinal cord injury.
2 ELISA of embodiment (enzyme-linked immunosorbent assay) detection cAMP (adenosine cyclophosphate) contents (0,7,14 day)
R＆D companies cAMP immune detection ELISA kits detect cAMP contents using Enzyme-linked Immunosorbent Assay competition law.
Preparation stage：
1st, reagent prepares：
Dcq buffer liquid：30ml concentration cold buffer washes add in distilled water and are diluted to 300ml.
Acetylation reagent：0.5ml acetic anhydrides are added in 1ml triethylamines, it is spare.
CAMP standard items (non-acetylation)：900 μ l ED2 detection buffer solutions is taken to add in test tube 1 (200pmol/ml), remaining 4
It is slow that a test tube (50pmol/ml, 12.5pmol/ml, 3.12pmol/ml, 0.78pmol/ml) is separately added into 750 μ l ED2 detections
Fliud flushing.100ul is taken to add in test tube 1 from cAMP standard items (2000pmol/ml)；250ul is taken to add in test tube 2, test tube from test tube 1
2 take 250ul liquid to add in test tube 3, and test tube 3 takes 250ul liquid to add in test tube 4, and test tube 4 takes 250ul liquid to add in test tube 5.With
1 solution of test tube is cAMP content high standard product (200pmol/ml), and ED2 detection buffer solutions are zero standard product (0pmol/ml), and 1 is small
When interior use.
CAMP standard items (acetylation)：Take 990 μ l ED2 detection buffer solution add in test tube 1 (20pmol/ml), remaining 4
Test tube (5pmol/ml, 1.25pmol/ml, 0.312pmol/ml, 0.078pmol/ml) is separately added into 750 μ l ED2 detection bufferings
Liquid.10 μ l is taken to add in test tube 1 from cAMP standard items (2000pmol/ml)；250 μ l is taken to add in test tube 2 from test tube 1, test tube 2 takes
250ul liquid adds in test tube 3, and test tube 3 takes 250ul liquid to add in test tube 4, and test tube 4 takes 250 μ l liquid to add in test tube 5.With test tube
1 solution is cAMP content high standard product (20pmol/ml), and ED2 detection buffer solutions are zero standard product (0pmol/ml), in half an hour
It uses.
2nd, sample prepares
The grouping of SD rats and treatment processing are tested with aforementioned " experiment material and method ".
Sample is drawn materials：Suck etherization, cut comprising hinder section spinal cord backbone and left and right sides be connected rib cage remove it is one section long
About 1cm backbones are wrapped up with masking foil and immerse liquid nitrogen container preservation for ELISA measure cAMP.Sample grinding is taken out from liquid nitrogen container
It weighs, adds in 10 times of 5% trichloroacetic acids of solvent, centrifugation goes supernatant to add in 3 times of volume hydration ether, and drying adds in ED2 after removing water
It is spare to detect buffer solution.
3rd, standard items and sample acetylation
Per 200ulcAMP standard items or sample to be measured adds in 10ul acetylation reagents, the quasi- ED2 detections buffering per 1ml zero standards
Liquid adds in 50ul acetylation reagent acetylations.
Experimental procedure：
150 μ l buffer solutions are added in NSB micropores, 100ul buffer solutions is added in zero standard product micropore, adds in 100 μ l standards
Product or sample arrange remaining each micropore；50 μ l cAMP conjugates are added in each micropore outside gross activity and blank determination micropore；Add
Enter 50 μ l cAMP antibody-solutions to except NSB micropores, each micropore outside gross activity and blank determination micropore.Closed porosity room temperature is incubated
It educates 2 hours.
Board-washing is emptied each micropore and is rinsed 3 times with washing buffer, pours out remaining liquid.
Gross activity, which measures, adds in 5 μ l lcAMP conjugates in micropore.
200 μ l of p-nitrophenyl agent are added in all micropores, are incubated at room temperature 1 hour.
50 μ l of stopping of reaction solution are added in all micropores.
Each micropore optical density OD values are measured with microplate reader (U.S. Bole BIO-RAD 680, Detection wavelength 450nm).
Result judgement：
Each standard items and sample OD means are calculated, subtracts the OD means of NSB.
Calculate percentage Percentage bound B/B0(%), with sample or titer absorbance value (B) division by 0 standard absorbance value (B0)
× 100%, B/B0(%)=(OD-NSB)/(OD0- NSB) × 100, OD is given sample light absorption value, OD0Suction for positive control
Light value, NSB are the absorbance value of negative control；
Using acetylation cAMP titers log concentration as abscissa, OD values are ordinate, standard curve are drawn, according to standard
Curve measures sample cAMP concentration.
Fig. 2 is cAMP changes of contents curve graphs in the spinal cord of rat after spinal cord injury.As seen from the figure：
Spinal cord injury blank control group (i.e. A groups) cAMP is 102.3 ± 9.3pg/ml.
During spinal cord injury 0 day, the cAMP contents of B groups drop to 38.4 ± 2.3pg/ml, the cAMP contents of C groups for 78.3 ±
The cAMP contents of 4.2pg/ml, D group are 112.3 ± 4.3pg/ml.
During spinal cord injury 7 days, the cAMP contents of B groups are 42.1 ± 1.8pg/ml, the cAMP contents of C groups are 90.6 ±
The cAMP contents of 3.6pg/ml, D group are 151.3 ± 4.6pg/ml.
It is statistically analyzed, p<0.05, significant difference.
During spinal cord injury 14 days, the cAMP contents of B groups are 53.2 ± 1.9pg/ml, the cAMP contents of C groups are 110 ±
The cAMP contents of 3.8pg/ml, D group are 148.6 ± 5.2pg/ml.
It is statistically analyzed, p<0.05, significant difference.
Thus, it is possible to infer, Calcium Dibutyryladenosine Cyclophosph-ate can more effectively improve the content of adenosine cyclophosphate in damage spinal cord
Or its synthesis.
Influence of 3 Calcium Dibutyryladenosine Cyclophosph-ate of embodiment to neuron reparation
The grouping of SD rats and treatment processing are tested with aforementioned " experiment material and method ".
7 days and 14 day time point are selected after Spinal Cord Injury in Rats, excessive 1% amobarbital is injected intraperitoneally, with 400ml 4%
Paraformaldehyde is fixed through heart perfusion.During materials centered on spinal cord crushes place, the tissue for taking 1mm is cut at rostral 1.0cm.
It immerses in 25% sucrose solution and is dehydrated.Slice room temperature is dried, and 30min is closed with the 1%BSA room temperatures of 0.3%TritonX-100,
Then primary antibody (mouse anti-NeuN, Abcam, 1 are added in:1000), 4 DEG C of overnight incubations, the PBS of 0.01M are washed three times, are added
Enter with the matched fluorescence secondary antibody of primary antibody, be incubated at room temperature 2 hours, the PBS of 0.01M is washed three times, is buffered after glycerine mounting in fluorescence
Microscope (BX51, Olympus) detects spinal cord axons growing state under (40X).Image-Proplus 5.0 is utilized after taking pictures
Software carries out image analysis counting.
Fig. 3 is the neuron number variation diagram of rat after spinal cord injury, as can be seen from the figure：
The NeuN positive neuron numbers of 7 days are as follows：
A groups 11029 ± 1230, B groups 1501 ± 173, C groups 2418 ± 120, D groups 6321 ± 244.
It is statistically analyzed, P<0.05, significant difference.
NeuN positive neuron numbers are as follows within 14 days：
A groups 12013 ± 1240, B groups 1291 ± 120, C groups 4230 ± 230, D groups 8430 ± 536.
It is statistically analyzed, P<0.05, significant difference.
As a result show that Calcium Dibutyryladenosine Cyclophosph-ate can promote to damage the reparation of neuron in myeloid tissue.
Claims (9)
1. application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury, which is characterized in that two fourths
Acyl adenosine cyclophosphate calcium includes C18H23N5O8P1/2Ca and C18H23N5O8P·1/2Ca·2.3H2O。
2. application as described in claim 1, which is characterized in that the Calcium Dibutyryladenosine Cyclophosph-ate is C18H23N5O8P·1/
2Ca·2.3H2O。
3. application as described in claim 1, which is characterized in that the spinal cord injury include neuronal cell denaturation, necrosis,
With aixs cylinder regression.
4. application as described in claim 1, which is characterized in that the drug is with a effective amount of Calcium Dibutyryladenosine Cyclophosph-ate
For active constituent, in addition the pharmaceutical preparation that pharmaceutically acceptable complementary ingredient is prepared.
5. application as claimed in claim 4, which is characterized in that the complementary ingredient is auxiliary material.
6. apply as described in claim 4 or 5, which is characterized in that the pharmaceutical preparation is freeze-dried powder or parenteral solution.
7. application as claimed in claim 6, which is characterized in that the pharmaceutical preparation is freeze-dried powder.
8. application as described in claim 1, which is characterized in that the dosage of the Calcium Dibutyryladenosine Cyclophosph-ate is 0.6
~1.0mg/kg body weight/days.
9. application as claimed in claim 8, which is characterized in that the administering mode of the Calcium Dibutyryladenosine Cyclophosph-ate is muscle
Injection or intravenous injection.
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| CN103242403A (en) * | 2012-06-21 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof |
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Non-Patent Citations (1)
| Title |
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| "Cyclic AMP promotes axon regeneration, lesion repair and neuronal survival in lampreys after spinal cord injury";Billy Y.B. Lau et al.;《Experimental Neurology》;20130913;摘要 * |
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