CN108186669A - Application of the chitosan as treatment traumatic optic neuropathy drug - Google Patents
Application of the chitosan as treatment traumatic optic neuropathy drug Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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Abstract
The invention discloses the novel clinical use of chitosan, specially application of the chitosan as treatment traumatic optic neuropathy drug.The disclosed new application is the application of chitosan or its pharmaceutically acceptable salt, fat, solvate in traumatic optic neuropathy drug is treated.It has the characteristics that：1) survival of optic nerve RGCs can be promoted；2) death of retina R GCs is reduced；3) promote the regeneration of optic nerve；4) promote the recovery of optic nerve flash visual evoked potential (F VEP)；5) compared to the drug of other treatment treatment traumatic optic neuropathy, safety is ripe, and toxic side effect is low；6) since chitosan is clinically widely used, as treatment traumatic optic neuropathy drug, research cost can be reduced, is economized on resources, shorten the development cycle.
Description
Technical field
Novel clinical use more particularly to chitosan the present invention relates to chitosan is as treatment Traumatic optic neuropathy
Become the application of drug.
Background technology
Traumatic optic neuropathy (Traumatic Optic Neuropathy, TON) refers to contusion injuries or penetrability
Serious optic nerve injury disease caused by head or facial wound, clinical signs are dyschromatopsia, visual field defects, pupil
Afferent, visual loss etc..
TON includes primary injury and secondary lesion, and primary TON is mainly led by the optic nerve that wound directly results in
Damage, contusion etc. are drawn, pathological change is shown as：Optic nerve oedema, local vascular compression or optic nerve caused by dyshaemia
It is scorching；Optic nerve injury caused by optic nerve ischemia oedema etc. caused by secondary TON refers mainly to primary wound, pathological change performance
For：The different degrees of death of retinal ganglial cells (Retinal Ganglion Cells, RGCs), secondary injury morbidity machine
System is still not clear at present.Zooscopy confirms that the pathologic basis that optic nerve injury back vision function declines is the degeneration with axonal fibers
Based on the dead and secondary forfeitures of RGCs.Therefore, how to promote to damage the reparation of optic nerve, save visual function as possible is to face
One of hot spot studied in bed and the important topic of basic research and world today's medical domain.
Current clinically most common therapy is Hormone stosstherapy, but no matter Clinical Follow-up and zoopery
As a result it proves：Hormonotherapy does not improve visual performance or even increases hormone dosage can aggravate the damage of aixs cylinder instead, lead
Cause RGCs further death (Steinsapir 2000；Diem 2003；Yu-Wai-Man&Griffiths,2007).Therefore, it looks for
It is the traumatic optic nerve for the treatment of to the apoptosis of a kind of safe and effective and without side-effects Drug inhibition RGCs and promotion nerve regneration
The hot issue of lesion.The technical problem to be solved by the present invention is to：Further expand chitosan in clinical new application.
Chitosan (Chitosan) is from chitin also known as chitosan (chitosan) molecular formula：
(C6H11O4N) n is from Crustaceans, fungi, yeast, diatom sponge, rudimentary plant mushroom, algae, mollusk and compacted
A kind of gucosamine polymer containing a large amount of cations extracted in the cell walls such as worm, the preparation method of chitosan can
With referring to (a kind of preparation method of chitosan disclosed in Chinese patent, 105542034 B of Authorization Notice No. CN, Granted publication
Day 2018.01.30) or (a kind of chitosan preparation method, Authorization Notice No. CN 104045741 disclosed in Chinese patent
B, authorized announcement date 2016.09.07) extraction.
In rat body carry out chitosan gavage after pharmacokinetics and biodegradation research shows that：It is gathered in
Chitosan in liver and kidney is most, secondly mostly in heart, brain and spleen, while it has also been found that since chitosan is big
Molecular polysaccharide, in the chitosan that each histoorgan detects be its catabolite and molecular weight is less than 65KD, therefore in group
Knit catabolite really work in organ and chitosan.The metabolite chitin oligo saccharide of chitosan passes through inhibition
The raising of Bax/Bcl-2 and the activity of caspase-3 avoid the generation of apoptosis and then significantly inhibit what glutamate induced
PC12 cell deaths.In the neurodegenerative disease alzheimer rat model of A β 1-42 inductions, oral chitin oligo saccharide can
Oxidative pressure and inflammatory reaction to be inhibited effectively to slow down the decline of study, memory and cognitive ability.Chitosan can also inhibit
Apoptosis, the damage of mitochondrial membrane potential and the generation of ROS are to increase the survival of cell.Since chitin oligo saccharide can pass through
Regulate and control the death of hippocampal neuron that the increase of calcium ion prevents glutamate from inducing, therefore chitosan and catabolite chitin
Oligosaccharides can be used for treating Parkinson's disease.Chitin oligo saccharide can also be by reducing the neurotoxicity of glutamate and the production of active oxygen
Raw treatment Huntington chorea.Find that part can promote cell membrane using chitosan in the experiment of guinea pig spinal cord injury
Closing restores the nerve impulse of spinal cord.After peripheral nerve injury, chitin oligo saccharide can promote nerve regneration, send out simultaneously
Existing chitin oligo saccharide can dramatically increase the quantity of regeneration medullated fibers, muscle action potential, meat fiber cross-sectional area with
And myelinogenetic thickness again.Equally, in Rats'Sciatic Nerve Injury model, chitin oligo saccharide can promote peripheral nerve again
It is raw.For the catabolite chitin oligo saccharide of chitosan by promoting Chemokines CC CL2, induction and recruitment macrophage reach damage
Site reconstructs the microenvironment of damage location, promotes peripheral nerve regeneration.
Meanwhile in clinical practice, chitosan can not only prevent and treat the postoperative tissue adhesion of customer, alleviate
The degenerative arthritis such as knee joint and Bones and joints, additionally it is possible to reduce blood glucose and blood fat, mitigate atherosclerosis, adjust sleep etc.
(" application of chitosan clinically ", Wan Li, Tian Wei, Shenyang Medical College journal, the 2nd phase of volume 15, in June, 2013).
In summary, the key for treating traumatic optic neuropathy is to find a kind of apoptosis and rush that can reduce RGCs
Into the regenerated drug of optic nerve.The god of chitosan and its catabolite in neurodegenerative disease and other neurological diseases
Mainly include through protective effect following：Anti-oxidant, inhibition neuroinflamation inhibits exitotoxicity, reduces apoptotic effect, controlling gene
Expression and ion channel, metal ion chelation agent, neurotrophic factor, metal protease inhibitors.And chitosan is facing
Largely use, is very safe drugs in bed.And chitosan promote nerve fiber and other tissue growths healing it is potential
Function undoubtedly brings hope for the neuropathy disease that there is no effective therapy at present.But so far, in TON
The unmanned report of the effect of chitosan.Meanwhile chitosan mechanism in TON is also unclear in traumatic optic neuropathy.
Invention content
It is an object of the present invention to provide the new application of chitosan clinically.
To achieve these goals, the present invention provides a new application of chitosan：Chitosan or its pharmaceutically may be used
Application of the salt, fat, solvate of receiving in traumatic optic neuropathy drug is treated.
In above application, the traumatic optic neuropathy is caused by the head or facial wound of contusion injuries or penetrability
Optic nerve injury disease.
The selection of above-mentioned disease it is following any one：Dyschromatopsia, visual field defects, pupil afferent, visual loss.
The treatment object of above-mentioned disease is：The disease is the crowd of traumatic optic nerve injury.
In above application, a concentration of 30mg/kg/day, 100mg/kg/day, 300mg/kg/day of the chitosan.
In above application, the concentration of the chitosan is preferably 300mg/kg/day.
The present invention provides a kind of drug for treating traumatic optic neuropathy, and active constituent is chitosan or its pharmacy
Upper acceptable salt, fat, solvate.
Said medicine causes for treating traumatic optic neuropathy for the head or facial wound of contusion injuries or penetrability
Optic nerve injury disease, predominantly it is following any one：Dyschromatopsia, visual field defects, pupil afferent, eyesight funeral
It loses.
Said medicine is used to treat the crowd of traumatic optic nerve injury.
In said medicine, a concentration of 300mg/kg/day of chitosan.
Beneficial effects of the present invention：It is that one kind is used to treat traumatic optic nerve that the present invention, which is experimentally confirmed chitosan,
Lesion drug, has the following advantages that：
(1) the results show, chitosan can promote the survival of optic nerve RGCs.
(2) the results show, chitosan replace previous hormonotherapy, improve visual performance, reduce and regard retina
The death of RGCs.
(3) the results show, chitosan promote the regeneration of optic nerve.
(4) the results show, chitosan promote the recovery of optic nerve flash visual evoked potential (F-VEP).
(5) compared to the drug of other treatment treatment traumatic optic neuropathy, safety is ripe, and toxic side effect is low.
(6) it since chitosan is clinically widely used, as treatment traumatic optic neuropathy drug, can drop
Low research cost, economizes on resources, and shortens the development cycle.
Description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention, for those of ordinary skill in the art, without creative efforts, can be with
Other attached drawings are obtained according to these attached drawings.
Fig. 1 be various concentration chitosan gavage after rat body weight variation diagram；
Fig. 2 be various concentration chitosan gavage after optic nerve HE coloration result figures；
Fig. 3 be various concentration chitosan gavage after rat retina HE coloration result comparison diagrams；
A is the quantity variation diagram of GCL layers of RGCs of different experiments group rat retina in Fig. 4；B is different experiments group Rat Visual
The quantity variation electron microscope of GCL layers of RGCs of nethike embrane；
A is the quantity variation diagram of GCL layers of RGCs of operation group and dosing group different number of days rat retina in Fig. 5；B is operation
Group and the quantity of GCL layers of RGCs of dosing group different number of days rat retina variation electron microscope；
Fig. 6 be chitosan promote optic nerve clamping optic nerve regeneration (asterisk be labeled as optic nerve clamping part
Position) figure；
Fig. 7 is the recovery figure that chitosan promotes flash visual evoked potential (F-VEP).
Specific embodiment
Below in conjunction with the attached drawing in the embodiment of the present invention, the technical solution in the embodiment of the present invention is carried out clear, complete
Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, those of ordinary skill in the art are obtained every other without making creative work
Embodiment shall fall within the protection scope of the present invention.
It is conventional experimental method if the experimental method used in following embodiments is without specified otherwise.
Experiment one：Explore the influence of chitosan concentration in optic nerve Clamping damage model
Step 1：Stable optic nerve clamping is established using opening epilemma through bulbar conjunctiva outer canthus portion and crushing optic nerve method
Wound model；
Step 2：Since commodity chito polysaccharide molecular weight is larger and indissoluble, by gavage mode by various concentration
Chitosan injection optic nerve clip-model in, various concentration is i.e. using 30mg/kg/day, 100mg/kg/day, 300mg/
The chitosan of kg/day；
Step 3：The chitosan for injecting various concentration is observed continuously 18 days later, record experimental result (referring to Fig. 1).
It is shown by experimental result it is found that gavage is after 18 days, finds the chitosan of various concentration to rat body weight without shadow
It rings, and with operation group without significant difference, therefore various concentration chitosan has no toxic action to rat.
Experiment two：Explore effect of the chitosan to optic nerve and its retina in rat clip-model
Step 1 and step 2 are the same as the step of above-described embodiment one one and step 2；
Step 3：After optic nerve clamps 14 days, by hematoxylin eosin staining, result is observed.
Optic nerve clamp 14 days after (referring to Fig. 2), regarding for sham-operation group is can see that after hematoxylin eosin staining
Neural even dyeing.Present streak, Deiter's cells nuclear arrangement is neat, and vacuole is few；And after optic nerve clamping
It was found that Deiter's cells nuclear arrangement is disorderly, Cytoplasm reduction, vacuole increases, and oedema phenomenon occurs；Compared with operation group,
The optic nerve dyeing of 30mg/kg/day and 100mg/kg/day concentration groups is inhomogenous, and cell arrangement is disorderly, and vacuole is still very much,
And 300mg/kg/day concentration group is compared with operation group, even dyeing, vacuole significantly reduces, and cytoplasm increases.
Optic nerve clamp 14 days after (referring to Fig. 3), also pass through HE coloration results discovery, compared with sham-operation group, hand
The retinal thickness of art group is significantly thinning, and GCL layers and each confluent monolayer cells number significantly reduce, and inner nuclear layer and outer nuclear layer show thin.
As it can be seen that retinal thickness significantly increases compared with operation group after dosing, interior outer nuclear layer is significantly thickened compared with operation group.
Experiment three：Explore survival condition of the chitosan to promotion RGCs after optic nerve clamping of various concentration
Step 1 and step 2 are the same as the step of above-described embodiment one one and step 2；
Step 3：Eyeball is taken out by heart perfusion, frozen section carries out immunofluorescence dyeing, observes result.
Experimental result shows (referring to Fig. 4), and compared with sham-operation group, operation group RGCs numbers substantially reduce, and by giving
Chitosan is given to be later discovered that, the number of RGCs increases to some extent, and the quantity of RGCs is with chitosan concentration
Increase present growth trend, by statistical analysis, 100mg/kg/day and 300mg/kg/day concentration groups compared with operation,
RGC quantity increases statistically significant (P>0.05).
Experiment four：Explore the death condition that chitosan reduces different time points retina R GCs
The various embodiments described above the result shows that, the chitosan of 300mg/kg/day concentration has no animal bad in itself
It influences, and by HE as a result, it has been found that the chitosan of the concentration has certain protective role for retina and optic structure.
Therefore, the present embodiment further study 300mg/kg/day concentration after optic nerve Clamping damage different time points to retina and
Chitosan possible mechanism of action in optic nerve Clamping damage is explored in the effect of optic nerve.
First, immunofluorescence dyeing is carried out by NeuN antibody, compares work of the chitosan to RGCs of different time points
With as a result display is (referring to Fig. 5), and compared with sham-operation group, after clamping optic nerve, RGCs numbers are gradual with the extension of time
It reduces, and after the different time points dosing clamped, number all increases to some extent, and there were significant differences with operation group, because
This, chitosan has protective effect for the RGCs of different time points.
Experiment five：Explore the regeneration situation that chitosan promotes optic nerve clamping optic nerve
Growth associated protein (Growth associated protein, GAP-43) is the specificity marker of nerve regneration
Object, the expression of GAP-43 can reflect the situation for hindering back vision function recovery to a certain extent, therefore utilize the method for immunofluorescence
Whether detection chitosan can promote the regeneration of optic nerve.
(with reference to Fig. 6) GAP-43 is almost without expression in the optic nerve normally organized, after clamping 3 days and 7 days, dosing group and
Operation group indifference, without optic nerve regeneration, and clamp 14 days groups as a result, it has been found that the GAP-43 expression of dosing group is apparent increases
(white arrow is signified), prompts chitosan that can promote optic nerve regeneration.
Experiment six：Explore the recovery situation that chitosan promotes flash visual evoked potential (F-VEP)
(referring to Fig. 7) F-VEP indicates the light sensation conduction function on optic nerve Clamping damage backsight road.Right eye is operation eye,
Operation group amplitude reduces, and there is no improve with time delay；Compared with operation group, dosing group amplitude is significantly replied.Into one
Step shows that chitosan promotes the recovery of visual performance.
Specific embodiments of the present invention
By taking the patient of traumatic optic neuropathy as an example, the specific embodiment of new medicine use of the present invention is said
It is bright.
20 patients for suffering from traumatic optic neuropathy are chosen in the first step, acquisition sampling, and the age is male at 20 years old or more
Female is unlimited.It is as follows that patient enters group condition：
1) it does not have undergone surgery or other drugs is treated；
2) without serious drug allergy history；
It 3) can be with oral drugs；
4) Written informed consent is signed；
5) the major organs function such as blood picture, the heart, lung, liver, kidney is normal, and blood routine examination checks normal.
Second step：20 patients are divided into two groups by grouping by random blind check experiment method：Test group, control group are each
10 people.
Third walks：It is tested, according to 300mg/kg/day concentration, takes chitosan to everyone of test group, often
It is taken once, and each course for the treatment of seven days continuously takes 5 course for the treatment of；Placebo is taken to everyone of control group, is not treated.
Third walks：After 2 courses for the treatment of of medication, the patient of two groups is checked, it is found that each patient of test group regards
Power significantly has improvement, without apparent side effect.And the individual patient of control group, it does not change significantly.
After 3 courses for the treatment of of medication, the patient of two groups is checked, find test group each patient's vision have it is good
Turn, and normal before the ratio of the visual field, without apparent side effect.And the individual patient of control group, it does not change significantly.
After 4 courses for the treatment of of medication, the patient of two groups is checked, it is found that each patient's vision of test group is better than in the past
, the visual field is more normal, and eyeball can inwardly, upper and lower is to freedom of movement.The individual patient of control group is still without apparent
Variation.
After 5 courses for the treatment of of medication, the patient of two groups is checked, finding each patient's vision of test group has significantly
Rise, the visual field become it is normal, eyeball inwardly, upper and lower to freedom of movement, eyeball is downward and abduction exercise is normal.Control group
Individual patient do not change significantly still.
It follows that compared to the patient for not taking remedy measures, the later patient's vision of medication has rise, and the visual field becomes
It is normal, eyeball inwardly, upper and lower to freedom of movement, eyeball is downward and abduction exercise is normal.Therefore drug chitosan is external
The treatment of the patient of wound property optic neuropathy has apparent therapeutic effect.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the scope of the present invention.It is all
Any modification, equivalent replacement, improvement and so within the spirit and principles in the present invention, are all contained in protection scope of the present invention
It is interior.
Claims (10)
1. chitosan or its pharmaceutically acceptable salt, fat, solvate are in traumatic optic neuropathy drug is treated
Using.
2. application according to claim 1, it is characterised in that：The traumatic optic neuropathy is contusion injuries or penetrability
Head or facial wound caused by optic nerve injury disease.
3. application according to claim 2, it is characterised in that：Described disease selection it is following any one：Dyschromatopsia,
Visual field defects, pupil afferent, visual loss.
4. application according to claim 3, it is characterised in that：The disease is the crowd of traumatic optic nerve injury.
5. application according to claim 1, it is characterised in that：A concentration of 30mg/kg/day of the chitosan,
100mg/kg/day、300mg/kg/day。
6. application according to claim 4, it is characterised in that：The concentration of the chitosan is preferably 300mg/kg/
day。
7. a kind of drug for treating traumatic optic neuropathy, active constituent is chitosan or its is pharmaceutically acceptable
Salt, fat, solvate.
8. drug according to claim 7, it is characterised in that：The drug is blunt for treating traumatic optic neuropathy
Dampen or penetrability head or facial wound caused by optic nerve injury disease, predominantly it is following any one：Colour vision hinders
Hinder, visual field defects, pupil afferent, visual loss.
9. drug according to claim 7, it is characterised in that：The drug is used to treat the people of traumatic optic nerve injury
Group.
10. drug according to claim 7, it is characterised in that：A concentration of 300mg/kg/ of chitosan in the drug
day。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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Application publication date: 20180622 |