Application of the compound epothilone B in the medicine for preparing repairing corneal traumatic nerve injury
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of compound epothilone B (EpothiloneB,
EpoB) the application in the medicine for preparing repairing corneal traumatic nerve injury.
Background technology
Corneal nerve is found in corneal limbus from Sohlemm in 1830, the research of corneal nerve there has been huge progress.Angle
Membrane tissue does not have blood vessel, but containing abundant nerve fibre, is one of people's nerves within the body most intensive tissue, is providing nutrition generation
Played an important role in the normal configuration and function of thanking, maintain cornea.Corneal sensitivity is the characteristics of corneal nerve is most prominent, is had
Sharp sensory function.Corneal nerve belongs to peripheral nerve, with incomplete power of regeneration, although after wound, corneal nerve
It can slowly regenerate, but be difficult that can recover normal neuronal density and function.
Surgical injury, illness in eye and long-term ophthalmic administration will all cause corneal nerve abnormal.Surgical injury is direct
Destroy corneal nerve.Illness in eye is mostly keratitis, xerophthalmia, diabetes:Central corneal hypothallus nerve with keratitis
Density is significantly lower than normal cornea, there is the neural structural anomaly of obvious corneal stroma;The corneal nerve quantity of patients with dry eye,
Flexibility, nervous ramification all increase;Diabetes are a kind of systemic metabolic diseases, can involve whole body each organ, can also cause
The exception of corneal nerve, the matrix nerve fibre bundle quantity of its patient is significantly reduced, and the sensitiveness of cornea is also remarkably decreased.It is long
Phase can cause the reduction of neural quantity and density under corneal epithelium using ocular drug.Patient suffering can't bear, but at present, clinic is still
Without a kind for the treatment of method for accelerating cornea CO2 laser weld and functional rehabilitation to work well and measure.
Compound EpoB molecular formula is:C27H41NO6S, molecular weight is 507.68, EpoB stable as a kind of tubulin
Agent, focuses mostly in the research of its antitumaous effect.Cornea traumatic nerve injury is accelerated to repair and functional rehabilitation currently without using EpoB
Correlative study is reported.
The content of the invention
In order to overcome the shortcoming and deficiency of prior art, prepared it is an object of the invention to provide a kind of compound EpoB
Application in the medicine of repairing corneal traumatic nerve injury.Specifically related to compound EpoB is preparing acceleration due to refractive surgery, cornea
Cornea neuropathy caused by transplantation, herpes simplex keratitis, xerophthalmia, diabetes and long-term use eye drip medicine etc.
The effect repaired with function damage.
The purpose of the present invention is achieved through the following technical solutions:
The present invention provides applications of the compound EpoB in the medicine for preparing repairing corneal traumatic nerve injury.
The present invention provides application of the composition of the EpoB containing compound in the medicine for preparing repairing corneal traumatic nerve injury.
Described compound EpoB structural formula is as follows:
The formulation that the medicine of described repairing corneal traumatic nerve injury is suitable for clinically using for any one, such as tablet,
Capsule, oral liquid, injection, powder-injection, eye drops or eye ointment (or gel) etc., and be made of nanometer technique tablet,
Capsule, oral liquid, injection or powder-injection, eye drops or eye ointment (or gel) etc..
Described corneal nerve wound is included due to refractive surgery, corneal transplantation, herpes simplex keratitis, dry eyes
Cornea neuropathy and function damage caused by eye drip medicine etc. is used for a long time in disease, diabetes.
The present invention has the following advantages and effect relative to prior art:
(1) present invention has found that EpoB can dramatically increase mouse to carry out the mouse after corneal wound as experimental subjects
The area of corneal nerve, and close to normal level.
(2) EpoB can stablize cornea tubulin, make neural aggregation growth at random.
(3) EpoB can make the just basic recovery in 6 days after injury of cornea of rats consciousness, and control group corneal sensation is difficult extensive
It is multiple.
(4) by EpoB be used for prepare corneal nerve damage repair medicine, in safe-dosaging limits, can to surgical injury,
Illness in eye and long-term ophthalmic administration will all cause corneal nerve to have preferable therapeutic action extremely, can mitigate eye's disease
Shape.
(5) the compounds of this invention EpoB can promote tubulin polymerization and suppress micro-pipe by stablizing tubulin binding
Depolymerization, lift the concentration of tubulin, promote the reparation and reconstruction of neurotrosis, maintain cornea normal configuration and function.This
EpoB is invented to due to refractive surgery, corneal transplantation, herpes simplex keratitis, xerophthalmia, diabetes and long-term use
Cornea neuropathy and function damage have preferable therapeutic action caused by eye drip medicine etc., can mitigate eye's symptom;
Drug toxicity is small, and stability is good, with important exploitation and application prospect.
Brief description of the drawings
Fig. 1 is the result figure of corneal nerve gross area change after mouse cornea wound.
Fig. 2 is cornea CO2 laser weld situation after mouse cornea wound.
Fig. 3 is the result figure of cornea neurotubule expressing quantity after mouse cornea wound.
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited
In this.
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition.
Embodiment 1, EpoB accelerate mouse cornea traumatic nerve injury to repair
1. experimental animal
The C57/BL6 female mices of 8 weeks, 15~20g of body weight is purchased from Guangdong Province's Experimental Animal Center.Preceding 24 mouse of experiment
The eyes of animal are checked, it is ensured that experiment mice is without eye illness, corneal defect and conjunctival damage.
2. Experimental agents
EpoB is dissolved in DMSO (dimethyl sulfoxide (DMSO)), the solution that concentration is 5mg/mL is made into, it is stand-by.EpoB storing solutions
With 1:200 add normal saline dilution, and the sky of equivalent is injected intraperitoneally in mouse peritoneal injection 0.1mg/mL EpoB, control group mice
White solvent.
3. experimental method
Screening 20 is normal without eye illness mouse, is randomly divided into wound control group and EpoB administration groups.Each group mouse carries out phase
Answer after dosing techniques, mark Central corneal region with a diameter of 2mm trepan, golf sample knife mechanical scratch corneal epithelium is thin
Born of the same parents' layer, makes mouse cornea center cause wound, and a diameter of 2mm border circular areas is presented.Carried out after wound every 24 hours
The reparation situation (using corneal nerve relative density as index) of materials observation corneal nerve, and the analysis that takes statistics, progress angstrom are rich mould
The pharmacodynamic evaluation of plain B (EpoB).And corneal nerve tubulin expression quantity is determined using western-blotting methods.
4. experimental result
EpoB after mouse cornea wound to accelerating cornea nerve repair function to see Fig. 1 and 2:Fig. 1 shows, mouse cornea wound
24h afterwards, the neural relative density of mouse cornea for giving EpoB treatments starts above wound control group mice, and corneal nerve density
Continue to increase 5 days.Although although wound control group mice corneal nerve density also has increase, resume speed is well below EpoB
Administration group.Fig. 2 results are shown, the 5th day after corneal nerve wound, and EpoB administration group corneal nerve density is significantly higher than control group,
And it is unobvious to substantially return to nerve recovery at normal level, control group corneal center.Fig. 3 results are shown, micro- in corneal nerve
Tubulin is significantly reduced after corneal nerve damage, after EpoB intraperitoneal administrations, tubulin expression quantity showed increased.Result above
Show, EpoB is remarkably improved corneal nerve tubulin expression quantity, increase damaged corneal nerve area, accelerate corneal nerve wound
Wound is repaired.
Embodiment 2, EpoB accelerate rat to be wound corneal nerve functional rehabilitation
1. experimental animal
The male 8 week old SD rats 30 of health, body weight about 250 ± 20g is purchased from Guangdong Province's Experimental Animal Center.Before experiment
The eyes of animal are checked in 24 hours, tested with the animal without eyes irritative symptoms, corneal defect or conjunctival damage.
2. Experimental agents
SR8278 (being purchased from sigma companies of the U.S.) is dissolved in appropriate DMSO, injection soybean oil is added, is configured to
Content of dispersion is 0.2% SR8278 oiliness eye drops.
3. cornea of rats nerve injury animals model is set up
Rat Su Mian Xin (being purchased from Hua Mu animal health-care products Co., Ltd of Jilin Province) anesthesia, under the microscope with a diameter of
3mm belt carcass corneal trephine drills through the belt otch that an a diameter of 3mm, depth are 0.5mm in corneal center, notes avoiding damage to
Descemet's membrane and endodermis under it, that is, be made cornea of rats nerve injury animals model.Dyed and shown using corneal fluorescein
The region of damage, eye anterior segment analysis system is taken a picture and analyzes the size of damage field.
4. the treatment after cornea of rats neurotrosis
20 normal without eye illness rat, is randomly divided into wound control group and EpoB administration groups.EpoB administration groups use EpoB
Oiliness eye drops (EpoB oiliness eye drops is the soybean finish containing 0.2%EpoB) eye drip, 3 times a day;Wound control group, is used
Deng metering blank solvent eye drip, 3 times a day.
5. cornea of rats neural sensitivity degree is determined
The 2nd after modeling, known using the cornea after homemade nylon yarn corneal sensation tester measurement rat anesthesia within 4,6,8 days
Feel.The nylon yarn of corneal sensation tester is gently touched to the Central corneal of eye subject since 150mm.Corneal sensation is normal
Person, nylon yarn bends and can occur reflectivity immediately and twinkles or have a perception.It is that cornea is known if winking reflex or unaware do not occur
Feel and disappear.As winking reflex is blunt or it is insensitive to perceive, by nylon yarn from 150mm successively by amount (interval 10mm) reduce up to
10mm, the active force of nylon yarn is calculated by standard curve, and cornea of rats Perceptual sensitivity is reflected with the size of active force,
Record result.Corneal sensation tester standard curve determination:Nylon yarn from 150mm successively by amount (interval 10mm) reduce up to
10mm, assay balance is touched by nylon yarn, measures the power needed for the bending of different length nylon yarn, using length as abscissa, effect
Power is ordinate, draws standard curve.
6. experimental result
EpoB administration groups the 2nd day, 4 days, the active force of 6 days be all remarkably higher than wound control group, the results are shown in Table 1.EpoB gives
Medicine group corneal sensation just basic recovery in 6 days almost after injury, and the corneal sensation of wound control group recovers slow.
The cornea of rats consciousness of table 1 determines (N)
Time |
Wound control group |
EpoB administration groups |
2 days |
0.1137±0.0152 |
0.0864±0.0131* |
4 days |
0.0986±0.0215 |
0.0465±0.0312*** |
6 days |
0.0725±0.0132 |
0.0059±0.0033*** |
8 days |
0.0558±0.0158 |
0.0062±0.0048*** |
*p<0.1, * * * p<0.005
Above-described embodiment is preferably embodiment, but embodiments of the present invention are not by above-described embodiment of the invention
Limitation, other any Spirit Essences without departing from the present invention and the change made under principle, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.