CN116019818B - Composition for preventing, improving and/or treating cochlear synaptic injury and application thereof - Google Patents
Composition for preventing, improving and/or treating cochlear synaptic injury and application thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a composition for preventing, improving and/or treating cochlear synaptic injury and application thereof, and relates to the field of medicines. The effect of the independent use and the combined use of the L-5-methyltetrahydrofolate calcium and the MitoQ on two kinds of cochlear synaptic injury is evaluated through a mouse model experiment of the noise cochlear synaptic injury of mice, the L-5-MTHF-Ca and the MitoQ and the combined administration thereof are found to have good protection effects on mitochondrial injury and apoptosis caused by noise exposure, have remarkable protection effects on the reduction of the quantity of inner hair cell zonal synapses during the noise exposure and the hearing loss after the noise exposure, and have synergistic effects after the combined administration, so that the L-5-MTHF-Ca+MitoQ combined medicament is intuitively verified to have prevention, improvement and/or treatment effects on cochlear synaptic injury, can be used for preparing medicaments for preventing and treating acquired sensorineural deafness, and has good research and application prospects.
Description
Technical Field
The invention relates to the field of medicines, in particular to a composition for preventing, improving and/or treating cochlear synaptic injury and application thereof.
Background
Currently, about 11 hundred million young people (between 12 and 35 years old) are facing irreversible hearing loss, and by 2030, about 6.3 hundred million people all over the world will suffer hearing loss; by 2050, this number would rise to over 9 hundred million people. Therefore, the method has extremely important scientific significance and social benefit for preventing and treating the deafness. The person with impaired hair cells due to factors such as noise, drugs, infection, genetics, etc. is called sensorineural deafness, wherein noise exposure is a main cause of acquired deafness, and the pathogenic mechanism is mainly cochlear synapse (inner hair cell zona synapse) injury. In addition, inner hair cell zonal synaptic damage is also a common pathological change in drug-induced deafness, and therefore effective intervention on inner hair cell zonal synaptic damage may become an important means of treating and preventing hearing loss.
At present, no effective medicine is clinically available for preventing and treating the noisy inner hair cell zona synaptic injury. In basic scientific research, only the prevention and treatment effects of glutamate antagonists, neurotrophic factors, calcium channel blockers, antioxidants, anti-inflammatory drugs, vasodilators and the like on noise hearing loss are reported, but the effects are poor and the inner hair cell zona synaptic injury caused by noise cannot be prevented. The root cause of this is that the pathogenesis of acquired sensorineural deafness is not clear. In addition, it is currently accepted that noise exposure and deafness drugs can lead to increased oxidation-reduction of the inner ear mitochondria, but the effect of applying anti-oxidation-reduction agents is often not very good.
The inner ear hair cell is a sensory nerve cell responsible for converting the mechanical signal of sound waves into an electrical signal. In the nervous system, damage to DNA can lead to neurodegenerative disorders, such as: neurodegenerative diseases such as Alzheimer's disease, parkinson's disease and lateral sclerosis. Mature neural cells are cells that terminally differentiate and no longer proliferate. Thus, damage to cellular DNA gradually accumulates as the damage factor continues, ultimately causing apoptosis. Although there are a number of DNA damage repair mechanisms involved in different neurological diseases. However, the decline of nerve cell function and even apoptosis caused by DNA damage repair disorder is one of common pathological mechanisms of many acquired and neurodegenerative diseases.
The L-5-methyltetrahydrofolate calcium (L-5-MTHF-Ca) is a novel folic acid medicine, can participate in a plurality of important biochemical reactions in the body, and has important pharmacological actions. The medicine is dissolved in water, can permeate through blood brain barrier, and can prevent senile dementia, cell anemia and other symptoms. However, research and study on the effects of L-5-methyltetrahydrofolate calcium and preparations thereof on preventing and treating acquired sensorineural hearing loss such as noisiness and pharmacology have not been reported yet through looking up relevant documents at home and abroad. The effects of the compound in combination with a mitochondrial targeting antioxidant (MitoQ) in synergistic prevention and treatment of acquired sensorineural deafness are not seen.
Disclosure of Invention
The present invention aims to solve the problem of rarity of the existing medicines for preventing and treating acquired sensorineural hearing loss, particularly effectively interfering with inner hair cell zonal synaptic injury, and provides a composition for preventing, improving and/or treating cochlear synaptic injury and application thereof, wherein the composition comprises the following components: the composition has the effects of preventing, improving and/or treating cochlear synapse damage, and can be used for preparing medicines for preventing and treating acquired sensorineural deafness.
To solve the above problems, the present invention first provides a composition for preventing, improving and/or treating cochlear synaptic injury, the composition comprising: the calcium L-5-methyltetrahydrofolate and MitoQ are in a mass ratio of 1:0.1 to 1:10.
preferably, the mass ratio of the L-5-methyltetrahydrofolate calcium to the MitoQ is 1:0.5 to 1:3.
preferably, the mass ratio of the L-5-methyltetrahydrofolate calcium to the MitoQ is 1:1.2.
in another aspect, the invention also provides the use of a composition for preventing, ameliorating and/or treating cochlear synaptic injury as defined in any of the preceding claims in the preparation of a medicament for the prevention and treatment of acquired sensorineural deafness.
Preferably, the acquired sensorineural deafness is caused by noise or cochlear synapse damage caused by ototoxic drugs.
In another aspect, the invention also provides a pharmaceutical composition for preventing and treating acquired sensorineural hearing loss, which comprises the composition for preventing, improving and/or treating cochlear synaptic injury described in any of the preceding claims and a pharmaceutically acceptable carrier.
Preferably, the dosage form of the pharmaceutical composition includes a solid dosage form and a liquid dosage form.
Preferably, the solid dosage form comprises a tablet, capsule, granule, pill, suppository, film, gel, paste or powder.
Preferably, the liquid dosage forms comprise injection, mixture, oral liquid, syrup, medicated wine, sol and emulsion.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, through a mouse model experiment of noise cochlear synapse damage, the influence of independent use and combined use of L-5-methyltetrahydrofolate calcium and MitoQ on noise cochlear synapse damage is evaluated, and the L-5-MTHF-Ca and MitoQ and combined administration thereof have good protection effects on mitochondrial damage and apoptosis caused by noise exposure, have remarkable protection effects on the reduction of the quantity of inner hair cell zonal synapses during noise exposure and hearing loss after noise exposure, and have synergistic effects after combined administration, so that the L-5-MTHF-Ca+MitoQ has prevention, improvement and/or treatment effects on cochlear synapse damage and can be used for preparing medicines for preventing and treating acquired sensorineural deafness.
Drawings
FIG. 1 shows the results of the hearing ABR test of mice on days 1 and 3 before and after noise exposure in the control and experimental groups; wherein:
a is the change of the hearing threshold of the mice in the control group and the experimental group before and after the noise exposure on day 1;
b is the change in hearing threshold on day 3 before and after noise exposure in mice of control and experimental groups;
FIG. 2 is a graph showing the change in the number of hair cell zona synapses in control and experimental mice on day 1 after noise exposure; wherein:
a is a cochlea basal immunofluorescence staining chart of a control group and an experimental group of mice;
b is a comparison graph of the number of ribbon synapses of hair cells in mice of a control group and an experimental group;
fig. 3 shows changes in hair cell damage marker expression in control and experimental mice on day 1 after noise exposure.
In the figure: * **: p <0.001,: p <0.01,: p <0.05.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and examples.
The applicant of the invention discovers through researches that the gene expression changes after the noise exposure and the ototoxic drug use are mainly concentrated on DNA damage and DNA damage repair, and the pathogenesis of acquired sensorineural deafness is presumed to be related to the accumulation of the DNA damage, which is probably a common pathological process of the occurrence of the acquired sensorineural deafness, so that the promotion of the DNA damage repair is presumed to be a key for preventing and treating the acquired sensorineural deafness. In addition, free radicals generated by redox reactions can damage DNA, so that combined application of promoting DNA damage repair and inhibiting oxidative stress reactions is probably a key for preventing and treating cochlear synapse damage and acquired sensorineural deafness.
Based on the above findings, the present applicant has made extensive studies and screening, and has first provided a composition for preventing, ameliorating and/or treating cochlear synaptic injury, the composition comprising: calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca) and MitoQ, wherein the mass ratio of the calcium L-5-methyltetrahydrofolate to the MitoQ is 1:0.1 to 1:10.
in some embodiments, the mass ratio of the L-5-methyltetrahydrofolate calcium to the MitoQ is 1:0.5 to 1:3.
in some embodiments, the mass ratio of the L-5-methyltetrahydrofolate calcium to the MitoQ is 1:1.2.
in another aspect, the invention also provides the use of a composition for preventing, ameliorating and/or treating cochlear synaptic injury as defined in any of the preceding claims in the preparation of a medicament for the prevention and treatment of acquired sensorineural deafness.
Preferably, the acquired sensorineural deafness is caused by noise or cochlear synapse damage caused by ototoxic drugs.
In another aspect, the invention also provides a pharmaceutical composition for preventing and treating acquired sensorineural hearing loss, which comprises the composition for preventing, improving and/or treating cochlear synaptic injury described in any of the preceding claims and a pharmaceutically acceptable carrier.
Suitable pharmaceutically acceptable carriers are well known to those of ordinary skill in the art. A sufficient description of pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences. The pharmaceutically acceptable carrier in the composition may contain a liquid such as water, phosphate buffer, ringer's solution, physiological saline, balanced salt solution, glycerin or sorbitol, etc. In addition, auxiliary substances such as lubricants, glidants, wetting or emulsifying agents, pH buffering substances and stabilizers, such as albumin, may also be present in these carriers. In use, a safe and effective amount of the cannabinoid composition of the present invention is administered to a mammal (e.g., a human). Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. For a given condition, the effective amount can be determined by routine experimentation and can be determined by a clinician.
In some embodiments, the dosage form of the pharmaceutical composition includes a solid dosage form and a liquid dosage form. The solid dosage forms comprise tablets, capsules, granules, pills, suppositories, films, gels, pastes or powders; the liquid dosage forms comprise injection, mixture, oral liquid, syrup, medicated wine, sol and emulsion.
According to the invention, through a mouse model experiment of noise cochlear synapse damage of a mouse, the influence of independent use and combined use of L-5-methyltetrahydrofolate calcium and MitoQ on two cochlear synapse damages is evaluated, and the result shows that the L-5-methyltetrahydrofolate calcium and MitoQ have good protection effects on the number of internal hair cell synapses and mitochondrial damage after noise exposure, wherein when the two medicaments are used in combination, the synergistic protection effect is obvious, and the prevention and treatment effects of the L-5-methyltetrahydrofolate calcium and MitoQ on cochlear synapse damage and acquired sensorineural deafness are intuitively verified.
The experimental process and experimental results of the invention are described in detail below, so that the prevention, improvement and/or treatment effects of L-5-methyltetrahydrofolate calcium and MitoQ on cochlear synaptic injury are described in detail, and the invention can be used for preparing medicines for preventing and treating acquired sensorineural deafness.
Experimental materials
1. Reagent(s)
Calcium L-5-methyltetrahydrofolate solution: precisely weighing a proper amount of L-5-methyltetrahydrofolate calcium (purchased from selectk biotechnology Co., ltd., catalog number: S5264, CAS: 151533-22-1), adding double distilled water for dissolution, preparing a stock solution with the mass concentration of 300mg/mL, and storing at-80 ℃ for later use.
Mitochondrial targeting antioxidant (MitoQ) solution: a proper amount of MitoQ (available from selectk Biotechnology Co., ltd., catalog number: S8978, CAS: 845959-50-4) was precisely weighed, dissolved in double distilled water to prepare a stock solution with a mass concentration of 250mg/mL, and stored at-80℃for use.
2. Animals
Several C57/b6J male mice (Shanghai) of 4 weeks of age were selected, middle and inner ear diseases were excluded, and ABR threshold detection was performed to screen normal mice for ABR threshold as subjects. The experimental animal feeding is maintained at room temperature of 24 ℃, sufficient water and food are given, the black-white period is 12 hours, and the environmental noise is less than 40dB SPL. All experimental procedures were approved by the institutional animal ethics committee of Shanghai university of transportation.
(II) Experimental methods
1. Animal grouping and processing
Experimental animals were randomly divided into 4 groups, including:
control group, control group mice were intraperitoneally injected with physiological saline of the same volume as the experimental group mice.
The experimental groups were further divided into the group L-5-MTHF-Ca (30 mg/g of L-5-MTHF-Ca alone) and the group MitoQ (25 mg/g of MitoQ alone) and the group L-5-MTHF-Ca+MitoQ (30 mg/g of L-5-MTHF-Ca+25mg/g of MitoQ in combination). By intraperitoneal administration, each group was administered by intraperitoneal injection, 3 days before and 3 days after the noise exposure, once a day.
2. Experimental animal noise exposure
All experimental mice were placed in different intervals of the iron cage, and the mice were free to move in the cage intervals. The speaker was placed on top of the cage directly above. The noise signal is generated by a real-time signal processor (TDT system). The sound of the loudspeaker is calibrated before each noise exposure, and the probe of the sound level meter is placed in the cage during calibration, wherein the sound intensity change of each part in the cage is less than 1dB. The exposure time of the noise is 2 hours, and the exposure time is 2-20kHz, and the exposure is carried out by adopting the noise with the sound intensity of 103dB SPL.
(III) detection
1. Hearing brainstem response (Auditory brainstem response, ABR)
The change in the base value and the post-noise-exposure hearing threshold were measured 1 day and 3 days before and after the noise exposure, respectively. The specific method comprises the following steps: the experimental mice of each group were selected and weighed, and anesthetized by intraperitoneal injection of 5% chloral hydrate at a dose of 10 mg/mL. Anesthesia was indicated to be moderate when mice breathed slowly and smoothly, corneal reflex and auricle pain reflex disappeared without hiccup. The anesthetized mice are placed on a constant temperature pad, the temperature is set to be 37 ℃, and the temperature is regulated according to the anus temperature of the mice, so that the accuracy of ABR measurement is ensured, and death caused by temperature reduction of the anesthetized mice is prevented. The acoustic mode of the ABR test is an open sound field, and the loudspeaker is positioned in front of the mouse and is 10cm away from the midpoint of the binaural connecting line. The recording electrode was placed under the mid-parietal region of the mice subcutaneously, the reference electrode was placed under the mastoid region subcutaneously, and the ground electrode was placed under the shoulder of the upper limb subcutaneously. After the electrodes are connected, the resistances between the electrodes are firstly checked respectively, the resistance between any two electrodes is not more than 10Ω, and the smaller the resistance is, the smaller the waveform disturbance and wake caused is, which is more beneficial and accurate for judging the hearing threshold. The ABR TDT system stimulates short pure tones at acoustic frequencies of 4.0, 5.6, 8.0, 11.3, 16.0, 22.6 and 32.0 kHz. The stimulation rate is 10 times/s, the stimulation duration is 5ms, the rising time and the falling time are 1ms, the repetition rate is 21 times/s, the filtering bandwidth is 100-3000 Hz, and the superposition frequency is 400; the sound delivery intensity starts at 90dB SPL and decreases at 5dB SPL until the individual waveforms disappear before being defined as the hearing threshold. When the threshold is approached, the comparison waveform is generally repeatedly checked for coincidence more than two times. Each index is displayed, recorded, calculated and stored in real time by software attached to the test instrument.
2. Counting the number of hair cell zonal synapses in cochlea basement membrane immunofluorescence staining
The first day after noise exposure, a portion of mice from each group were given excessive anesthesia to kill, decapitated, and double-sided hearing bubbles were quickly removed under direct vision and placed in 4% Paraformaldehyde (PFA). Under an dissecting microscope, the acoustic bubbles and surrounding soft tissue were removed with microscopic forceps. The cochlea tip was drilled with a 1mL syringe and the round and oval windows were opened, 4% pfa was aspirated and injected into the cochlea through the round and oval windows, respectively, and the fluid in the cochlea was seen to flow out until clear. Three round window and oval window 4% pfa perfusion were performed to allow adequate fixation of cochlear tissue, and the cochlear tissue was placed in a refrigerator at 4 ℃ for fixation overnight. Under a microscope, spiral ligaments, basal lamina, a worm shaft and the like are fully exposed by removing spiral bone from the top of the worm to the bottom of the worm layer by layer, and the spiral ligaments and vascular veins are peeled downwards by rotating the worm shaft serving as a fulcrum. The bone screw plate is gently pressed down by the microdissection forceps to separate from the worm shaft, and the basement membrane is gradually torn off. To enhance the staining effect, the wide, fragile vestibular membrane and the elongated, tough covering membrane are removed. The separated substrate membrane was placed in an organic glass coagulum, washed 3 times with PBS for 5 minutes each. After 30 minutes at room temperature 5% Triton X-100, PBS was washed 3 times for 5 minutes each. The non-specific sites were blocked by adding PBS blocking solution containing 5% BSA (bovine serum albumin ) and left to stand at room temperature for 2 hours. Configuration 1 with 1% BSA: 100 mouse anti-CtBP2IgG1. The substrate film was washed 3 times for 5 minutes with PBS. And adding the prepared primary antibody, and placing the primary antibody in a refrigerator at 4 ℃ for fixation overnight. The next day was rinsed 3 times for 5 minutes with PBS. Configuration 1 with 1% bsa: 200 Alexa Fluor 568-conjugated goat anti mouse IgG1. Adding the prepared secondary antibody and dyeing for 1 hour at room temperature in dark. The PBS was washed 3 times for 5 minutes each. An anti-fluorescence quenching caplet (containing DAPI) was dropped onto a polylysine-treated slide, and the basement membrane was held with microdissection forceps and transferred to the slide. The basement membrane was laid down under a microscope and slowly lowered from the side of the coverslip droplet using an 8 x 8mm coverslip to ensure no air bubbles between the slide and the coverslip, and the coverslip was fixed with nail polish.
The carrier patch containing the cochlear basement membrane was placed under a laser confocal microscope, and the field of view was selected with a 60x water microscope and observed for staining effects. Laser wavelengths with the wavelength of 561nm and 633nm are selected for excitation. Scanning hair cells from top to bottom in a selected area, continuously observing each layer of images of a specimen, and after scanning signals of each layer are obtained, displaying the signals on the same layer surface, so that the later observation and counting of the number of the signals are facilitated, and the scanning layer distance set by scanning in the experiment of the embodiment is 0.5 mu m.
3. Detection of apoptotic pathway protein expression
(1) Cochlear protein extraction
5% chloral hydrate anesthetized mice, the bilateral cochlea was removed with scissors broken, the auditory bulb was removed, and placed in an anatomic dish containing ice-cold PBS. And removing redundant tissues and blood clots attached to the cochlea by using microdissection forceps, and moving the cleaned cochlea into a new dish. The cochlea basal membranes are quickly separated from the top ring to the bottom ring and put into an EP tube, 6 basal membranes are used as a group, 400 mu l of RIPA solution is added into each tube for protein cleavage, and the mixture is kept stand on ice for 30 minutes and shaken every 10 minutes. After the completion of the cleavage, the mixture was centrifuged at 12000rpm and 4℃for 10 minutes, and the supernatant was collected to obtain a protein sample.
(2) Protein quantification
The embodiment adopts a Biyundian BCA protein concentration determination kit. 0.8mL of the protein standard preparation is added into a tube of protein standard (20 mg BSA), and the protein standard solution of 25mg/mL is prepared after complete dissolution. And (5) taking a proper amount of protein standard solution, and diluting to obtain a protein standard with a final concentration of 0.5 mg/mL. And adding 1 part by volume of BCA reagent B (50:1) into 50 parts by volume of BCA reagent A to prepare a proper amount of BCA working solution, and fully and uniformly mixing. Standards were added to 96-well plates at 0, 1, 2, 4, 8, 12, 16, 20 μl, less than 20 μl was made up with standard dilutions. 6 μl of the protein sample to be tested was pipetted into a 96-well plate and made up to 20 μl with standard dilutions. 200 μl BCA working solution was added to each well, and the mixture was allowed to stand at 37℃for 20 minutes. Absorbance at 562nm was detected using a microplate reader. The protein concentration of the sample was calculated from the standard curve.
(3) DS-PAGE gel electrophoresis and transfer
This example used a Biyundian SDS-PAGE pre-gel (Tris-Gly, 10%,12 wells). 12 μl of each group of samples was taken, diluted to 15 μl with a 5×loading Buffer, boiled at 100deg.C for 5-10 min, thoroughly mixed, centrifuged, and stored on ice. And (3) introducing a proper amount of electrophoresis liquid into an electrophoresis tank, fixing the preformed adhesive in the electrophoresis tank, smoothly and slowly pulling out the comb, adding 15 mu l of a sample to be detected into each hole, adding 5 mu l of protein markers into two sides of the sample to be detected, and supplementing the protein markers to 15 mu l by using 1×loading Buffer. 80V electrophoresis for 30 min, 110V electrophoresis for 90 min. After electrophoresis, the gel is carefully taken down, the PVDF membrane is soaked in a proper amount of methanol for 1-2 minutes, and then the PVDF membrane is put into an ice box and is filled with membrane transferring liquid.
(4) Closure
After the transfer printing is finished, the PVDF film is taken out, cut and put into a plastic box interval, and a proper amount of sealing liquid is poured. The shaker was blocked for 1 hour at room temperature, blocking non-specific binding sites.
(5) The primary antibody was incubated overnight, the next day, and washed three times with wash solution for 10 minutes each time. After the washing is finished, the corresponding secondary antibody is diluted by secondary antibody diluent according to the following weight ratio of 1: diluting with 5000 a. Incubate for 1 hour at room temperature. After the incubation was completed, the wash solution was washed 3 times for 10 minutes each.
(6) ECL substrate development
The ECL luminous solution was uniformly spread on the PVDF film, and allowed to stand for 2 minutes. The reacted PVDF membrane was put into a gel imaging system (Amersham Imager 600) for photo exposure and the pictures were collected.
(IV) statistical method
Experimental data results were expressed using mean±sem, and were statistically analyzed and plotted using Prism and Igor. Using one-way or two-way ANOVA followed by Bonferroni post-hoc test or using unpaired Student's t-test (data is consistent with both normal distribution and variance alignment, and Mann-Whitney U test if not). The difference was statistically significant as defined by P <0.05.
(fifth) experimental results
Effect of L-5-MTHF-Ca+MitoQ on mouse ABR after noise exposure
As shown in fig. 1, the efficacy of L-5-MTHF-Ca and MitoQ and combinations thereof on noisy synaptic injury was reflected by detecting changes in ABR before and after noise exposure in control, single-dose (L-5-MTHF-Ca, mitoQ) and combination-dose (L-5-MTHF-ca+mitoq) mice.
The results showed that both control mice and 3 experimental mice had a rise in the hearing threshold on day 1 after noise exposure, but the rise in the hearing threshold was significantly greater for the control mice than for the 3 experimental mice, where the rise in the hearing threshold was minimal for the mice in the combination administration group, i.e., the combination administration of L-5-MTHF-Ca + MitoQ had a significant synergistic effect compared to the administration of L-5-MTHF-Ca or MitoQ alone, and the protection effect for hearing loss after noise exposure was better (a of fig. 1). Following the hearing threshold of the mice on day 3 after noise exposure, the hearing of the mice in the co-administered L-5-MTHF-Ca+MitoQ group was found to have been substantially restored (FIG. 1B).
The above experimental results show that the combined administration of L-5-MTHF-Ca and MitoQ can effectively prevent and treat noise-induced hearing loss.
Effect of L-5-MTHF-Ca+MitoQ on the number of hair cell zona synapses in mice after noise exposure
As shown in fig. 2, panels a and B, the number of hair cell zona synapses in the control group, 3 experimental groups of mice on day 1 after noise exposure was counted. The results show that on day 1 after noise exposure, the number of hair cell zonal synapses in mice in the experimental group is significantly greater than that in mice in the control group, wherein the number of zonal synapses in mice in the combined administration of L-5-MTHF-Ca+MitoQ group is significantly greater than that in mice in the independent administration of L-5-MTHF-Ca or MitoQ group, and the combined administration of L-5-MTHF-Ca+MitoQ has a significant protective effect on zonal synapse damage caused by noise exposure.
L-5-MTHF-Ca+MitoQ has protective effect on mitochondrial injury and apoptosis caused by noise exposure
As shown in FIG. 3, on day 1 after noise exposure, each group of mouse basement membranes was taken for detection of changes in BAX, bcl-2, cytochrome C and clear caspase-3 expression. The results show that the combined administration of L-5-MTHF-Ca+MitoQ can obviously reduce the expression quantity of pro-apoptotic protein clear caspase-3 and mitochondrial injury related protein cytochrome C, improve the expression quantity of anti-apoptotic protein Bcl-2, and has obvious protection effect on mitochondrial injury and apoptosis caused by noise exposure.
In conclusion, the invention discovers that the combined administration of L-5-MTHF-Ca and MitoQ has good protective effect on mitochondrial injury and apoptosis caused by noise exposure, has remarkable protective effect on the reduction of the number of inner hair cell zonal synapses during noise exposure and the hearing loss after noise exposure, intuitively verifies that the L-5-MTHF-Ca+MitoQ has preventive, ameliorative and/or therapeutic effects on cochlear synapse injury, and can be used for preparing medicaments for preventing and treating acquired sensorineural hearing loss.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing. Accordingly, the scope of the invention should be limited only by the attached claims.
Claims (9)
1. A composition for preventing, ameliorating and/or treating cochlear synaptic injury, the composition comprising L-5-methyltetrahydrofolate calcium and MitoQ in a mass ratio of 1: 0.1-1: 10.
2. the composition for preventing, ameliorating and/or treating cochlear synaptic injury according to claim 1, wherein the mass ratio of L-5-methyltetrahydrofolate calcium to MitoQ is 1: 0.5-1: 3.
3. the composition for preventing, ameliorating and/or treating cochlear synaptic injury according to claim 1, wherein the mass ratio of L-5-methyltetrahydrofolate calcium to MitoQ is 1:1.2.
4. use of a composition for preventing, ameliorating and/or treating cochlear synaptic injury as claimed in any of claims 1-3 in the manufacture of a medicament for preventing acquired sensorineural deafness.
5. The use of claim 4, wherein the acquired sensorineural hearing loss is caused by cochlear synapse damage due to noise or ototoxic drugs.
6. A pharmaceutical composition for preventing and treating acquired sensorineural hearing loss, characterized in that it consists of a composition for preventing, ameliorating and/or treating cochlear synaptic injury according to any of claims 1-3, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition for preventing and treating acquired sensorineural hearing loss according to claim 6, wherein the pharmaceutical composition is selected from the group consisting of solid and liquid dosage forms.
8. The pharmaceutical composition for preventing and treating acquired sensorineural hearing loss according to claim 7, wherein the solid dosage form is selected from the group consisting of tablets, capsules, granules, pills, suppositories, films, gels, pastes and powders.
9. The pharmaceutical composition for pre-treatment of acquired sensorineural hearing loss according to claim 7, wherein the liquid formulation is selected from the group consisting of injection, mixture, oral liquid, syrup, medicated wine, sol, emulsion.
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| CN102014957A (en) * | 2008-04-21 | 2011-04-13 | 奥德纳米有限公司 | Auris formulations for treating otic diseases and conditions |
| CN111172091A (en) * | 2020-02-17 | 2020-05-19 | 江南大学 | Bacillus subtilis with improved 5-methyltetrahydrofolate yield and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014957A (en) * | 2008-04-21 | 2011-04-13 | 奥德纳米有限公司 | Auris formulations for treating otic diseases and conditions |
| CN111172091A (en) * | 2020-02-17 | 2020-05-19 | 江南大学 | Bacillus subtilis with improved 5-methyltetrahydrofolate yield and application thereof |
Non-Patent Citations (2)
| Title |
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| Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review.;Chisato Fujimoto 等;Antioxidants;20190424;第8卷(第4期);109，第1-19页 * |
| 抗氧化应激防治噪声性聋的研究进展;顾晓娜 等;临床耳鼻咽喉头颈外科杂志;20211231;第35卷(第9期);第850-853页，特别是第851页1.3 * |
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