CN112915080B - Application of p276-00 in preparation of medicine for preventing and treating noise-induced hearing loss - Google Patents
Application of p276-00 in preparation of medicine for preventing and treating noise-induced hearing loss Download PDFInfo
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- CN112915080B CN112915080B CN202110337525.4A CN202110337525A CN112915080B CN 112915080 B CN112915080 B CN 112915080B CN 202110337525 A CN202110337525 A CN 202110337525A CN 112915080 B CN112915080 B CN 112915080B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61P27/16—Otologicals
Abstract
The invention discloses an application of Riviciclib hydrochloride (p276-00) in preparation of a medicine for preventing and treating noise-induced hearing loss, relates to the field of medicines, and is used for solving the problem that the existing medicine for preventing and treating the noise-induced hearing loss is rare. By applying an animal model experiment method of noise hearing loss, the hearing and inner hair cell functions of a mouse after noise exposure are detected, the Rivicili hydrochloride (p276-00) is found to have a good protection effect on the number and functions of inner hair cell contacts when the noise is exposed, the prevention and treatment effect of the Rivicili hydrochloride (p276-00) on the noise hearing loss is visually verified, the Rivicili hydrochloride (p276-00) can be used for preparing a medicine for preventing and treating the noise hearing loss, and the research and application prospects are good.
Description
Technical Field
The invention relates to the field of medicines, in particular to a new application of Rivicilib hydrochloride (p276-00), and more particularly relates to an application of Rivicilib hydrochloride (p276-00) in preparation of a medicine for preventing and treating noise hearing loss.
Background
Noise deafness is one of the most common acquired sensorineural hearing losses, and currently more than about 12% of the global population is at risk of noise hearing loss. With the increasing prevalence of traffic noise, entertainment noise and other exposure in life, the banded synaptic injury between inner hair cells and afferent nerves after the noise exposure is often hidden, which not only accelerates the occurrence of presbycusis, but also increases the occurrence risk of dementia, becomes a serious potential health threat, and causes serious social problems and economic burden. The internal hair cell banded synaptic injury induced by noise exposure is a pathological representation of early stage of noise deafness, which provides an important breakthrough for preventing and treating noise hearing loss, and in addition, the internal hair cell banded synaptic injury is also a common pathological change of presbycusis and drug deafness, so that effective intervention on the banded synaptic injury can become an important means for treating and preventing the hearing loss.
At present, no effective medicine for preventing and treating noise inner hair cell banded synapse damage exists clinically. 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-induced hearing loss are reported, but the effects are poor and the inner hair cell banded synapse damage caused by noise cannot be prevented.
The inner hair cell is a sensory nerve cell responsible for converting the mechanical signal of sound waves into electrical signals. Inner hair cell banded synapses have the functions of coding sound information and sensing sound source positioning, and are also the most common lesion parts of sensorineural deafness. Thus, a decrease in speech encoding ability and even an increase in hearing threshold can occur after a banded synaptic injury. The cell cycle is the basic process of cell life activity, and cell proliferation, division, degeneration, necrosis, apoptosis, etc. all occur in a certain phase of the cell cycle in which it is located. Therefore, the cell cycle is closely related to the occurrence and development of diseases. It has been thought that mature nerve cells are cells that have terminally differentiated and no longer proliferate. More and more studies have now found that in pathological situations, which lead to abnormal activation of the terminally differentiated neural cell cycle, the neural cells will go towards death rather than proliferation. Although there are a variety of cell cycle mechanisms involved in different neurological diseases, abnormal entry of nerve cells into the cell cycle leading to nerve cell damage is one of the common pathological mechanisms of many acquired and neurodegenerative diseases.
Riviciciclib hydrochloride (p276-00) is a CDK1, 4, 9 inhibitor and is a cell cycle inhibitory drug which is currently subjected to three-phase clinical trials. However, only the research report of the Rivicilib hydrochloride (p276-00) on tumor inhibition is found through the examination of related documents at home and abroad, and the research report of the Rivicilib hydrochloride (p276-00) on the aspect of protecting the noise hearing loss is not found.
Disclosure of Invention
The invention aims to solve the problem of rare medicines for preventing and treating noise-induced hearing loss, and aims to provide application of Riviciclib hydrochloride (p276-00) in preparation of medicines for preventing and treating noise-induced hearing loss.
Preferably, the Riviciclib hydrochloride (p276-00) is used alone.
Preferably, said Riviciclib hydrochloride (p276-00) is used in the form of a pharmaceutical composition.
Preferably, the medicament is a medicinal preparation prepared from Riviciclib hydrochloride (p276-00) and pharmaceutical excipients.
Further, the dosage form of the pharmaceutical preparation includes a solid dosage form and a liquid dosage form.
The solid dosage form comprises tablets, capsules, granules, pills, suppositories, films, gels, pastes or powders.
The liquid dosage form comprises injection, mixture, oral liquid, syrup, medicinal liquor, sol, emulsion or eye drop.
Compared with the prior art, the invention has the beneficial effects that:
the invention utilizes a noisy hearing loss animal model to find that Rivicili hydrochloride (p276-00) has good protection effect on the number and the function of synapses of inner hair cells when the Rivicili hydrochloride (p276-00) is exposed to noise, so that the prevention and treatment effect of the Rivicili hydrochloride (p276-00) on noisy synapse damage is intuitively verified, and the Rivicili hydrochloride (p276-00) can be used for preparing the medicine for preventing and treating the noisy hearing loss.
Drawings
FIG. 1 shows ABR test results of mouse hearing before noise exposure and 1 st and 14 th days after noise exposure in control group and P50 group; wherein:
A-C is a schematic diagram of hearing threshold change and ABR I wave amplitude change before and after noise exposure of a control group;
D-F is a schematic diagram of the change of the hearing threshold value and the change of the amplitude of the ABR I wave before and after the exposure of P50 groups of noise;
g, K is the ABR I wave amplitude change at 8.0kHz and 16.0kHz at 14 days after the noise exposure of the control group;
h, L is the ABR I wave amplitude change at 8.0kHz and 16.0kHz at 14 days after the exposure of the noise of the experimental group;
j, M is the comparison of the relative change value of ABR I wave amplitude (PND14/Pre) of the control group and the experimental group at day 14 before and after the noise exposure.
Fig. 2 shows the results of ABR test of hearing in mice before and after noise exposure in P10 and P30 groups, wherein:
a is the change of the hearing threshold value of the P10 mice before and after noise exposure;
b is the ABR I amplitude change at 16.0kHz at 14 days after P10 group noise exposure;
c is the change of the hearing threshold value before and after noise exposure of the P30 group mice;
d is the change in amplitude of the ABR I wave at 16.0kHz at 14 days after P30 group noise exposure.
FIG. 3 is a graph of the change in the number of hair cell synapses in control and P50 groups of mice at day 14 post-noise exposure.
Fig. 4 is a graph of the patch clamp recording calcium current and membrane capacitance of hair cells, where:
a is a graph of the recorded calcium current of the P50 group and the control group;
b is the maximum calcium current (I) of inner hair cells of mice in P50 group and control groupmax)；
C is a schematic diagram of calcium current and membrane capacitance change recorded when the depolarization reaches-14 mv and the time course is 200 ms;
d is the delta C of mice in P50 group and control group given different depolarization timesmComparing;
e is Q of mice in P50 group and control group when being given different depolarization timeCaAnd (6) comparing.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings and examples.
Through research, the gene expression change after noise exposure is mainly enriched on a cell cycle signal path, and the expression of CDK1 and Cyclin B is up-regulated after the noise exposure through qPCR verification. Thus, it was concluded that noisy hearing loss was associated with activation of CDK 1.
Rivicili hydrochloride (p276-00) is a CDK1, 4, 9 inhibitor, so the invention provides a new application of Rivicili hydrochloride (p276-00), namely the application of Rivicili hydrochloride (p276-00) in preparing a medicine for preventing and treating noise hearing loss.
The Riviciclib hydrochloride (p276-00) can be independently used when preparing a medicine for preventing and treating noise hearing loss; can also be used in the form of pharmaceutical compositions; or making into pharmaceutical preparation with pharmaceutical adjuvants, such as tablet, capsule, granule, pill, suppository, pellicle, colloid, unguent, powder, injection, mixture, oral liquid, syrup, medicated liquor, sol, emulsion or eye drop.
According to the invention, the influence of the Rivicili hydrochloride (p276-00) on the noise synaptic injury is evaluated through a mouse model experiment of the noise recessive hearing loss of a mouse, and the result shows that the Rivicili hydrochloride (p276-00) has a good protection effect on the number and the function of inner hair cell synapses in noise exposure, so that the prevention and treatment effect of the Rivicili hydrochloride (p276-00) on the noise hearing loss is intuitively verified.
The experimental process and the experimental results of the invention are explained in detail below, so that the prevention and treatment effect of Riviciclib hydrochloride (p276-00) on noise-induced hearing loss is explained in detail, and the Riviciclib hydrochloride can be used for preparing the medicine for preventing and treating the noise-induced hearing loss.
(I) test materials
1. Reagent
Riviciciclib hydrochloride (p276-00) solution: precisely weighing a proper amount of Riviciclib hydrochloride (p276-00), adding ultrapure water for dissolving, preparing stock solutions with the mass concentrations of 100mg/ml, 300 mg/ml and 500mg/ml, and storing at the temperature of 80 ℃ for later use.
2. Animal(s) production
Selecting a plurality of CBA/caJ male mice (Shanghai) with the age of 4 weeks, eliminating diseases of middle ear and inner ear, carrying out ABR threshold detection, and screening the mice with normal ABR thresholds as experimental objects. The experimental animals were kept at room temperature 24 ℃ and given sufficient water and food for a black and white cycle of 12 hours with an environmental noise of less than 40dB SPL. All experimental procedures were approved by the animal ethics committee of the medical college of shanghai university of transportation.
(II) Experimental method
1. Animal grouping and handling
Experimental animals were randomly divided into 4 groups including:
in the control group, the mice in the control group are injected with normal saline with the same volume as the mice in the experimental group.
Experimental groups, further divided into P10, P30 and P50 groups, wherein: group P10, administered at a dose of 10 mg/g; group P30, administered at a dose of 30 mg/g; and the dosage of the P50 group is 50 mg/g. The method is characterized in that an intraperitoneal administration mode is adopted, each group is subjected to intraperitoneal injection administration 2-3 hours before noise exposure, and administration is carried out once every day from 1 st day to 6 th day after the noise exposure.
2. Experimental animal noise exposure
All experimental mice were placed in different intervals in an iron mesh cage, and the mice were free to move in the cage intervals. The speaker is placed on the top end right above the cage. The noise signal is generated by a real-time signal processor (TDT system). The sound of the loudspeaker needs to be calibrated before each noise exposure, a probe of the sound level meter is arranged in a cage during calibration, and the sound intensity of each part in the cage changes by less than 1 dB. And exposing the noise by adopting the noise with the frequency of 2-20kHz and the sound intensity of 103dB SPL for 2 hours.
(III) detection
1. Auditory Brainstem Response (ABR)
Changes in the basal value and the post-noise-exposure hearing threshold were measured 1 day and 14 days before and after 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. Moderate anesthesia was indicated when the mice breathed slowly and smoothly, the corneal reflex and the auricle painful reflex disappeared and were not burped. The anesthetized mouse is placed on a constant temperature pad, the temperature is set to be 37 ℃, and the temperature is adjusted according to the anal temperature of the mouse, so that the accuracy of ABR measurement is ensured, and the death of the mouse caused by body temperature reduction after anesthesia is prevented. The sound giving mode of the ABR test is an open sound field, and a loudspeaker is positioned right in front of a mouse and 10cm away from the middle point of a connecting line of two ears. The recording electrode is placed under the centre of the skull of the mouse, the reference electrode is placed under the skin of the mastoid region, and the grounding electrode is placed under the skin of the shoulder of the upper limb. Short pure tones with the ABR TDT system stimulation sound frequency of 4.0, 5.6, 8.0, 11.3, 16.0, 22.6 and 32.0kHz are provided, the stimulation rate is 10 times/s, the stimulation duration is 5ms, the rising time and the falling time are both 1ms, the repetition rate is 21 times/s, the filtering bandwidth is 100-3000 Hz, and the superposition frequency is 400; the sound intensity was decreased from 90dB SPL to 5dB SPL until the hearing threshold was defined before the disappearance of each waveform. When the threshold value is approached, the detection of whether the comparison waveforms are consistent is generally repeated twice or more. All indexes are displayed, recorded, calculated and stored in real time by software attached to the testing instrument.
2. Counting the number of zonal synapses of inner hair cells by immunofluorescence staining of cochlear basement membrane
The experimental mice were sacrificed and the cochlea was quickly removed and fully fixed with 4% paraformaldehyde. Basement membrane was dissected, the tegument and vestibular membrane were removed, and immunofluorescence staining was performed for inner hair cell zonal synapse-associated protein (Ribbon, GluA 2). The specimen was scanned in layers (Z-step 0.38 μm) using a Zeiss LSM 880 laser confocal and the number of banded synapses per inner hair cell was counted.
3. Membrane clamp detection of inner hair cell banded synapse function
(1) Drawn glass electrode
And drawing the glass electrode with the resistance of 5-6M omega by using a vertical drawing instrument. The paraffin wax was heated to melt, the wax was applied to the glass electrode tip under a microscope, and the integrity of the tip was checked.
(2) Configuration of patch clamp to record used extracellular and intracellular fluids
Extracellular fluid (mM): NaCl 130, KCl 2.8, CaCl 2 10，MgCl 21, HEPES 10, and D-glucose 10. The pH was adjusted to 7.40 with NaOH and the osmolality of the extracellular fluid was adjusted to 300mOsm with D-glucose.
Intracellular fluid (mM): cs-methanesulfonate 135, CsCl 10, TEACl 10, HEPES 10, EGTA2, Mg-ATP 3 and Na-GTP 0.5. The pH was adjusted to 7.20 with CsOH and the intracellular fluid osmolality was adjusted to 290mOsm with CsCl. The prepared intracellular solution was filtered through a 0.22 μm microporous filter and dispensed into 300. mu.l/EP, and stored in a refrigerator at-20 ℃.
(3) Patch clamp recording method
After the mice were sacrificed by excess anesthesia, the cochlear basement membrane was dissected rapidly and transferred to a patch clamp recording chamber containing extracellular fluid. The target cells were found and the objective lens was lifted under an upright microscope (60X) of the patch clamp system. The intracellular fluid was injected into the glass electrode, which was held by an electrode holding arm and given positive pressure before the electrode was immersed in water. Under the guidance of a microscope, the electrode is pushed to a target cell, when the cell is blown out of a pit by positive pressure, the positive pressure is removed and certain negative pressure is given, so that the cell and the glass electrode are sealed in a high-resistance manner (>1G omega). A larger negative pressure is given, and cell membranes are broken by suction to form a Whole-cell pattern.
Depolarization stimuli of-80 mV to +30mV were given and inner hair cell calcium currents were recorded. After data are obtained, the leakage current of the corresponding voltage is subtracted from the calcium current under different voltages to obtain an I-V curve, and the current peak value in the I-V curve is the maximum calcium current Imax. A depolarization to-14 mV stimulus was given and changes in hair cell membrane capacitance (Δ C) were recorded at different depolarization times (50, 100 and 200ms)m) And the change of charge (Q) during stimulationCa)。
(IV) statistical method
Results of experimental data are expressed using mean + -SEM, statistical analysis and mapping should be done for Prism and Igor. One-way or two-way ANOVA fallen by Bonferroni post-hoc test or unpaired Student's t-test (data fit both normal distribution and fair variance, and Mann-Whitney U test if not). Differences were defined as P <0.05 and were statistically significant.
(V) results of the experiment
Effect of Riviciciclib Hydrochloride on mouse ABR after noise Exposure
As shown in FIG. 1, the efficacy of Rivicilib hydrochloride (P276-00) on noisy synaptic lesions was first reflected by measuring the change in ABR before and after noise exposure in control and P50 group mice. The results showed that the hearing thresholds were shifted up on day 1 after noise exposure and restored on day 14 in the control and P50 mice (a, D in fig. 1), but the ABR I wave amplitude change graphs showed no significant restoration of ABR I wave amplitude in the control (B, C in fig. 1), indicating that we successfully constructed an animal model of noisy recessive hearing loss (an animal model of inner hair cell zonal synapse damage).
ABR I amplitude reflects primarily the magnitude of excitability of cochlear afferent nerve fibers, and therefore, ABR I amplitude at 8.0kHz and 16.0kHz on day 14 post-noise exposure of experimental mice was analyzed after hearing threshold recovery, respectively. As a result, ABR I wave amplitude was not completely restored in the control mice, indicating that noise caused damage to the inner ear synapses (G, K in fig. 1); however, the ABR I wave amplitude was fully restored at day 14 after noise exposure in the P50 group, indicating that Riviciclib hydrochloride (P276-00) had a protective effect on synapses at noise exposure (H, L of fig. 1).
As shown in FIG. 2, the protective effect of Riviciclib hydrochloride (P276-00) on synapses was further verified by experiments of group P10 and group P30. The results show that experimental mice likewise restored hearing thresholds at day 14 after noise exposure when administered at doses of 10mg/g and 30mg/g, respectively (fig. 2 a, C); however, the ABR I wave amplitudes in both groups were not fully restored, and the protective effect on the synaptophia zonata was not exhibited when the dose was 10mg/g, but some synaptophia zonata was exhibited when the dose was 30mg/g (B, D in FIG. 2).
Effect of Riviciclib Hydrochoride (p276-00) on the number of hair cell synapses in mice after noise exposure
Changes in the number of inner hair cell processes before noise exposure, after noise exposure in the control group and the P50 group were counted as shown in fig. 3. The results show that the control group shows the phenomenon that the number of inner hair cell banded synapses is reduced after noise exposure, while the number of inner hair cell banded synapses in the P50 group is not obviously different from that before the noise exposure, which indicates that Rivicilib hydrochloride (P276-00) has protective effect on the banded synapses.
Effect of Riviciciclib hydrochloride (p276-00) on Calcilla Current and synaptic vesicle Release ability in mice after noise Exposure
As shown in fig. 4, the function of inner hair cells was recorded at day 14 after noise exposure in the control group and P50 group. We used a depolarization stimulus of-80 mV to +30mV and recorded the inner hair cell calcium current (a of fig. 4), and the results showed that the maximum calcium current of the inner hair cells was significantly decreased at day 14 after the noise exposure of the control group, however, the maximum calcium current of the inner hair cells was not significantly decreased in the P50 group (B of fig. 4).
Further, synaptic vesicle release function of inner hair cells was recorded. Depolarization of the inner hair cells can trigger synapse release of neurotransmitters by exocytosis. The fusion of vesicles and cell membranes during exocytosis increases the cell membrane area, thereby increasing the cell membrane capacitance. And the increase in membrane capacitance before and after stimulation (Δ C)m) Reflecting the amount of transmitter released. We administered a depolarization to-14 mV stimulus to inner hair cells, varying the depolarization times (50, 100 and 200ms) and recording the change in membrane capacitance (Δ C) of the inner hair cellm) And change in calcium charge (Q)Ca) (C in fig. 4), the results showed that the vesicle release function and calcium charge of the control group were significantly reduced after noise exposure, while the vesicle release function and calcium charge of the P50 group were not significantly different from those before noise exposure (D, E in fig. 4), indicating that Riviciclib hydrochloride (P276-00) protected the function of inner hair cell zonal synapse.
In conclusion, Riviciclib hydrochloride (p276-00) can effectively protect the number and the function of zonal synapses of inner hair cells during noise exposure, and can be used for preparing a medicine for preventing and treating noise hearing loss.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.
Claims (7)
- Application of p276-00 in preparing medicines for preventing and treating noise-induced hearing loss.
- 2. The use of claim 1, wherein p276-00 is used alone.
- 3. The use of claim 1, wherein p276-00 is used in the form of a pharmaceutical composition.
- 4. The use of claim 1, wherein the medicament is a pharmaceutical formulation comprising p276-00 and a pharmaceutical excipient.
- 5. The use of claim 4, wherein the dosage form of the pharmaceutical formulation comprises a solid dosage form and a liquid dosage form.
- 6. The use of claim 5, wherein said solid dosage form comprises a tablet, capsule, granule, pill, suppository, film, gel, paste or powder.
- 7. The use of claim 5, wherein the liquid dosage form comprises an injection, a cocktail, an oral liquid, a syrup, a wine, a sol or an emulsion.
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| WO2013106494A1 (en) * | 2012-01-12 | 2013-07-18 | Quark Pharmaceuticals, Inc. | Combination therapy for treating hearing and balance disorders |
| WO2020023502A1 (en) * | 2018-07-23 | 2020-01-30 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
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| US20070270362A1 (en) * | 2006-05-18 | 2007-11-22 | The University Of Washington | Methods and compositions for prevention or treatment of inflammatory-related diseases and disorders |
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| WO2013106494A1 (en) * | 2012-01-12 | 2013-07-18 | Quark Pharmaceuticals, Inc. | Combination therapy for treating hearing and balance disorders |
| WO2020023502A1 (en) * | 2018-07-23 | 2020-01-30 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
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