CN102406648A - Application of imatinib mesylate in preparation of drugs for resisting Parkinson's disease (PD) - Google Patents
Application of imatinib mesylate in preparation of drugs for resisting Parkinson's disease (PD) Download PDFInfo
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Abstract
The invention discloses an application of imatinib mesylate in preparation of drugs for resisting Parkinson's disease (PD). The application of imatinib mesylate (STI571) in preparation of drugs for treating neurodegenerative diseases belongs to the protective range of the invention, and the neurodegenerative diseases can be PD. An experiment proves that by continuous administration of the STI571, the dyskinesia induced by MPTP can be obviously improved, and the cognitive dysfunction of mice can be improved. The STI571 can obviously improve the dopaminergic neuron loss induced by the MPTP, can inhibit the rat CA1 and DG (diacylglycerol) region nerve cell apoptosis reaction induced by rotenone, can obviously inhibit the primary substantia nigra neuron apoptosis and Lewy protein expression induced by rotenone, and can inhibit the phosphorylation activation of PKC (Protein Kinase C) and Akt. The STI571 used as a specific inhibitor of c-Ab1 can resist the formation of PD, can improve the behavioral abnormity and cognitive dysfunction of PD, can be used as a new candidate drug for resisting neurodegenerative diseases such as PD and the like, and has favorable application prospects; and the clinical indications of the STI571 are greatly expanded.
Description
Technical field
The present invention relates to the application of imatinib mesylate in the Parkinsonian medicine of preparation treatment.
Background technology
Imatinib mesylate (STI571); Chemical name is 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline mesylate; Mainly use it for the treatment of chronic lymphocytic leukemia at present abroad, STI571 can obviously suppress Leukemia Cell Proliferation, and cell blocks the phase in G0/G1; And have tangible apoptosis-induced effect, can make ubiquitous Abelson EGFR-TK (Ab1) inactivation.
Other function to imatinib mesylate does not also have bibliographical information at present.
Summary of the invention
The object of the present invention is to provide the application of imatinib mesylate (STI571) in the medicine of preparation treatment neurodegenerative diseases.
In the application of imatinib mesylate provided by the invention in the medicine of preparation treatment neurodegenerative diseases, above-mentioned neurodegenerative diseases can specifically be parkinson disease.
Above-mentioned parkinson disease can be the inductive experimental parkinson disease of mitochondrion electron transport chain inhibitor.
Further, above-mentioned mitochondrion electron transport chain inhibitor is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone.
The application of imatinib mesylate in the product of preparation dyskinesia and/or cognitive dysfunction also belongs within protection scope of the present invention.
The application of imatinib mesylate in the preparation of preparation inhibition neuronal apoptosis reaction also belongs within protection scope of the present invention.
Further, above-mentioned inhibition neuronal apoptosis reaction can realize through the phosphorylation that suppresses neuron MST1 albumen T183 site; The proteic aminoacid sequence of said neuron MST1 is shown in sequence in the sequence table 1.
Specifically, above-mentioned neurocyte is the CA1 of Mus and/or the neurocyte in DG district.
Above-mentioned neuronal apoptosis reaction is the symptom that MPTP or rotenone are induced formation.
Imatinib mesylate also belongs within protection scope of the present invention in the application that preparation improves in the medicine of dopamine neuron forfeiture.
Above-mentioned dopamine neuron forfeiture is the symptom that MPTP or rotenone are induced formation.
The experiment proof: one week of STI571 successive administration, two weeks, can significantly improve the inductive dyskinesia of MPTP, show as the significant prolongation bull stick time; STI571 also can significantly improve the inductive spontaneous activity of MPTP and reduce, and compares with the MPTP model group, and spontaneous activity distance and average speed all significantly increase, thereby improve the inductive dyskinesia of MPTP.Therefore STI571 can improve the dyskinesia of Mus.Find that through orientation navigation test, space exploration test STI571 can improve the cognitive dysfunction of Mus.Further Analysis on Mechanism shows: forfeiture, the STI571 that STI571 can significantly improve the inductive dopamine neuron of MPTP suppresses inductive rat CA1 of rotenone and the reaction of DG district neuronal apoptosis and STI571 can significantly suppress rotenone black substance Neuron Apoptosis of inductive former generation and Lewy corpusculum protein expression, suppresses the phosphorylation activation of PKC and Akt.Therefore; STI571 is as the specific inhibitor of c-Ab1; Can effectively resist PD and form, the behavioristics when improving PD reaches cognitive dysfunction unusually, maybe be as candidate's new drug of neurodegenerative diseases such as anti-parkinson; Have a good application prospect, greatly degree has been expanded the clinical indication of STI571.
Description of drawings
Fig. 1 is the influence of STI571 to the three-dimensional site-specific delivery of drugs of rotenone (rotenone) (3h-3d) rat CA1 district and DG district neuron p-MST1-T183 protein expression, when A, B are 3,6,12,24,48,72 hours respectively to the coloration result in rat CA1 and DG district; C is the proteic AO of neuron p-MST1-T183, is B figure DG district quantitative results; Be 3,6,12,24,48,72 hours result.
Fig. 2 is the influence of STI571 to the apoptotic response of the inhibition three-dimensional site-specific delivery of drugs of rotenone (rotenone) (24-72h) rat CA1 district and DG district neurocyte, and A is that percentage of cell apoptosis is DG district 24h, 48h, the result of three time points statistics of 72h; When B is 24,48,72 hours to the TUNEL coloration result in rat CA1 district; C is the TUNEL coloration result in DG district.
Fig. 3 is the bull stick experiment, and A, B and C are respectively the result of the tests in STI571 successive administration three days, a week and two weeks;
*P＜0.01 vs control, ##p＜0.01 vs MPTP.
Fig. 4 is automatic exercise testing, and two figure among the A are respectively the distance and the average speed result of spontaneous activity from left to right, and B is representational spontaneous activity track;
*P＜0.01 vs control, ##p＜0.01 vs MPTP.
Fig. 5 is the concealment platform experiments, and A is the incubation period of absconding; B finds concealment platform distance to go; C is average swimming rate, and D is quadrant swimming distance at the platform place, and E is the time of staying;
*P＜0.01 vs control, ##p＜0.01 vs MPTP.
Fig. 6 is a number of times of crossing over platform for space exploration experiment, A; B finds original platform position required time, C to find the required distance to go in original platform position; D is that quadrant swimming distance, E are the time of staying at the platform place;
*P＜0.01 vs control, ##p＜0.01 vs MPTP.
Fig. 7 is the visualisation platforms experiment, and A is that the incubation period, the B that find platform are that swimming distance, C are that average speed, the D that mice is swum is that platform place quadrant swimming distance and E are the time of staying,
*P＜0.05 vs control, ##p＜0.01vs MPTP.
Fig. 8 is a representative swimming track in constant-bearing navigation experiment, space exploration experiment and the visualisation platforms experiment, and A is the constant-bearing navigation experiment swimming track of experiment for the first time; B is the swimming track of the last experiment of constant-bearing navigation experiment; C is the swimming track of space exploration experiment; The swimming track of D visualisation platforms experiment.
Fig. 9 seeks platform track classification (A) and ratio (B) for the representativeness of MPTP (20mg.kg-1, i.p, 2 weeks) model group and STI571 (30mg.kg-1, i.p, 2 weeks) treatment group in the constant-bearing navigation experiment.
Figure 10 is lose (A, wherein left figure are that black substance position TH SABC result, right figure are the AOs of TH positive neuron) of tyrosine hydroxylase (TH) positive neuron; Increase the proteic expression of nigrostriatum position TH (B), Hippo is that Hippocampus, Cortex are that cortex, Striatum are striatum among the figure, and N is normal; M is MPTP; S is STI571.
Figure 11 is respectively the protein expression of cleavage-capase 3; The protein expression that suppresses α-synuclein; The protein expression that suppresses p-PKC and p-Akt; Ctrl, 5nM Rotenone, 5nM Rotenone+5uMSTI571 are respectively normal control group, rotenone model group and the STI571 treatment group in the model experiment of the pregnant Mus of SD black substance neuron of former generation PD like cell.
Wherein: the DMSO among Fig. 1 and Fig. 2, Rotenone and STI571+Rotenone are respectively STI571 and suppress normal control group, rotenone model group and STI571 treatment group in inductive rat CA1 of rotenone and the DG district neuronal apoptosis reaction experiment.Among Fig. 3-Figure 10, control, MPTP and STI571 are that MPTP induces normal control group, rotenone model group and the STI571 treatment group in the chronic PD model of the c57BL/6J mice related experiment.
The specific embodiment
Below in conjunction with specific embodiment the present invention is described further, but the present invention is not limited to following examples.
Among the following embodiment,, be conventional method like no specified otherwise.
One, STI571 can significantly improve the inductive mice chronic Parkinson disease of MPTP dyskinesia
Parkinson disease mainly are that dopamine is synthetic to be reduced because of after the cell generation pathologic change that is arranged in substantia nigra of midbrain, and the excitation of acetylcholine strengthens relatively, and " Parkinsonism " just appearred in the result that both are unbalance.Sickness rate accounts for the 1st in old neurodegenerative disease.Its main behavioristics shows as slow in one's movements and disappearance, muscular rigidity, and static tremor and posture are unstable.
1, modeling
With the c57BL/6J mice of 8 week sizes at random be divided into 3 groups, 10 every group, by following mode intraperitoneal administration, be administered once every day, two weeks of successive administration.[1] control group: normal saline; [2] MPTP group: MPTP (20mg/kg is dissolved in normal saline); [3] STI571+MPTP group: STI571 (30mg/kg is dissolved in normal saline) lumbar injection is after one hour, more then to MPTP (20mg/kg is dissolved in normal saline); (Hayato Kuroiwa; Hironori Yokoyama; Hiroki Kimoto; Hiroyuki Kato, Tsutomu Araki (2010) Biochemical alterations of the striatum in an MPTP-treated mouse model of Parkinson ' s disease Metab Brain Dis 25:177-183).
According to above method to c57BL/6J mice (available from dimension tonneau China company) with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induce chronic Parkinson disease (parkinson ' s disease, PD) model.
2, divide into groups
Following three groups of c57BL/6J mices are carried out bull stick experiment and autonomic movement experiment:
Normal control group: intraperitoneal injection of saline every day (0.1ml/10g);
MPTP model group:, MPTP is injected continuous 14 days to mouse peritoneal according to the dosage of 20mg/kg body weight;
STI571 treatment group: according to the dosage of 30mg/kg body weight, the STI571 lumbar injection is advanced mice, after one hour,, MPTP is injected continuous 14 days simultaneously to mouse peritoneal according to the dosage of 20mg/kg body weight.
3, bull stick experiment (Rotorod)
Bull stick experiment: mice is clocked after beginning on the bull stick to creep automatically, when bull stick falls, can be monitored by infrared facility, stops automatically clocking and show the time that mice moves on bull stick.Carry out after this experiment three days during giving ST1571 or MPTP 14 days, a week and two weeks.It is that per minute 40 changes that rotating speed is adopted in experiment.
The result is as shown in Figure 3, one week of STI571 successive administration, two weeks, can significantly improve the inductive dyskinesia of MPTP, and show as the significant prolongation bull stick time.
4, autonomic movement experiment (Locomoter activity test)
Autonomic movement experiment: mice is placed autonomic movement monitor (circle, diameter 50cm) central part, keep environment quiet.In the autonomic movement monitor, there is the multi beam infrared ray to pass, intercepts ir beams during animal activity, can be detected and numeration.Behind the pre-adaptation 2min, autonomic movement number of times in the record mice 10min.This experiment is carried out after two weeks giving ST1571.
The result is as shown in Figure 4; On the chronic PD model of the inductive c57BL/6J mice of MPTP, STI571 also can significantly improve the inductive spontaneous activity of MPTP and reduce, and compares with the MPTP model group; Spontaneous activity distance and average speed all significantly increase, thereby improve the inductive dyskinesia of MPTP.
Two, STI571 can significantly improve the inductive mice chronic Parkinson disease of MPTP cognitive dysfunction
The Morris water maze in early 1980s design and be applied to the research of learning and memory brain mechanism, is the method for the most reliable and effective check animal behavior memory function at present by Britain psychologist Morris.Required time, the strategy of employing and the track of their swimming of ferret out after the animal entry can observed and write down to this device, helps to analyze and infer the ability of the aspects such as study, memory, spatial orientation and cognitive function of unit.Be widely used at present in the basic and applied research in neurobiology field.The Morris water maze comprises a round pool that is filled with water, is hidden under water platform and automatic collection of a cover image and processing system (video camera, display and analysis software etc.).Comparatively classical Morris water maze test program comprises that mainly orientation navigation is tested (place navigation) and sky asks exploratory experiment (Spatial probe trail) two parts.
1, orientation navigation test (concealment platform experiments)
Experimental procedure: last 7 days; Put into the water several times from 3 place of entry with Mus (the normal control group in the step 1, MPTP model group and STI571 treatment group) respectively towards pool wall every day; Write down it and search out the time that is hidden in the underwater platform; Be escape latency (escape latency, EL).Detected be mice in training repeatedly, the hiding platform of fixed position is sought by association, forms stable spatial cognition, this spatial cognition is the formation of processing space information.Residing position of the position of platform and Mus and state are irrelevant, be a kind of with different I be that reference of reference point is cognitive, formed memory is that a kind of georeferencing is remembered.
The result is as shown in Figure 5, and on the chronic PD model of the inductive c57BL/6J mice of MPTP, in the concealment platform experiments, MPTP inducing mouse space learning ability significantly reduces, and shows as (Fig. 5 A) significant prolongation of absconding incubation period; Find concealment platform distance to go (Fig. 5 B) significant prolongation; Average swimming rate (Fig. 5 C) significantly reduces; Significantly shorten in the platform place quadrant swimming distance (Fig. 5 D) and the time of staying (Fig. 5 E).The STI571 successive administration can significantly improve above-mentioned space learning dysmnesia after two weeks.
2, space exploration test
Experimental procedure: platform is removed in the location navigation test back above-mentioned; Optional then place of entry is put into the pond with mice (normal control group, MPTP model group and STI571 treatment group); Write down its swimming track within a certain period of time, investigate the hold facility of mice the locus memory of original platform.The parameter that test can supply be analyzed is more, comprises that all quadrants swimming distance, original platform quadrant swimming distance and the ratio of total distance, cross-platform number of times and China and foreign countries tour around the percentage ratio of swimming distance etc.
The result is as shown in Figure 6, and on the chronic PD model of the inductive c57BL/6J mice of MPTP, in the space exploration experiment, MPTP inducing mouse spatial memory ability significantly reduces, and shows as the number of times (Fig. 6 A) of crossing over platform and significantly reduces; Find original platform position required distance to go (Fig. 6 B, 6C) significant prolongation; Significantly shorten in the platform place quadrant swimming distance (Fig. 6 D) and the time of staying (Fig. 6 E).The STI571 successive administration can significantly improve above-mentioned spatial memory obstacle after two weeks.
3, visualisation platforms experiment
Experimental procedure: compare with the concealment platform experiments, just undersurface platform is transferred on the water surface, all the other steps are identical.
The result is as shown in Figure 7; On the chronic PD model of the inductive c57BL/6J mice of MPTP; In the visualisation platforms experiment; MPTP and STI571 treatment group mice are in the incubation period of finding platform (Fig. 7 A), swimming distance (Fig. 7 B) and platform place quadrant swimming distance (Fig. 7 D) and all do not have significant difference on the time of staying (Fig. 7 E), only show as MPTP and induce average swimming rate to reduce (Fig. 7 C) of STI571 alleviation.
4, STI571 is to the influence of movement locus in the constant-bearing navigation of PD mice, space exploration and the visualisation platforms experiment
In the above-mentioned orientation navigation test, on the chronic PD model of the inductive c57BL/6J mice of MPTP, constant-bearing navigation experiment MPTP model group mice swimming route showed increased can significantly reduce the swimming route (Fig. 8 A) that arrives platform after the STI571 two weeks treatment; Compare each group swimming route all have clear improvement (Fig. 8 B) through training mice and second day mice of training after 7 days.
In the experiment of above-mentioned space exploration and visualisation platforms, each group swimming track and constant-bearing navigation experiment law similar (Fig. 8 C, 8D).
5, the movement locus category analysis of STI571 in the constant-bearing navigation experiment
In the above-mentioned constant-bearing navigation experiment, on the chronic PD model of the inductive c57BL/6J mice of MPTP, the representativeness of MPTPMPTP model group and STI571 treatment group is sought platform track classification (Fig. 9 A) and ratio (Fig. 9 B) in the constant-bearing navigation experiment.MPTPMPTP model group mice is main with stochastic pattern (Random) swimming track, and the normal control group is main with linear type (Beeline) swimming track, and STI571 treatment group is main with trend type (Tropism) swimming track then.
Motion and cognitive dysfunction when in sum, STI571 can effectively improve PD.
Embodiment 2, mechanism research
One, STI571 can significantly improve the forfeiture of the inductive dopamine neuron of MPTP
Experimental procedure: above-mentioned normal control group, MPTP model group and STI571 treatment group mice are respectively got two and at first use 4% paraformaldehyde perfusion fixation; Perfusion after accomplishing takes out mouse brain; Put into 4% paraformaldehyde and continued fixing 3 days, after fixing the completion, make frozen section to the black substance district.Ready-made frozen section use TH antibody (1: 100, sigma, T1299) immunostaining utilizes the AO of image pro plus software statistics TH positive neuron to coloration result.After the disconnected neck of remaining mice is put to death, get Hippocampus, cortex, striatum albumen, RIPA (5ul/1g albumen) is cracking 30min on ice, and centrifugal 45min behind the ultrasonic 9s/9s three times gets supernatant lysate-80 ℃ preservation.Organize subsequently in the western blot experiment, and use TH antibody (1: 5000, sigma is T1299) with two anti-(anti-mouse IgG; (1: 10000), GE healthcare, the Lot386066) expression of TH in the test set tissue samples.
The result is shown in figure 10, and on the chronic PD model of the inductive c57BL/6J mice of MPTP, STI571 can significantly suppress losing of the inductive tyrosine hydroxylase of MPTP (TH) positive neuron, and the damage of DA serotonergic neuron when promptly suppressing PD improves PD symptom (Figure 10 A); STI571 also can improve the reduction (Figure 10 B) of the inductive nigrostriatum of MPTP position cerebral tissue TH protein expression.
Two, STI571 suppresses inductive rat CA1 of rotenone and the reaction of DG district neuronal apoptosis
1, modeling
The SD rat of getting 180-200g size is divided into three groups, the method for the three-dimensional locating injection of requiring mental skill in rat DG district by following mode administration, 3h after the administration, 6h, 12h, 24h, 48h puts to death behind the 72h, gets cerebral tissue perfusion fixation making hippocampus paraffin section.[1] control group: DMSO 4ul; [2] rotenone group: Rotenone 4ul (2.5ug/ul is dissolved in DMSO); [3] STI571+MPTP group: STI571 4ul (20mM; Be dissolved in normal saline)+Rotenone 4ul (2.5ug/ul; Be dissolved in DMSO) (Gonzalo I.Cancinol, Enrique M.Toledo, Nancy R.Leall; Diego E.Hernandezl; L.Fernanda Y é venesl, Nibaldo C (2008) STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer ' s beta-amyloid deposits Brain131:2425-42).
According to above method SD rat (can available from dimension tonneau China company) is reacted with inductive rat CA1 of rotenone and DG district neuronal apoptosis.
2, divide into groups
Normal control group: DMSO 4ul
MPTP model group: Rotenone 4ul (2.5ug/ul is dissolved in DMSO)
STI571 treatment group: STI571 4ul (20mM is dissolved in normal saline)+Rotenone 4ul (2.5ug/ul,
Be dissolved in DMSO)
1, the proteic expression of p-MST1-T183
The three-dimensional location in SD rat brain CA1 and DG district gives rotenone (rotenone, 10 μ g with the micro-sampling pump; 3-72h), give simultaneously STI571 (42mg, 3-72h); With p-Mst1-T183 antibody (1: 100, Cell Signal technology) and two anti-(anti-Rabbit IgG; (1: 200), GE healthcare) carries out DAB (middle shirt Golden Bridge) immunohistochemical staining, observe the change of CA1 and DG district neuron p-MST1-T183 protein expression.To painted result, utilize image pro plus software to average the photodensitometric quantitation analysis.The result shows; Rotenone is handled the inductive CA1 of 6h-3d to STI571 and DG district neuronal damage all has remarkable inhibitory action; The protein expression that suppresses p-MST1-T183 also promptly suppresses the phosphorylation in neuron MST1 albumen T183 site, thereby suppresses neuronal apoptosis reaction (Fig. 1).
2, morphological observation
When above-mentioned three-dimensional site-specific delivery of drugs 24h, 48h, 72h, (ApopTag Flurescein In Situ Apoptosis Detection Kit S7110 CHEMICON) observes the neuronal apoptosis reaction in TUNEL dyeing.
Utilize the number of image pro plus software statistics Hoechest painted (blueness) cell and the number of TUNEL test kit painted (green) cell, the latter and the former ratio are apoptotic percentage ratio.The result is as shown in Figure 2, and STI571 can significantly suppress rotenone and handle the neuronal apoptosis reaction of the inductive CA1 of 24h district; Suppress rotenone and handle the inductive DG of 24-72h district's neuronal apoptosis reaction (Fig. 2).
Three, STI571 can significantly suppress rotenone black substance Neuron Apoptosis of inductive former generation and Lewy corpusculum protein expression, suppresses the phosphorylation activation of PKC and Akt
1, experimental procedure
Get the black substance culture of primary neurons of 12 days SD tire Mus and support (Thomas Fath1; Yazi D Ke2; Peter Gunning1, Ju ¨ rgen Go ¨ tz2 & Lars M Ittner (2009) Primary support cultures of hippocampal and substantia nigra neurons NATURE PROTOCOLS 4:78-85), break up after 3 days; Be divided into three groups, respectively by following method drug treating.[1] control group: no drug treating [2] rotenone group: Rotenone (final concentration 5uM) handles 30min; [3] STI571+MPTP group: STI571 (final concentration 5uM) pretreatment added Rotenone (final concentration 5uM) and handles 30min after one hour; Collecting cell is used the RIPA cracking, goes after centrifugal supernatant to preserve.
On the pregnant Mus of the inductive SD of rotenone (Rotenone) black substance neuron of former generation PD like cell model, STI571 can significantly suppress the expression of the inductive apoptotic response albumen of rotenone cleavage-capase 3; Suppress the expression of Lewy corpusculum protein alpha-synuclein; The protein expression that suppresses p-PKC and p-Akt; Involved antibody is respectively anti-cleavage-capase3 (cell signal); Anti-α-synuclein (ABCOM); Anti-p-PKC (santa), anti-p-Akt (cell signal) and two anti-anti-mouse and anti-Rabbit IgG (GEhealth) are (Figure 11).
Therefore; STI571 is as the specific inhibitor of c-Ab1; Can effectively resist PD and form, the behavioristics when improving PD reaches cognitive dysfunction unusually, maybe be as candidate's new drug of neurodegenerative diseases such as anti-parkinson; Have a good application prospect, greatly degree has been expanded the clinical indication of STI571.
Claims (8)
1. the application of imatinib mesylate in the medicine of preparation treatment neurodegenerative diseases.
2. application as claimed in claim 1 is characterized in that: said neurodegenerative diseases is parkinson disease.
3. the application of imatinib mesylate in the product of preparation dyskinesia and/or cognitive dysfunction.
4. the application of imatinib mesylate in the preparation of preparation inhibition neuronal apoptosis reaction.
5. application as claimed in claim 4 is characterized in that: said inhibition neuronal apoptosis reaction is to realize through the phosphorylation that suppresses neuron MST1 albumen T183 site; The proteic aminoacid sequence of said neuron MST1 is shown in sequence in the sequence table 1.
6. the application described in claim 4 or 5 is characterized in that: said neuronal apoptosis reaction is 1-methyl-4-phenyl-1,2,3, and 6-tetrahydropyridine or rotenone are induced the symptom of formation.
7. imatinib mesylate improves the application in the medicine of dopamine neuron forfeiture in preparation.
8. the application described in claim 7 is characterized in that: said dopamine neuron forfeiture is 1-methyl-4-phenyl-1,2,3, and 6-tetrahydropyridine or rotenone are induced the symptom of formation.
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| US11407747B2 (en) | 2015-04-23 | 2022-08-09 | Inhibikase Therapeutics, Inc. | Compositions and methods for inhibiting kinases |
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| JP2019535680A (en) * | 2016-10-25 | 2019-12-12 | インヒビカーセ セラピューティクス，インコーポレーテッド | Compositions and methods for inhibiting kinases |
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| CN111374977A (en) * | 2018-12-27 | 2020-07-07 | 浙江大学 | Application of axitinib and analogues thereof in preparation of blood brain barrier permeability regulator |
| CN111374977B (en) * | 2018-12-27 | 2022-03-18 | 浙江大学 | Application of axitinib and analogues thereof in preparation of blood brain barrier permeability regulator |
| CN115429782A (en) * | 2022-07-20 | 2022-12-06 | 中国科学院动物研究所 | Application of acetate in preparation of medicine for preventing or treating development disorder of nervous system |
| CN115429782B (en) * | 2022-07-20 | 2024-03-29 | 中国科学院动物研究所 | Application of acetate in preparation of medicine for preventing or treating nervous system development disorder |
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