CN107648235B - Application of ponatinib in preparation of medicine for treating ischemia/reperfusion injury - Google Patents
Application of ponatinib in preparation of medicine for treating ischemia/reperfusion injury Download PDFInfo
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- CN107648235B CN107648235B CN201710021141.5A CN201710021141A CN107648235B CN 107648235 B CN107648235 B CN 107648235B CN 201710021141 A CN201710021141 A CN 201710021141A CN 107648235 B CN107648235 B CN 107648235B
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention discloses an application of ponatinib in preparation of a medicine for treating ischemia/reperfusion injury. The ponatinib is used for treating ischemia/reperfusion injury, particularly treating brain tissue neuropathy, more particularly has a protective effect on ischemic stroke, and can remarkably relieve the cerebral ischemia/reperfusion injury.
Description
Technical Field
The invention belongs to the field of biological medicines, and provides a new application and a drug delivery mode of a tyrosine kinase inhibitor Ponatinib (Ponatinib), which have a protective effect on cerebral ischemia/reperfusion (ischemic stroke) and expand the range of indications of Ponatinib.
Background
Ischemic stroke is a common and frequently-occurring disease seriously harming human health, and has become the first cause of disability and the third cause of death globally, and the incidence rate of ischemic stroke accounts for about 70-80% of cerebrovascular diseases.
Cerebral ischemic injury is related to various mechanisms such as excessive formation of free radicals, toxic action of excitatory amino acids, intracellular calcium overload, inflammatory reaction and the like, and the final outcome of any mechanism can cause nerve cell death, functional damage and cerebral infarction focus formation. The modes of cell death are mainly two pathways, necrosis and apoptosis. Traditionally, necrosis is considered a random, unexpected and unregulated passive mode of death, whereas apoptosis is a tightly regulated active mode of death. Recent studies have shown that necrosis is also tightly regulated by various signaling pathways, called regulatory necrosis, including programmed necrosis (programmed necrosis), iron necrosis (ferroptosis), CypD-dependent necrosis, and the like. Among these, RIPK1/RIPK3 dependent programmed necrosis is of the greatest concern. Studies have shown that RIPK1/RIPK3 dependent programmed necrosis is present in a variety of injury-related diseases, including myocardial infarction and ischemic stroke. Therefore, the inhibition of RIPK1/RIPK3 dependent programmed necrosis has become an effective way for reducing ischemic stroke nerve cell death. The literature reports that the inhibitor necrostatin-1(Nec-1) of RIPK1 can reduce the cerebral ischemic injury of mice and improve the nerve function, and the effect is closely related to the inhibition of the programmed necrosis of nerve cells. However, Nec-1 is only used as a tool medicine for animal experiments, and no RIPK1/RIPK3 medicine is clinically used for treating ischemic stroke at present.
Recent research finds that the tyrosine kinase inhibitor ponatinib has a new function, can specifically down-regulate protein expression levels of RIPK1 and RIPK3, and inhibits apoptosis. However, there is no report of ponatinib for treating ischemic stroke.
Disclosure of Invention
The structural formula of the ponatinib is shown as the formula I:
the chemical name is as follows:
3- (2- (imidozo [1,2-b ] pyridazin-3-yl) ethyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethylphenyl) benzyl) benzamide; the molecular formula is: C29H27F3N 6O; the molecular weight is: 532.56.
experiments show that the ponatinib is superior to the current commonly used cerebrovascular drugs in the effects of inhibiting nerve cell programmed necrosis, remarkably reducing the volume of cerebral ischemic infarction and protecting cerebral ischemia/reperfusion injury by inhibiting the specificity of receptor interaction protein kinase 1(RIPK1) and receptor interaction protein kinase 3(RIPK 3). Ponatinib can reduce programmed cell necrosis of ischemic/reperfused brain tissue. Therefore, ponatinib can be used for preparing a medicament for treating ischemia and/or reperfusion injury (herein, the "/" below both mean "and/or"). Preferably, the ischemia/reperfusion injury comprises cerebral ischemia/reperfusion injury, myocardial ischemia/reperfusion injury, hepatic ischemia/reperfusion injury, and renal ischemia/reperfusion injury. More preferably, the cerebral ischemia/reperfusion injury comprises ischemic stroke.
The invention expands the indications of ponatinib, and is applicable to cerebral ischemia/reperfusion injury; compared with an injection administration mode, the invention adopts oral administration, has simple operation and small irritation, and enhances the compliance of patients.
Ponatinib is currently used to treat adult Chronic Myeloid Leukemia (CML) and "philadelphia chromosome positive" (Ph +) Acute Lymphocytic Leukemia (ALL) that develop resistance to the tyrosine kinase inhibitor imatinib, dasatinib or nilotinib due to the T315I mutation. According to the invention, the ponatinib is used for treating the rat ischemic stroke model for the first time, and the ponatinib is found to be capable of reducing the protein expression levels of RIPK1 and RIPK3 in rat brain tissues, reducing the brain infarction volume of the rat and improving the neurological function, and the effect is superior to that of a positive tool drug Nec-1. The invention proves that the medicine ponatinib for treating leukemia can be used for treating cerebral arterial thrombosis for the first time. Unlike the mechanism of treating leukemia (inhibition of tyrosine kinases), ponatinib acts by inhibiting programmed necrosis of nerve cells by down-regulating the expression levels of RIPK1 and RIPK 3. The medicine for treating cerebral arterial thrombosis is an acute and short-term medicine, so that adverse reactions of the ponatinib can be greatly reduced. The invention enlarges the existing indication range of the ponatinib and discovers a new drug action mechanism of the ponatinib. Ischemic stroke is a common clinical disease, and the ponatinib has a wide application prospect.
In a word, the invention uses the ponatinib in treating brain tissue neuropathy, particularly has protective effect on ischemic stroke, and can obviously relieve cerebral ischemia/reperfusion injury.
Drawings
FIG. 1: administration 15 minutes before operation, A-rat brain tissue TTC staining and infarct volume determination, B-rat neurological function scoring;
FIG. 2: the medicine is administrated after 2h of ischemia and 1h of reperfusion, A-rat brain tissue TTC staining and infarct volume determination, and B-rat neurological function score.
Detailed Description
Animal experiments: protective effect of ponatinib on cerebral ischemic stroke
Implementation of the medicine: sodium carboxymethylcellulose (CMC-Na) was purchased from Shanghai Shanpu chemical Co., Ltd.
Ponatinib was made into a suspension with 0.5% sodium carboxymethylcellulose (CMC-Na) as the vehicle.
Experimental animals: 48 healthy male SD rats weighing 250-300 g. The experimental animals are raised in the environment with the temperature of 25 ℃, the relative humidity of 60%, free drinking water and fixed amount at regular time for one week, and then the oral administration is carried out according to the requirements of each group of the experiment.
The modeling method comprises the following steps: the rat cerebral ischemia/reperfusion injury model is prepared by a Middle Cerebral Artery Occlusion (MCAO) method. The method comprises the following steps: (1) isolating the external carotid artery (CCA), the right External Carotid Artery (ECA) and the Internal Carotid Artery (ICA) upwards; (2) temporarily occluding the ECA and ICA with ophthalmic forceps and ligating the CCA proximal; (3) placing a knotted standby silk thread at the distal end of the CCA, cutting a small opening at the lower end of the thread, inserting the embolus into the internal carotid artery, tightening the silk thread, releasing artery clamps on the ECA and the ICA, and sending the embolus into the cranium along the ICA; (4) stopping when meeting resistance, and the insertion depth is about 18-20 mm from the bifurcation of the CCA; (5) after 120min of ischemia, the plug thread was pulled out, the skin was sutured, and the animals were treated after 24h of reperfusion.
The model success criterion was used to score neurological deficit from ischemic injury in the rat brain using Longa "score 5". 0 minute: no symptoms of neurological deficit; 1 minute: the right forelimb cannot be fully straightened; and 2, dividing: rotating to the right; and 3, dividing: the walking is inclined towards the right side; and 4, dividing: the patient can not walk spontaneously and the consciousness is lost. 1-4 are classified into effective models.
Rat brain TTC staining and infarct volume determination. After anesthetizing the rats, the brains were quickly removed, the olfactory bulbs and hindbrains were removed, 4 coronary brain slices, about 2.0mm thick, were cut from the frontal pole, immediately placed in 1% TTC solution, and incubated in the dark at 37 ℃ for 30 min. Then soaking and fixing the mixture by using 10% paraformaldehyde solution. The infarcted areas appeared white and the non-infarcted areas appeared red. And (5) scanning after the brain slices of each group are arranged in order. And measuring the infarct area of each brain slice by using ImageJ, and according to a formula: the infarct volume is [ (sum of the positive infarct areas + sum of the negative infarct areas)/2 ] × thickness per tablet, and the whole brain volume was calculated in the same manner.
Grouping experiments: experimental animals were randomized into 6 groups, i.e.:
control group (control group): no treatment is done.
Sham group (sham group): the plug wire is inserted into the bifurcation of the artery in the brain and stops.
Ischemia/reperfusion group (I/R): cerebral ischemia for 2h, and reperfusion for 24 h.
Ponatinib + cerebral ischemia/reperfusion group (Ponatinib + I/R) 1: the stomach was perfused 15 minutes before the operation (the ponatinib was made into a suspension with 0.5% sodium carboxymethylcellulose, the dosage of ponatinib was 20 mg/kg). Ponatinib + cerebral ischemia/reperfusion group (Ponatinib + I/R) 2: gavage 1 hour after reperfusion after 2 hours of ischemia (the dosage of the ponatinib is 20 mg/kg); vehicle + cerebral ischemia/reperfusion group (vehicle + I/R): gavage 0.5% sodium carboxymethylcellulose (10ml/kg) 1 hour after reperfusion after 2 hours of ischemia.
Detection indexes are as follows: rat neurological score and infarct volume determination.
Results of the experiment
Effect of ponatinib on cerebral infarction volume and nerve function of rats
As shown in A in figure 1, I/R group had obvious white infarction focus, while rats given ponatinib (L) before operation had significantly reduced cerebral infarction focus, significantly alleviating cerebral ischemic injury. In FIG. B, rats in cerebral ischemic group (I/R) showed marked neuromotor dysfunction, while ponatinib significantly improved neurological deficit symptoms (p < 0.01).
As shown in A in figure 2, the I/R group has obvious white infarction focus, and the cerebral infarction focus of rats given with ponatinib (L) group is obviously reduced after 2h of ischemia and 1h of refilling, so that the cerebral ischemia injury is obviously relieved. In FIG. B, rats in cerebral ischemic group (I/R) showed marked neuromotor dysfunction, while ponatinib significantly improved neurological deficit symptoms (p < 0.01).
However, the medicine is not limited to cerebral ischemia/reperfusion injury, and because the heart, liver and kidney ischemia/reperfusion injury also has RIPK1/RIPK3 enzyme activity up-regulated, the medicine is also suitable for treating the heart, liver and kidney ischemia/reperfusion injury.
Claims (4)
1. Use of ponatinib in the manufacture of a medicament for the treatment of ischemia/reperfusion injury, wherein the ischemia/reperfusion injury is cerebral ischemia/reperfusion injury.
2. The use of claim 1, wherein the cerebral ischemia/reperfusion injury comprises ischemic stroke.
3. The use of claim 1, wherein the administration is subcutaneous, intravenous, intramuscular, or oral.
4. The use of claim 3, wherein the mode of administration in said use is oral.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710021141.5A CN107648235B (en) | 2017-01-12 | 2017-01-12 | Application of ponatinib in preparation of medicine for treating ischemia/reperfusion injury |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710021141.5A CN107648235B (en) | 2017-01-12 | 2017-01-12 | Application of ponatinib in preparation of medicine for treating ischemia/reperfusion injury |
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| CN107648235A CN107648235A (en) | 2018-02-02 |
| CN107648235B true CN107648235B (en) | 2020-04-03 |
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Non-Patent Citations (3)
| Title |
|---|
| A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis;A Fauster et al;《Cell Death and Disease》;20150521;第6卷;1-6 * |
| Necroptosis in Immunity andIschemia-Reperfusion Injury;A. Linkermann et al.;《American Journal of Transplantation》;20131231;2797–2804 * |
| 坏死性凋亡在神经***疾病中作用的研究进展;孟俊杰等;《基础医学与临床》;20160930;第36卷(第9期);1290-1294 * |
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