CN109966278B - Application of oxalylmalic acid in the preparation of drugs for the treatment of nerve cell injury - Google Patents
Application of oxalylmalic acid in the preparation of drugs for the treatment of nerve cell injury Download PDFInfo
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Abstract
本发明涉及草酰苹果酸在制备治疗神经细胞损伤的药物中的应用。将草酰苹果酸用于治疗缺血再灌注损伤，尤其是治疗脑组织神经病，更尤其是对缺血性脑卒中的保护作用，能显著减轻脑缺血/再灌注损伤，减少脑神经细胞损伤和提高神经细胞功能。
The present invention relates to the application of oxalylmalic acid in preparing medicine for treating nerve cell damage. The use of oxalylmalic acid for the treatment of ischemia-reperfusion injury, especially the treatment of cerebral neuropathy, especially the protection of ischemic stroke, can significantly reduce cerebral ischemia/reperfusion injury and reduce brain nerve cell damage and improve nerve cell function.
Description
Technical Field
The invention relates to an application of oxalyl malic acid in preparing a medicament for treating nerve cell injury, belonging to the field of biological medicines.
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 ischemia injury is related to various mechanisms such as intracellular calcium overload and inflammatory reaction, and the final outcome of any mechanism can result in nerve cell death, functional destruction 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 necroptosis (necroptosis), CypD-dependent necrosis, and the like. Among them, RIPK1/RIPK 3/MLKL-dependent necrotic apoptosis received the most attention. Studies have shown that RIPK1/RIPK3/MLKL dependent necrotic apoptosis is present in a variety of injury-related diseases, including myocardial infarction and ischemic stroke. Therefore, the inhibition of RIPK1/RIPK 3-dependent necrotic apoptosis has become an effective way for reducing the death of nerve cells of ischemic stroke. The literature reports that the RIPK1 inhibitor neocystatin-1 (Nec-1) can reduce the cerebral ischemic injury of mice and improve the nerve function, and the effect is closely related to the inhibition of necrotic apoptosis of nerve cells. However, Nec-1 is only used as a tool medicine for animal experiments, and no report is provided for treating cerebral arterial thrombosis or nerve cell injury by using RIPK1/RIPK3/MLKL medicines clinically at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of oxalyl malic acid in preparing the medicine for treating nerve cell injury.
The structural formula of the oxalyl malic acid is shown as the following formula:
the molecular formula is: c6H3O8(ii) a The molecular weight is: 272.05.
further, the nerve cell includes a nerve cell associated with a central nervous system disease.
Further, the central nervous system disease includes traumatic central nervous system injury, brain injury, spinal cord injury, stroke, neurodegenerative disease, alzheimer's disease, huntington's disease, dementia, amyotrophic lateral sclerosis, parkinson's disease, multiple sclerosis, diabetic neuropathy, spinocerebellar ataxia, fahr's disease, menke's disease, wilson's disease, cerebral ischemia, prion disease, frontotemporal dementia, lewy body dementia, cortical basal degeneration, progressive supranuclear palsy, multiple system atrophy, and hereditary spastic paraplegia.
Further, the stroke includes ischemic stroke and/or hemorrhagic stroke.
Further, the ischemic stroke includes cerebral ischemia/reperfusion injury.
Further, the ischemia/reperfusion injury also comprises one or more of myocardial ischemia/reperfusion injury, liver ischemia/reperfusion injury, kidney ischemia/reperfusion injury and lung ischemia/reperfusion injury.
Furthermore, the medicine can be prepared into any pharmaceutically acceptable dosage form according to the known technology, such as oral liquid, injection, tablets, capsules, granules, powder, oral liquid or dropping pills, and preferably oral liquid.
Further, the dosage form of the medicine is oral preparation.
Optionally, the administration mode in the application is subcutaneous injection, intravenous injection, intramuscular injection, oral administration or mucosal administration.
Optionally, the administration mode in said use is oral administration.
Experiments show that the oxalyl malic acid can specifically reduce the level of phosphorylated MLKL, inhibit necrosis-like apoptosis of nerve cells, remarkably reduce the volume of cerebral ischemic infarction and neurobiological scores, reduce the death of cerebral nerve cells and improve the functions of the nerve cells. Therefore, the oxalyl malic acid can be applied to the preparation of the medicine for treating ischemia/reperfusion injury.
Experiments show that the oxalyl malic acid can obviously reduce the volume of cerebral ischemic infarction and neurobiological scores, reduce the death of cerebral nerve cells and improve the function of nerve cells, and can be applied to the preparation of cerebral nerve cell damage and nerve dysfunction caused by central nervous system diseases, wherein the central nervous system diseases comprise traumatic central nervous system damage, brain damage, spinal cord injury, neurodegenerative diseases, Alzheimer disease, Huntington disease, dementia, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, diabetic neuropathy, different types of spinocerebellar ataxia, hr faopathy, menopathy, Wilson disease, cerebral ischemia, prion disorders, ke-temporo dementia, Lewy body dementia, cortical basal degeneration, progressive supranuclear palsy, multi-system atrophy and hereditary spastic paraplegia.
The invention expands the indication of oxalyl malic acid, and can be applied to ischemia/reperfusion injury; compared with an injection administration mode, the invention can adopt oral administration, has simple operation and small irritation, and enhances the compliance of patients.
Oxalyl malate has not been reported to be used for treating cerebral apoplexy. The invention firstly uses oxalyl malic acid to treat a rat ischemic stroke model, and finds that oxalyl malic acid can reduce the level of phosphorylated MLKL in a rat brain tissue, reduce the brain infarction volume of the rat, reduce nerve cell injury and improve neurological function. The invention proves that oxalyl malic acid can be used for treating ischemic stroke for the first time, and the mechanism of oxalyl malic acid plays a role by down-regulating the MLKL phosphorylation level and inhibiting the necrotic apoptosis of nerve cells. The invention expands the indication range of oxalyl malic acid and discovers a new drug action mechanism of the oxalyl malic acid. Ischemic stroke is a common clinical disease, and oxalyl malic acid has a wide application prospect.
The research of the inventor finds that the oxalyl malate has a new function, can specifically reduce the level of phosphorylated MLKL and inhibit the necrotizing apoptosis of cells.
In conclusion, the oxalyl malate is used for treating the brain tissue neuropathy, particularly has the protective effect on ischemic stroke, and can obviously relieve cerebral ischemia/reperfusion injury.
Drawings
FIG. 1: administration 15 minutes before surgery, A-rat brain tissue TTC staining and infarct volume determination, B-rat neurological function scoring.
Detailed Description
Animal experiments: protective effect of oxalyl malate on cerebral arterial thrombosis
Implementation of the medicine: oxalyl malate was purchased from reagent companies.
Oxalyl malic acid was dissolved in physiological saline.
Experimental animals: 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 quantity at regular time for one week, and then the administration groups are orally administered according to the experimental requirements.
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 left 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 randomly divided into 4 groups, namely:
control group (control group): no treatment is done.
Sham group (sham group): no plug wire is inserted after the vessel is isolated.
Ischemia/reperfusion group (I/R): cerebral ischemia for 2h, and reperfusion for 24 h.
Oxalomalate + cerebral ischemia/reperfusion group (OMA + I/R): oxalyl malate (dosage: 10mg/kg) is perfused for 15 minutes before operation, and then cerebral ischemia is carried out for 2 hours, and reperfusion is carried out for 24 hours.
Detection indexes are as follows: rat neurological score and infarct volume determination.
Results of the experiment
Effect of oxalyl malic acid on cerebral infarction volume and nerve function of rats
As shown in A in figure 1, I/R group had a clear white infarct focus, while rats administered oxalomalic acid before surgery had a significantly reduced cerebral infarct focus, significantly alleviating cerebral ischemic injury (p < 0.01). In the panel B, rats in cerebral ischemia group (I/R) showed marked neuromotor dysfunction, while oxalomalate significantly improved neurological deficit symptoms (p < 0.01).
However, the patent is not limited to cerebral ischemia/reperfusion injury, and the medicine is also suitable for treating cardiac, hepatic, renal and pulmonary ischemia/reperfusion injury due to the necrotic apoptosis of cardiac, hepatic and renal ischemia/reperfusion injuries. In addition, the upregulation of necrosed apoptosis in central nervous system disorders leads to brain nerve cell damage and neurological dysfunction, and oxalomalate is therefore also useful in the treatment of these central nervous system disorders.
Claims (6)
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| CN106714814A (en) * | 2014-06-27 | 2017-05-24 | S生物医药公司 | Composition for treating ischemic diseases or neurogenic inflammation, containing, as active ingredient, neural progenitor cells or secretome thereof |
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| CN106714814A (en) * | 2014-06-27 | 2017-05-24 | S生物医药公司 | Composition for treating ischemic diseases or neurogenic inflammation, containing, as active ingredient, neural progenitor cells or secretome thereof |
Non-Patent Citations (5)
| Title |
|---|
| Induction of ferritin expression by oxalomalate;Santamaria, R et al.;《BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH》;20040503;第1691卷(第2-3期);第151-159页 * |
| Iron Depletion or Chelation Reduces Ischemia/Reperfusion-Induced Edema in Gerbil Brains;By Anita Patt et al.;《JOURNAL OF PEDIATRIC SURGERY》;19900228;第25卷(第2期);第224-228页 * |
| Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide;Regan, Raymond F et al.;《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》;20081010;第375卷(第1期);第6-10页 * |
| Oxalomalate, a competitive inhibitor of aconitase, modulates the RNA-binding activity of iron-regulatory proteins;Festa, M et al.;《BIOCHEMICAL JOURNAL》;20000601;第348卷;第315-320页 * |
| Tau介导的铁转运在局灶性脑缺血再灌注损伤中的作用;庹清章;《华中科技大学 硕士学位论文 2016年》;20180119;第1-110页 * |
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