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Oligonucleotide having neuroprotective effect, pharmaceutical composition and pharmaceutical use thereof

An oligonucleotide and neuroprotective technology, applied in the field of biomedicine, can solve problems such as unsatisfactory efficacy and safety, achieve good application prospects and reduce brain damage.

Inactive Publication Date: 2017-03-29
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the common clinical treatment for acute ischemic stroke is to use thrombolytic drugs to restore or improve the blood supply, and to cooperate with neuroprotective drugs to prevent the further development of cerebral ischemia. Security is still not ideal

Method used

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  • Oligonucleotide having neuroprotective effect, pharmaceutical composition and pharmaceutical use thereof
  • Oligonucleotide having neuroprotective effect, pharmaceutical composition and pharmaceutical use thereof
  • Oligonucleotide having neuroprotective effect, pharmaceutical composition and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] The preparation of embodiment 1 oligonucleotide

[0017] The oligonucleotide of the present invention is synthesized by Shanghai Gemma Pharmaceutical Technology Co., Ltd., modified with cholesterol at the 3' end, modified with two thioxyl skeletons at the 5' end, modified with four thioxyl skeletons at the 3' end, and modified with the whole chain of methoxy , dried in vacuum after quantification by ultraviolet light, and stored at -20°C for future use. The chemically modified oligonucleotide increases its stability and target affinity, reduces cytotoxicity, and can be injected intravenously, intramuscularly or intraperitoneally to achieve the purpose of biological treatment of ischemic brain injury.

[0018] By comparing with the GeneBank online blast sequence, the oligonucleotide sequence was obtained as shown in SEQ ID NO: 1: 5'-AGUGAAUUCUACCAGUGCCAUA-3', which has good specificity.

Embodiment 2

[0019] Example 2 Effect of oligonucleotides on hippocampal neuron damage caused by global cerebral ischemia-reperfusion in rats

[0020] (1) Main reagents

[0021] The oligonucleotide of the negative control was synthesized by Shanghai Jima Pharmaceutical Technology Co., Ltd., and its nucleotide sequence is shown in SEQ ID NO: 2: 5'-CAGUACUUUUGUGUAGUACAA-3'.

[0022] Isoflurane (2%) was purchased from Baxter, USA; chloral hydrate and other conventional chemical reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.; 2,3,5-triphenyltetrazolium chloride (TTC) was purchased from Ameresco .

[0023] (2) Main instruments

[0024] The small animal anesthesia machine (ABS-100) and the small animal induction box (IC-R) were purchased from Shanghai Yuyan Scientific Instrument Co., Ltd.; the small animal stereotaxic instrument was purchased from STOELTING, USA.

[0025] (3) Experimental animals

[0026] SPF grade Sprague-Dawley (SD) healthy male rats, weighing 220-300g, w...

Embodiment 3

[0038] Example 3 Effects of Oligonucleotides on Brain Damage Caused by Focal Cerebral Ischemia in Rats

[0039] A rat model of middle cerebral artery occlusion (MCAO) was established by using the suture method, referring to Longa et al. (Stroke, 1989, 20(1): 84-91). After ischemia, oligonucleotides or negative control were injected into the lateral ventricle (1 nmol per rat, completed 40 minutes after ischemia). 24 hours after MCAO (90min), 2,3,5-triphenyltetrazolium chloride (2,3,5-triphenyltetrazolium chloride, TTC; 2%) was stained to observe the effect of injection of drugs on the hindbrain after ischemia-reperfusion injury. Influence of infarct tissue size. The specific operation is as follows:

[0040] Animal feeding and operation temperature were controlled at about 25°C, and no food or water was allowed 12 hours before the operation. Male SD rats were anesthetized by intraperitoneal injection of 20% chloral hydrate (300mg / kg), fixed on the operating table in supine p...

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Abstract

The invention discloses an oligonucleotide having a neuroprotective effect, a pharmaceutical composition and a pharmaceutical use thereof. The sequence of the oligonucleotide is shown in the formula of SEQ ID NO: 1. The oligonucleotide is modified by cholesterol at the end 3', two sulfo-skeletons at the end 5', four sulfo-skeletons at the end 3' and methoxy groups on the whole chain. The oligonucleotide and an acceptable pharmaceutical carrier are combined to form the pharmaceutical composition. The pharmaceutical composition can treat diseases associated with ischemic neuronal damage through intravenous, intramuscular or intraperitoneal injection and especially treat ischemic cerebral stroke. After global cerebral ischemia and focal cerebral ischemia, the oligonucleotide can obviously mitigate the brain injury caused by ischemia-reperfusion and has a good application prospect.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to an oligonucleotide, in particular to an oligonucleotide with neuroprotective effect, a pharmaceutical composition and its medical application. Background technique [0002] Stroke (Stroke) is a major risk factor that threatens human life. It is a brain dysfunction syndrome caused by acute cerebral circulation disorder. It has the characteristics of high morbidity, high mortality, and high disability rate. The rate is increasing year by year. Acute ischemic stroke is brain tissue necrosis caused by insufficient blood supply to the brain, accounting for 60%-80% of all strokes. At present, the common clinical treatment for acute ischemic stroke is to use thrombolytic drugs to restore or improve the blood supply, and to cooperate with neuroprotective drugs to prevent the further development of cerebral ischemia. Security is still not ideal. Therefore, it is of great medical value and socia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11A61K31/7088A61P9/10A61P25/00
CPCC12N15/113A61K31/7088C12N2310/10C12N2320/30
Inventor 侯筱宇魏建峰姚桂英周婷婷魏涛岳军
Owner XUZHOU MEDICAL UNIV