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Application of S1P inhibitor in preparation of medicine for treating neurodegenerative diseases

A neurodegenerative and inhibitory technology, applied in nervous system diseases, drug combinations, active ingredients of heterocyclic compounds, etc., can solve the problem of unreported drug application in Parkinson's disease

Active Publication Date: 2021-05-11
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

S1P inhibitors have been used as drugs for the treatment of multiple sclerosis, and their role in vascular diseases has been reported, but their application as a drug for the treatment of Parkinson's disease has not been reported

Method used

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  • Application of S1P inhibitor in preparation of medicine for treating neurodegenerative diseases
  • Application of S1P inhibitor in preparation of medicine for treating neurodegenerative diseases
  • Application of S1P inhibitor in preparation of medicine for treating neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Cell experiment

[0026] The SH-SY5Y cells were divided into 1 × 10 4 Each well was seeded in a 96-well plate, and 7 groups (n=6) were set up. After the cells adhered to the wall, the Control group was not treated, and the MPP + group only added 1mM MPP + , PF group was added with 1mM MPP + And different concentrations (1μl, 2μl, 3μl, 3.5μl, 4μl) of PF429242, cultivated for 48h. The CCK-8 method was used to detect the cytotoxicity, and the ELx800UV microplate reader detected the absorbance (OD) value at a wavelength of 450 nm, reflecting the number of living cells.

[0027] The result is as figure 1 As shown, in human neuroblastoma SH-SY5Y cells with mature neuronal morphology and biochemical characteristics, 1 mM of the neurotoxic MPTP metabolite MPP was added + (Methyl-phenylpyridinium ion) significantly decreased the absorbance of cells, indicating that SH-SY5Y or the number of cells decreased, MPP + Has significant cytotoxicity. And joined the MPP ...

Embodiment 2

[0028] Embodiment 2 animal experiments

[0029] Thirty-two 6-week-old male C57BL / 6 mice were divided into four groups (n=8), namely Control, MPTP, MPTP+Saline, and MPTP+PF429242 groups, and were raised in a quiet environment with free access to water and food. One week later, the MPTP group was intraperitoneally injected with MPTP solution (6.25mg / ml) at a dose of 25mg / kg for 2 weeks (the injection frequency was once a day); the MPTP+PF429242 group was injected with a dose of 25mg / kg MPTP solution (6.25mg / ml) ml) while injecting 150ul of PF429242 (0.125g / L) intraperitoneally; the MPTP+Saline group was intraperitoneally injecting MPTP solution (6.25mg / ml) at a dose of 25mg / kg and simultaneously injecting 150ul of normal saline intraperitoneally. The rotarod test and the balance beam test were carried out to evaluate the depression and exercise ability of the four groups of mice. The results are as follows: figure 2 and image 3 shown.

[0030] figure 2 and image 3 The r...

Embodiment 3

[0031] Example 3 Morphological experiment-neuron cells

[0032] The mice in the Control, MPTP, MPTP+Saline, and MPTP+PF429242 groups in Example 2 were weighed separately, and the dosage of 1% pentobarbital sodium (0.01ml / g) was calculated according to the body weight, and then injected intraperitoneally for anesthesia. Open the chest and abdomen to fully expose the heart and liver, open the pericardium with tweezers, insert the perfusion needle into the left ventricle and fix it, turn on the perfusion pump switch, and cut the right atrial appendage at the same time. First perfuse with 0.9% NaCl pre-cooled at 4°C until the liver gradually turns white and the right atrial appendage flows out clear liquid, and then perfuse with paraformaldehyde fixative solution pre-cooled at 4°C. After the fixative fluid entered the blood vessels, the limbs and tail of the mice began to twitch, indicating that the perfusion fluid entered the brain. After the twitching stopped and the tissues and...

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Abstract

The invention discloses an application of an S1P inhibitor in preparation of a medicine for treating neurodegenerative diseases, the S1P inhibitor prevents dopaminergic neuron loss and neuroinflammation cascade reaction by inhibiting activation of microglia and astrocytes; and by protecting dopaminergic neurons and increasing tyrosine hydroxylase to recover the normal secretion level of dopamine, so that the motility symptom and the non-motility symptom are improved, and the S1P inhibitor has the potential of preparing the medicine for treating the neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the field of drugs for treating neurodegenerative diseases, and in particular relates to the application of an S1P inhibitor in the preparation of drugs for treating neurodegenerative diseases. Background technique [0002] Parkinson's disease (PD) is the second most common neurodegenerative disease, and the main clinicopathological features of PD are the loss of dopamine (DA) neurons in the substantia nigra and α-synuclein as the main The presence of Lewy bodies in the composition. The clinical manifestations of PD are generally divided into motor symptoms and non-motor symptoms. Motor symptoms include resting tremor, muscle stiffness, slow movement, flustered gait, etc. At the same time, non-motor symptoms show abnormal smell, mental cognitive impairment, Depression and gastrointestinal dysfunction, etc. [0003] At present, for the treatment of PD, dopamine preparations, drugs that inhibit the degradation of dopamine, or d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40A61P25/16A61P25/28
CPCA61K31/40A61P25/16A61P25/28
Inventor 牛海晨陈闯张忠海徐洲王德广
Owner XUZHOU MEDICAL UNIV
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