阅读说明：本技术 ***素e1在制备治疗脑出血的药物中的应用 (Application of the prostaglandin E1 in the drug of preparation treatment cerebral hemorrhage ) 是由 柯开富 沈加兵 曹茂红 梁晶晶 于 2019-09-02 设计创作，主要内容包括：本发明提供了前列腺素E1在制备脑出血的药物中的应用,属于生物医药技术领域。与现有技术相比,本发明通过PGE1治疗脑出血,与NaCl空白对照治疗组比较：脑出血病人预后功能学明显改善；脑出血小鼠的运动能力恢复及神经功能改善得到明显提高,脑出血小鼠脑血肿周围组织凋亡神经细胞数目显著降低、存活神经细胞数目显著增加,星形胶质细胞的增殖、小胶质细胞的活化以及氧化应激反应得到明显抑制；同时PGE1在体外实验,可以减少细胞活力的降低、LDH的释放以及神经元的凋亡。(The present invention provides application of the prostaglandin E1 in the drug of preparation cerebral hemorrhage, belong to biomedicine technical field.Compared with prior art, the present invention treats cerebral hemorrhage by PGE1, and compared with NaCl placebo treatment group: Patients with Cerebral Hemorrhage prognostic function is obviously improved；The locomitivity of cerebral hemorrhage mouse is restored and nervous function improvement is improved significantly, cerebral hemorrhage mouse brain Hematoma number of apoptosis neurons mesh significantly reduces, viable neuronal cell number dramatically increases, and the proliferation of astroglia, the activation of microglia and response to oxidative stress are significantly suppressed；PGE1 is tested in vitro simultaneously, it is possible to reduce the apoptosis of the reduction of cell viability, the release of LDH and neuron.)

1. application of the prostaglandin E1 in the drug of preparation treatment cerebral hemorrhage.

2. application according to claim 1, which is characterized in that improve brain by protection Hematoma after Cerebral Hemorrhage The prognosis of bleeding patients.

3. application according to claim 2, which is characterized in that by the low brain blood flow shape in part for improving Hematoma State protects Hematoma after Cerebral Hemorrhage.

4. application according to claim 2, which is characterized in that protect hemotoncus week after cerebral hemorrhage by promoting absorption of hematoma Enclose tissue.

5. application according to claim 2, which is characterized in that protect cerebral hemorrhage by reducing perihematoma damage field Hematoma afterwards.

6. application according to claim 1, which is characterized in that by reduce Hematoma cell viability reduction come Improve patients with cerebral hemorrhage prognosis.

7. application according to claim 1, which is characterized in that by the release for reducing Hematoma lactic dehydrogenase To improve patients with cerebral hemorrhage prognosis.

8. application according to claim 1, which is characterized in that improved by reducing Hematoma Neuron Apoptosis Patients with cerebral hemorrhage prognosis.

9. according to application described in claim 1, which is characterized in that by carrying out neuroprotection to Hematoma after Cerebral Hemorrhage To treat cerebral hemorrhage.

10. application according to claim 9, which is characterized in that by the increasing for inhibiting perihematoma domain astroglia It grows, inhibit the activation of microglia and the one or more of response to oxidative stress approach is inhibited to carry out neuroprotection.

Technical field

The invention belongs to biomedicine technical fields more particularly to prostaglandin E1 in the drug of preparation cerebral hemorrhage Using.

Background technique

Cerebral hemorrhage (Intracerebral hemorrhage, ICH) refers to that non-traumatic cerebral blood vessel Spontaneous Rupture is drawn The brain parenchym bleeding risen is one of cerebral apoplexy hypotype, accounts for about the 20%~30% of whole cerebral apoplexies in China.ICH is neurology department Common disease, morbidity is anxious, state of an illness weight, though being studied for many years, treatment means are limited so far, and acute stage case fatality rate is 30%~ 40%, there are the sequelae such as different degrees of dyskinesia, cognitive disorder, speech aphetite disorder for majority in survivor.This disease High mortality and high disability rate bring heavy pain and burden, with aging of population, endanger caused by ICH to family, society Evil is on the rise.

Be mainly at present internal medicine symptomatic treatment or surgical operation therapy to the treatment of cerebral hemorrhage, remaining there is no it is breakthrough into Exhibition there is no the drug of the specific treatment for Hematoma protection.In the prior art, prostaglandin E1 is clinically led Myocardial infarction, the diseases such as thromboangiitis, arteriosclerosis are used for, but also there is which kind of about prostaglandin E1 Effect, then do not report.

Summary of the invention

In view of this, the application the purpose of the present invention is to provide prostaglandin E1 in the drug of preparation cerebral hemorrhage, mentions The new application of prostaglandin E1 is supplied.

In order to achieve the above-mentioned object of the invention, the present invention provides following technical schemes:

The present invention provides application of the prostaglandin E1 in the drug of preparation treatment cerebral hemorrhage.

Preferably, patients with cerebral hemorrhage prognosis is improved by protection Hematoma after Cerebral Hemorrhage.

Preferably, perihematoma after cerebral hemorrhage is protected by improving the low brain circular blood stream state in part of Hematoma Tissue.

Preferably, Hematoma after Cerebral Hemorrhage is protected by promoting absorption of hematoma.

Preferably, Hematoma after Cerebral Hemorrhage is protected by reducing perihematoma damage field.

Preferably, improve patients with cerebral hemorrhage prognosis by reducing the reduction of Hematoma cell viability.

Preferably, improve patients with cerebral hemorrhage prognosis by reducing the release of Hematoma lactic dehydrogenase.

Preferably, improve patients with cerebral hemorrhage prognosis by reducing Hematoma Neuron Apoptosis.

Preferably, cerebral hemorrhage is treated by carrying out neuroprotection to Hematoma after Cerebral Hemorrhage.

Preferably, by inhibiting the proliferation of perihematoma domain astroglia, inhibiting the activation and suppression of microglia The one or more of oxygenerating stress reaction approach carry out neuroprotection.

The present invention provides application of the prostaglandin E1 in the drug of preparation cerebral hemorrhage, after prostaglandin E1, lead to Overprotection Hematoma after Cerebral Hemorrhage, the drop for reducing perihematoma damage field, reducing Hematoma cell viability Release that is low, reducing Hematoma lactic dehydrogenase reduces Hematoma Neuron Apoptosis and to perihematoma group It knits and carries out several approach such as neuroprotection to improve patients with cerebral hemorrhage prognosis, the protection Hematoma after Cerebral Hemorrhage is By improving the low brain circular blood stream state in part of Hematoma, promoting absorption of hematoma and reducing perihematoma damage field reality Existing, the neuroprotection is by inhibiting the proliferation of Hematoma astroglia, inhibiting microglia What activation and inhibition response to oxidative stress approach were realized.

The utility model has the advantages that

Compared with prior art, the present invention treats cerebral hemorrhage by PGE1, compared with NaCl placebo treatment group: SPECT prompt hemotoncus, proximally and distally radioactivity filler is obviously improved Hematoma, and rCBF value significantly improves, Ra value Also it is apparently higher than control group；The locomitivity of cerebral hemorrhage mouse is restored and nervous function improvement is improved significantly, and cerebral hemorrhage is small Murine brain Hematoma number of apoptosis neurons mesh significantly reduces, viable neuronal cell number dramatically increases, hemotoncus week The proliferation of tissue astroglia, the activation of microglia and response to oxidative stress is enclosed to be significantly suppressed；Simultaneously PGE1 is tested in vitro, it is possible to reduce the apoptosis of the reduction of cell viability, the release of LDH and neuron.

Detailed description of the invention

Fig. 1 is the chemical structural formula figure of PGE1；

Fig. 2 is local cerebral blood flow analysis chart, wherein A is PGE1 group the 5th day after cerebral hemorrhage；B is the 20th after cerebral hemorrhage It, PGE1 group；C is control group the 5th day after cerebral hemorrhage；D is control group the 20th day after cerebral hemorrhage；

Fig. 3 is the correlation of perihematoma volume of hematoma and Ra value；

Fig. 4 is the correlation of Hematoma volume and perihematoma region Ra value；

Fig. 5 is ICH mouse treatment neurological functional recovery result analysis chart, wherein A is that 24 method neurological deficits are commented Point；B is to accelerate rotation test；N=12, *, #p < 0.05, difference has statistical significance compared with corresponding time point control group；

Fig. 6 is ICH mouse volume of hematoma size and brain water content analysis chart, wherein A is 4 days volume of hematoma, brains after ICH The case where water content；B is 14 days volume of hematoma, brain water content situation after ICH；P < 0.05 N=6, *, compared with the control group difference With statistical significance；

Fig. 7 is regression neuron number analysis chart in perihematoma domain after ICH, wherein A ICH+NaCl, ICH+PGE1 10 μ g/kg and ICH+PGE1 20 μ g/kg to 4 days after ICH, the influence of 14 days perihematoma domain FJB positive cell numbers；B is A's Bar shaped statistics；N=6,4 visuals field of every sections observation, each brain tissue take 3 slices, are spaced 360 μm；N=6, * p < 0.05, difference has statistical significance compared with ICH+NaCl group；

Fig. 8 is the quantitative analysis figure of perihematoma domain perihematoma domain neuron, wherein A is 4 days various doses after ICH Perihematoma domain neuronal quantity situation after PGE1 treatment；Hemotoncus when after B being 20 μ g/kg of PGE1 4 days and 14 days after ICH Surrounding domain neuronal quantity situation；C and D is respectively the bar shaped statistics of A and B；N=6, *, #p < 0.05, with corresponding control group phase There is statistical significance than difference；

Fig. 9 is perihematoma domain Neuron Apoptosis situation, wherein A is various dose PGE1 1 day, 4 days and 14 after ICH It when, in the brain tissue of perihematoma domain activate Caspase-3 expression change influence；The bar shaped that B is A counts；C is shown TUNEL positive cell number statistical conditions, D are hemotoncus at 4 days and 14 days after ICH under the conditions of PGE1 10 μ g/kg and 20 μ g/kg The expression of surrounding domain TUNEL；N=6, *, #p < 0.05, difference has statistical significance compared with corresponding control group；

Figure 10 is perihematoma domain astrocytes situation analysis figure after ICH, wherein A shows 10 μ g/kg of PGE1 With 20 μ g/kg to the 4th day after ICH and the 14th day perihematoma domain astrocytes situation；Bar shaped statistics；N= 6, *, #p < 0.05, difference has statistical significance compared with corresponding control group；

Figure 11 is perihematoma domain Activated Microglia situation analysis figure, wherein A shows after ICH different treatment groups the 4 days, the 14th day perihematoma domain Iba-1 expression；Difference treatment group Iba-1 positive cell number bar shaped counts after B shows ICH； P < 0.05 N=6, *, difference has statistical significance compared with corresponding control group；

Figure 12 is the impact analysis figure of perihematoma domain oxidativestress damage, wherein A shows different disposal group the after ICH H in Hematoma at 4 days, the 14th day₂O₂The detection of content；Hemotoncus when B shows after ICH different disposal group the 4th day, the 14th day The detection of MDA content in surrounding tissue；When C shows after ICH different disposal group the 4th day, the 14th day in Hematoma The detection of CuZnMn-SOD；N=6, *, #p < 0.05, difference has statistical significance compared with corresponding control group；

Figure 13 is ferroheme induced neuronal apoptosis model (external ICH model) cell viability analysis chart, wherein A shows CCK-8 detects Primary cortical neurons cell viability situation under different hemin concentration incentive conditions；B shows in hemin in 50 μ Influence under M concentration incentive condition, to primary neuron different time points cell viability；C shows under phase contrast microscope, primary skin Layer neuron bright-field form under the conditions of different stimulated, scale bar are 100 μm；* p < 0.05, the difference compared with Normal group With statistical significance；

Figure 14 is function analysis figure of the PGE1 in hemin induced neuronal injury, wherein A shows that CCK-8 detection is primary Cortical neuron cell viability situation under different PGE1 concentration conditions；B shows the Primary cortical mind under different PGE1 concentration conditions Through LDH release conditions in first supernatant；C shows under phase contrast microscope, Primary cortical neurons bright-field under the conditions of different stimulated Form, scale bar are 100 μm；* p < 0.05, difference has statistical significance compared with Hemin group；

Figure 15 is function analysis figure of the PGE1 in the oxidativestress damage that hemin is induced, wherein A shows the original in culture For TRME fluorescent staining figure in cortical neuron；B shows the fluorescence intensity of TRME under the conditions of different stimulated；C shows at different conditions Total ROS content in primary neuron；* p < 0.05, difference is statistically significant compared with Normal group；#p < 0.05, with Hemin Group has statistical significance compared to difference；

Figure 16 is function analysis figure of the PGE1 in hemin induced neuronal apoptosis, wherein A shows in different PGE1 concentration items The expression of Caspase-3 is activated under part；B shows the bar shaped statistics of A；C shows that Primary cortical neurons cell Caspase-3 is living Property variation；D shows the protein level variation of Bcl-2, Bax and Cyt c, and E shows the bar shaped statistics of D；F shows that TUNEL positive cell number is united Meter；G shows that different PGE1 handle lower TUNEL variation；*, #p < 0.05, difference has statistics compared with control group (Hemin group) Meaning.

Specific embodiment

The present invention provides application of the prostaglandin E1 in the drug of preparation treatment cerebral hemorrhage.In the present invention, described The chemical name of prostaglandin E1 (PGE1) is (1R, 2R, 3R) -3- hydroxyl -2 (E)-(3S) -3- hydroxyl -1- octenyl -5- oxygen For cyclopentane heptanoic acid, molecular formula C₂₀H₃₄O₅, chemical structural formula is as shown in Fig. 1.In the present invention, the dosage form of the drug is excellent It is selected as microsome suspension.Content of the present invention to the prostaglandin E1 in drug is not particularly limited, and is using conventional It can.

The present invention preferably treats cerebral hemorrhage by protection Hematoma after Cerebral Hemorrhage.In the present invention, it is preferred to logical Crossing improves the low brain circular blood stream state in part of Hematoma, reduces volume of hematoma and reduce in perihematoma damage field One or more protect Hematoma after Cerebral Hemorrhage.

The present invention, which preferably passes through to reduce the reduction of cell viability, reduce the release of lactic dehydrogenase and reduce neuron, withers It one or more of dies to treat cerebral hemorrhage.In the present invention, the cell preferably includes C57BL/6 mouse primary cortex Neuron.

The present invention preferably treats cerebral hemorrhage by neuroprotection, and the present invention, which preferably passes through, inhibits Hematoma star The proliferation of shape spongiocyte, the activation for inhibiting microglia and inhibit the one or more of response to oxidative stress approach to send out Wave neuroprotection.

Technical solution provided by the invention is described in detail below with reference to embodiment, but they cannot be managed Solution is limiting the scope of the present invention.