CN107648218B

CN107648218B - Application of rotenone in preparation of acute kidney injury

Info

Publication number: CN107648218B
Application number: CN201710924467.9A
Authority: CN
Inventors: 贾占军; 华虎; 张爱华; 丁桂霞; 张正磊; 葛许华
Original assignee: Nanjing Childrens Hospital of Nanjing Medical University
Current assignee: Nanjing Childrens Hospital of Nanjing Medical University
Priority date: 2017-09-30
Filing date: 2017-09-30
Publication date: 2020-07-31
Anticipated expiration: 2037-09-30
Also published as: CN107648218A

Abstract

The application of rotenone in the preparation of the medicine for treating acute kidney injury obviously improves the kidney injury condition of mice after the treatment of small dose (250 ppm) of rotenone, and obviously reduces the levels of serum urea nitrogen enzyme (BUN) and creatinine (Cr).

Description

Application of rotenone in preparation of acute kidney injury

Technical Field

The invention relates to a new application of rotenone, in particular to a cinema for treating acute kidney injury by rotenone, belonging to the field of new application of medicaments.

Background

The kidney plays a role in metabolism and detoxification of human body. The kidney actually treats 180 liters of raw urine, 100 times as much as the former, in a round-robin fashion each day, as if the person excretes 1.5-2 liters of urine each day. Metabolism and excretion of drugs are also performed by the kidney, and the drug has a large molecular weight, fat solubility and protein affinity, which affect kidney metabolism and form accumulation. In the filtration process of the kidney, when the drug is repeatedly accumulated in the kidney for a long period of time, renal injury is likely to occur.

Acute Kidney Injury (AKI) is a group of clinical syndromes, which refer to sudden (within 1-7 d) and sustained (>24h) sudden decline in renal function with an increase of at least 0.5mg/dl in serum creatinine (SCr) manifested by azotemia, aqueous electrolyte and acid-base balance and systemic symptoms throughout the body, which may be accompanied by oliguria (< 400ml/24h or 17 ml/h) or anuria (< 100ml/24 h). When the renal function suddenly occurs, urination disorder occurs, and wastes accumulated in the body cannot be discharged, so that a series of symptoms of change are generated, and the symptoms are generally manifested by sudden urine volume reduction, edema, dizziness, nausea, vomiting, arrhythmia, dyspnea and the like. In China, nearly 400 million people suffer from the disease every year, and the number of people is also rising year by year. Particularly, the incidence and mortality of critical acute kidney injury are high, and international multi-center studies show that the mortality rate is as high as 60.3%. Renal causes are numerous, such as glomerular disease, acute tubulointerstitial injury, and persistent non-resolution of prerenal or postrenal diseases. Nephrotoxic drugs, especially antipyretic analgesics, antibiotics, unidentified Chinese medicines and the like, are common factors causing acute tubulointerstitial injury. However, a nephrotoxic drug sometimes has to be used clinically.

Acetaminophen is a common antipyretic analgesic in clinic and is widely used for relieving various symptoms such as pain, fever and the like. Clinical and epidemiological data at home and abroad show that the phenomenon of taking antipyretic and analgesic medicines for a long time in common people is common, and is as high as 1.43-23.70%. Meanwhile, various types of acute and chronic kidney damages caused by antipyretic analgesics are common in recent years and are one of the common pathogenic drugs for drug-induced nephropathy.

Rotenone (also known as poison derris, british name tubatoxin) is an isoflavone compound with remarkable biological activity separated from derris and other plants, exists in seeds, stems and roots of leguminous derris, is insoluble in water, and is soluble in alcohol, acetone, chloroform, carbon tetrachloride, ether and the like. It is mainly used as agricultural insecticide, and can also be used for preventing and controlling ectoparasite of human and animal, and for biochemical research. The control objects are as follows: aphids, plant hoppers, striped flea beetles, thrips, yellow watermelons, simian leafworms, cabbage caterpillars, prodenia litura, beet armyworms, diamond back moths and the like. It is a substance with strong specificity in toxicology, and has strong contact poisoning and stomach poisoning effects on insects, especially cabbage butterfly larva, diamondback moth and aphid. Early studies showed that rotenone acts mainly with a component between NADH dehydrogenase and coenzyme Q, and inhibits the electron transport chain of pest cells, thereby reducing ATP level in organism and finally preventing pest from energy supply, and then slowly dying due to action retardation and paralysis.

At present, there is no report on the use of rotenone for the treatment of acute kidney injury induced by overdose with acetaminophen drugs.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the application of rotenone in treating acute kidney injury and provide a novel treatment candidate drug. Supplement the existing therapeutic drugs.

The technical scheme adopted by the invention is as follows:

application of rotenone in treating acute kidney injury is provided.

The acute kidney injury is drug-induced and is induced by an overdose of antipyretic analgesics, more specifically by an overdose of acetaminophen.

Further, the dose of rotenone is a low dose.

Still further, the dose of rotenone is 250 ppm.

According to the invention, rotenone is used in a typical animal model of acetaminophen-induced acute kidney injury, under pathological conditions, because inflammation induced by drug overdose is an important reason for forming kidney injury, the rotenone obviously relieves the inflammatory reaction of kidney, obviously improves acetaminophen-induced acute kidney injury, greatly improves the pathological structure of kidney, obviously inhibits the increase of urea nitrogen and creatinine in blood, and further relieves the formation and the progress of acetaminophen-induced acute kidney injury.

The invention has the technical effects that:

1. in the invention, in an animal model of mice acute kidney injury induced by excessive acetaminophen, after a small dose (250 ppm) of rotenone is applied for treatment, the pathological condition of the kidney of the mice shows that the degree of kidney injury is obviously reduced, the serum biochemical indexes (BUN, Cr) are further detected to find that the renal function indexes of the mice in a rotenone treatment group are obviously improved, and the rotenone is shown to be an effective means for treating acute kidney injury caused by excessive acetaminophen, thereby providing possibility for the later-stage research and development of related preparation of the acute kidney injury disease medicines.

2. Rotenone, which is currently mainly used as an agricultural insecticide, has a strong poisoning effect on insects, and high doses of rotenone have toxic side effects on cells as well as on living individuals, so we chose a relatively safe low dose (250 ppm).

Drawings

FIG. 1 is a bar graph showing the change of serum renal function index of mice in a control group, an APAP model group and a rotenone administration group;

FIG. 2: HE staining patterns of the kidney of the mice in the control group, the APAP model group and the rotenone administration group;

FIG. 3: the results of the changes in the expression of the genes related to inflammation in the kidney of the mice in the control group, the APAP model group and the rotenone administration group.

Detailed Description

The technical solution of the present invention will be described in further detail with reference to the following embodiments and accompanying drawings.

Rotenone used in the following examples of the present invention was purchased from Sigma, and BA L B/c mice were purchased from the laboratory animal center of Nanjing medical university.

Example 1 Rotenone can reduce serum renal function index of APAP (acute renal injury) over-induced acute renal injury mice

The 21 mice were randomly divided into three groups, a normal control group, an APAP-induced renal injury model group, and an APAP-induced acute renal injury and rotenone-treated group, with 7 mice each. The normal control group and the model group are normally fed, and 250ppm of rotenone is added into the feed in the administration group. And detecting serum renal function indexes of the mice 24 hours after molding: urea Nitrogen (BUN) and creatinine (Cr), as shown in fig. 1, serum BUN and Cr were significantly reduced in rotenone treated mice compared to APAP model group with statistical differences.

Example 2 Rotenone can reduce the degree of pathological damage of kidney in mice with acute kidney injury induced by excessive APAP

The 21 mice were randomly divided into three groups, a normal control group, an APAP-induced renal injury model group, and an APAP-induced renal injury and rotenone-treated group, with 7 mice each. The normal control group and the model group are normally fed, and 250ppm of rotenone is added into the feed for the treatment group. After 24 hours of modeling, the kidney of the mouse is taken to be fixed by 4 percent polyformaldehyde, embedded by paraffin, sliced and then dyed by PAS, and the microscopic examination result shows that: the brush border of normal kidney tissue is clear and obvious, the size of glomerulus is normal, and the nephroscope of the model mouse shows that the brush border of renal tubule is partially lost and unclear and the glomerulus is enlarged. The pathological change of the kidney of the mice in the rotenone treatment group is obviously improved, the brush border structure is basically clear and complete, and the size of the glomerulus is close to that of a normal mouse. As shown in the results of FIG. 2, rotenone can reduce the degree of renal injury in APAP excess-induced acute renal injury mice.

Example 3 Rotenone can reduce inflammation of kidney in mice with acute kidney injury induced by excessive APAP

The method comprises the following steps of randomly dividing 21 mice into three groups, namely a normal control group, an APAP excessive induction renal injury model group and an APAP induced renal injury and feeding rotenone treatment group, wherein 7 mice are used in each group, the normal control group and the model group are both fed with normal diet, 250ppm of rotenone is added into feed in an administration group, after 24 hours of modeling, kidney tissues are taken, RNA is extracted, and then mRNA transcription levels of inflammation related factors (I L-6, MCP-1 and ICAM-1) in the kidney are detected through reverse transcription and real-time fluorescence quantitative PCR (polymerase chain reaction), and the result shows that the transcription levels of the inflammation factors in the kidney of the APAP model group mice are obviously increased, and the transcription levels of the inflammation factors in the kidney of the rotenone-treated mice are obviously reduced, as shown in figure 3, the rotenone can reduce the expression level of the inflammation factors in the kidney of the APAP excessive induction renal injury mice.

Claims

1. Use of rotenone in the manufacture of a medicament for the treatment of acute kidney injury induced by acetaminophen overdose, wherein the rotenone is present in an amount of 250 ppm.