CN118512467A - Application of adenosine in the preparation of drugs for preventing and/or treating cognitive impairment - Google Patents

Abstract

The invention discloses an application of adenosine in preparing a medicament for preventing and/or treating cognitive dysfunction, and belongs to the technical field of biological medicines. Experimental results prove that the adenosine can improve delirium and other related cognitive disorders such as Alzheimer's disease. Adenosine can be used as a novel drug for treating cognitive disorders.

Description

Application of adenosine in the preparation of drugs for preventing and/or treating cognitive impairment

Technical Field

The present invention belongs to the field of biomedicine technology and relates to a new pharmaceutical application of adenosine, and specifically to the application of adenosine in the preparation of a drug for preventing and/or treating cognitive impairment.

Background Art

Cognitive disorder refers to a decline or impairment in an individual's cognitive abilities such as thinking, memory, learning, understanding, concentration and decision-making. Cognitive disorder affects an individual's processing and acquisition of information and may have a negative impact on daily function and life. There are many risk factors that may cause cognitive disorder, such as high blood pressure, cardiovascular disease, diabetes, obesity, smoking, lack of exercise, low education level and genetic factors. In many different psychiatric and neurological diseases (for example, delirium, schizophrenia, bipolar disorder, stroke, epilepsy, Parkinson's disease, multiple sclerosis, Alzheimer's disease, etc.), there is a common core manifestation - cognitive disorder.

Delirium, also known as acute brain syndrome, is a serious neuropsychiatric syndrome characterized by acute cognitive impairment and attention deficit. The prevalence of critically ill patients can be as high as 60-80%. Delirium directly leads to an increase in health care costs and patient mortality, and also brings other negative effects, such as short-term effects such as falls and aspiration pneumonia and long-term effects such as irreversible damage to cognitive function. Among them, impaired cognitive function is an important factor affecting the prognosis of life satisfaction in delirium. The mainstream drugs used in the prevention and treatment of delirium are divided into two categories: antipsychotics and non-antipsychotics. Antipsychotics mainly include haloperidol, risperidone, olanzapine, etc., which treat delirium by blocking central dopamine/5-hydroxytryptamine receptors. However, it cannot effectively reduce the incidence and mortality of delirium, reduce hospitalization time, and improve the quality of life of patients after prognosis. Non-antipsychotic drugs mainly include dexmedetomidine, benzodiazepines, and melatonin receptor agonists. Among them, dexmedetomidine is more effective in reducing delirium-related agitation. Benzodiazepines can inhibit cerebral cortical function, but this may lead to the occurrence or aggravation of delirium. These two drugs have very limited effects on cognitive dysfunction caused by delirium.

In addition, Alzheimer's Disease (AD) is a progressive neurodegenerative disease. Clinically, it is characterized by global dementia such as memory impairment, aphasia, apraxia, agnosia, visual-spatial skill impairment, executive dysfunction, and personality and behavioral changes. The cause is still unknown. The mainstream drugs used in the prevention and treatment of Alzheimer's disease are glutamate receptor antagonists and cholinesterase inhibitors. The representative drug of glutamate receptor antagonists is memantine, which mainly acts on the glutamate-glutamine system in the brain and is commonly used in patients with moderate and severe Alzheimer's disease. Cholinesterase inhibitors mainly include donepezil, rivastigmine and galantamine. Among them, galantamine can also enhance the intrinsic effect of acetylcholine by binding to the allosteric site of nicotinic receptors. Donepezil increases the concentration of acetylcholine in the synaptic cleft of neurons by competitive/non-competitive inhibition of cholinesterase. However, they all have more serious side effects such as bradycardia, diarrhea, sleep disorders, etc.

Therefore, developing effective drugs to treat cognitive disorders such as delirium and Alzheimer's disease has important clinical value.

Adenosine is an endogenous purine nucleoside found throughout human cells. It can be phosphorylated to generate adenosine and participate in the body's energy metabolism. In addition, many tonic Chinese medicines contain a large amount of adenosine, such as ginseng, ganoderma lucidum, and astragalus. Its production cost advantage is obvious, and it has excellent safety. The clinical uses of adenosine reported so far mainly include the treatment of cardiovascular diseases such as hypertension, coronary heart disease, and ventricular tachycardia.

Summary of the invention

The purpose of the present invention is to overcome the shortcomings and deficiencies in the prior art and provide the use of adenosine in the preparation of drugs for preventing and/or treating cognitive impairment.

The purpose of the present invention is achieved through the following technical solutions:

The use of adenosine in the preparation of a drug for preventing and/or treating cognitive impairment, wherein the structural formula of adenosine is shown in Formula 1:

In the above application, the cognitive impairment includes but is not limited to delirium and cognitive impairment caused by Alzheimer's disease.

In the above application, the adenosine includes adenosine and pharmaceutically acceptable salts or prodrugs thereof.

In the above applications, one or more pharmaceutically acceptable carriers may be added to the drug, including but not limited to coating materials, solvents, solubilizers, adhesives, stabilizers, antioxidants, pH adjusters, flavoring agents, etc. commonly used in the pharmaceutical field.

In the above applications, the dosage form of the drug can be any medically recognized dosage form, including but not limited to tablets, capsules, granules, powders, powder injections, pills, emulsions, suspensions, solutions and the like.

In the above applications, the drug can be taken in any medically recognized manner, including but not limited to introduction into the body by injection, oral administration, absorption, physical or chemical mediation, such as vein, muscle, mucosal tissue; or introduced into the body after being mixed or wrapped with other substances.

In the above applications, the drug may include other Chinese and Western medicines that prevent and/or treat cognitive impairment, or be used in combination with treatment methods such as surgery.

Compared with the prior art, the present invention has the following advantages and effects:

In the present invention, we found that the adenosine content in the intestine, blood and brain tissue of LM-induced delirium model mice was reduced. After adenosine supplementation, the cognitive deficits of delirium mice were improved. Compared with the control group, adenosine can significantly reduce the cognitive dysfunction of delirium mice. In addition, we also found that after adenosine supplementation, the cognitive function of AD model mice was significantly improved. The experimental results of the present invention prove that adenosine can improve cognitive disorders related to delirium and Alzheimer's disease. Adenosine can be used as a new drug for the treatment of cognitive disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effect of adenosine supplementation on adenosine content in the intestine, blood, and hippocampal tissue of delirium mice.

Figure 2 shows the effect of adenosine supplementation on object preference and exploration time in a novel object recognition experiment in delirium mice.

FIG. 3 is a graph showing the effect of adenosine supplementation on the alternating behavior in the Y-maze of delirious mice.

Figure 4 shows the effect of adenosine supplementation on adenosine content in the intestine, blood, and hippocampal tissue of AD model mice

Figure 5 shows the effect of adenosine supplementation on object preference and exploration time in a new object recognition experiment in AD model mice.

FIG. 6 is a graph showing the effect of adenosine supplementation on the alternation behavior in the Y maze of AD model mice.

DETAILED DESCRIPTION

The present invention is further described in detail below in conjunction with the examples and drawings, but the embodiments of the present invention are not limited thereto. The methods described are all commonly used methods unless otherwise specified.

Example 1: Exogenous supplementation of adenosine can effectively increase adenosine content in delirium mice to normal levels

Healthy male mice of the C57BL/6 strain aged 8 to 12 weeks (purchased from Wellcome Animal Testing Co., Ltd.) were used for the experiment. All mice were housed in an SPF-grade environment with 12 hours of light/12 hours of darkness (6:00-18:00 as the light period) and a temperature of 22 to 25°C. We first conducted a 7-day environmental adaptation period for all experimental mice, during which standard feed and purified water were provided. After the adaptation period, the mice were randomly divided into three groups: a normal control group, a delirium model group, and adenosine replenishment group, with 10 mice in each group.

(1) Normal control group: mice were fed with standard feed for 21 days and given normal saline by intraperitoneal injection. Behavioral tests were performed 24 hours after administration.

(2) Delirium model group: After being fed with standard diet for 21 days, mice were intraperitoneally injected with LPS (200 μg/kg) + midazolam (10 mg/kg) to induce delirium-like behavior in mice. Behavioral tests were performed 24 h after administration.

(3) Adenosine supplementation group: After being fed with a diet containing 0.1% adenosine for 21 days, mice were intraperitoneally injected with LPS (200 μg/kg) + midazolam (10 mg/kg) to induce delirium-like behavior in mice. Behavioral tests were performed 24 hours after administration.

LC-MS/MS was used to detect the adenosine content in the intestinal tissue, blood and hippocampus of mice. The results showed that the adenosine content in the intestine, hippocampus and blood of the delirium model group mice was significantly lower than that of the normal control group mice, and the adenosine level in the adenosine supplement group mice was equivalent to that of the normal control group. It can be seen that exogenous adenosine supplementation can effectively increase the adenosine content in delirium mice to normal levels (Figure 1).

Example 2: Study on the significant therapeutic effect of adenosine on delirium

In the new object recognition experiment, the mice in the delirium model group showed no obvious preference for new or old objects, while the mice in the adenosine supplementation group showed a significantly higher preference for new objects than old objects, and the preference was comparable to that of the mice in the normal control group. At the same time, in terms of exploration time, the mice in the adenosine supplementation group also showed similar results to those of the mice in the normal control group, that is, they spent more time exploring new objects (Figure 2). In the Y-maze experiment, the spontaneous alternation behavior of the delirium model group decreased significantly (50%), while the number of spontaneous alternations of the delirium mice in the adenosine supplementation group was comparable to that of the mice in the normal control group (Figure 3).

The above experiments show that adenosine has the function of improving the memory ability and cognition of delirium mice.

Example 3: Exogenous supplementation of adenosine can effectively increase adenosine content in AD model mice to normal levels

The experiment was conducted using healthy 5×FAD male mice aged 5-6 months (purchased from Suzhou Xishan Biotechnology Co., Ltd., AD model mice). All mice were housed in an SPF-grade environment with 12 hours of light/12 hours of darkness (6:00-18:00 as the light period) and a temperature of 22-25°C. First, all experimental mice were subjected to a 7-day environmental adaptation period, during which standard feed and purified water were provided. After the adaptation period, the mice were randomly divided into two groups: an AD model group and an adenosine supplementation group, with 10 mice in each group.

(1) AD model group: The mice were fed with standard diet for 21 days and then behavioral tests were performed.

(2) Adenosine replenishment group: The mice were fed with a diet containing 0.1% adenosine for 21 days, and then behavioral tests were performed.

LC-MS/MS was used to detect the adenosine content in the intestinal tissue, blood and hippocampus of each group of mice. The results showed that adenosine replenishment for 21 days effectively increased the content in the intestine, hippocampus and blood of the AD model group mice (Figure 4).

Example 4: Adenosine supplementation can effectively improve cognitive deficits in AD model mice

5×FAD model mice showed impaired cognitive memory. After adenosine supplementation, 5×FAD mice showed a significantly higher preference for new objects than old objects in the new object recognition experiment. In terms of exploration time, the exploration time of 5×FAD mice supplemented with adenosine for new objects was also significantly higher than that of AD model group mice (Figure 5). In the Y-maze experiment, the number of spontaneous alternations of 5×FAD mice supplemented with adenosine was also significantly higher than that of AD model group mice (Figure 6).

The above experiments show that adenosine can effectively improve the cognitive memory ability of 5×FAD mice, and the cognitive function is significantly improved.

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims (10)

1. Use of adenosine in the preparation of drugs for preventing and/or treating cognitive impairment. 2. The use according to claim 1, characterized in that: the cognitive impairment includes cognitive impairment caused by delirium or Alzheimer's disease. 3. The use according to claim 1 or 2, characterized in that the adenosine comprises adenosine and a pharmaceutically acceptable salt or prodrug thereof. 4. The use according to claim 1 or 2, characterized in that one or more pharmaceutically acceptable carriers are added to the drug. 5. The use according to claim 4, characterized in that the carrier comprises a coating material, a solvent, a solubilizer, a binder, a stabilizer, an antioxidant, a pH adjuster, and a flavoring agent. 6. The use according to claim 1 or 2, characterized in that the dosage form of the drug is any dosage form recognized medically. 7. The use according to claim 6, characterized in that the drug is in the form of tablets, capsules, granules, powders, powder injections, pills, emulsions, suspensions or solutions. 8. The use according to claim 1 or 2, characterized in that the drug can be taken in any medically recognized manner. 9. The use according to claim 8, characterized in that: The drug is introduced into veins, muscles or mucosal tissues by injection, oral administration, absorption, physical or chemical mediation. 10. The use according to claim 1 or 2, characterized in that: The drugs include other Chinese and Western medicines that prevent and/or treat cognitive impairment, or are used in combination with treatments such as surgery.