Application of isorhynchophylline in preparation of medicine for treating or / and improving attention impairment

Abstract

The invention provides application of isorhynchophylline in preparation of a medicine for treating or / and improving attention impairment, relates to the technical field of medical application, and provides isorhynchophylline or an isorhynchophylline derivative for improving attention impairment for the first time. Experiments prove that the accuracy, the omission rate and the completion time of plantar electric shock mice are obviously improved by intraperitoneal injection of isorhynchophylline for continuous 7 days. Isorhynchophylline is shown to improve attention by adjusting alertness, orientation ability and execution control ability.

Description

Technical Field

[0001] The present invention relates to the field of medical application technology, and in particular to an application of isorhynchophylline in the preparation of a medicine for treating and / or improving attention impairment. Background Art

[0002] The mechanisms of attention impairment include neurophysiological mechanisms and psychological mechanisms. Neurophysiological mechanisms include changes in neurotransmitters, changes in brain region function, and changes in gene expression. Psychological mechanisms include attention allocation disorders, cognitive resource depletion, and emotional interference.

[0003] Current interventions include psychological and pharmacological interventions. Pharmacological interventions include neurotransmitter modulators, which improve attention impairment by regulating neurotransmitter levels, and anti-stress drugs, which alleviate stress responses and thus indirectly improve attention. However, neurotransmitter modulators and anti-stress drugs have strong adverse reactions. For example, dopamine receptor agonists may cause movement disorders, psychiatric symptoms (such as hallucinations and delusions), and cardiovascular problems. Central nervous system stimulants (such as methylphenidate) can increase dopaminergic neurotransmission, but may also cause adverse reactions such as appetite suppression, sleep disorders, increased heart rate and blood pressure, and irritability. Antidepressants (such as SSRIs) can regulate serotonin levels, but may also cause adverse reactions such as nausea, headache, and sexual dysfunction.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] One of the purposes of the present invention is to provide an application of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving attention impairment, and for the first time proposes that isorhynchophylline or an isorhynchophylline derivative be used to improve attention impairment.

[0006] A second object of the present invention is to provide a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving vigilance impairment.

[0007] The third object of the present invention is to provide a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving orientation impairment.

[0008] A fourth object of the present invention is to provide a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving executive control impairment.

[0009] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted: In a first aspect, the present invention provides a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving attention impairment.

[0010] In a second aspect, the present invention provides a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving vigilance impairment.

[0011] In a third aspect, the present invention provides a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving orientation impairment.

[0012] In a fourth aspect, the present invention provides a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving executive control impairment.

[0013] Furthermore, the attention impairment includes attention impairment caused by stress; Preferably, the attention impairment further includes attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease or depression.

[0014] Furthermore, the stress includes trauma and stress-related disorders; Preferably, the trauma and stress-related disorder comprises at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specified trauma and stress-related disorder or unspecified trauma and stress-related disorder.

[0015] Furthermore, the drug also includes pharmaceutically acceptable excipients.

[0016] Furthermore, the pharmaceutically acceptable excipients include at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

[0017] Furthermore, the dosage form of the drug includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

[0018] Furthermore, the isorhynchophylline and isorhynchophylline derivatives are obtained by plant extraction or chemical synthesis.

[0019] The present invention provides the use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or ameliorating attention impairment. This is the first application of isorhynchophylline or an isorhynchophylline derivative for ameliorating attention impairment. Experimental studies have shown that seven consecutive days of intraperitoneal injection of isorhynchophylline significantly improved the accuracy, omission rate, and completion time of foot shock-induced mice. This suggests that isorhynchophylline improves attention by regulating alertness, orientation, and executive control. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0021] Figure 1 This is a flow chart of the experiment on the effect of isorhynchophylline on the attention of normal mice or mice stressed by foot shock provided by the present invention; Figure 2 The effect of isorhynchophylline provided by the present invention on the attention of normal mice; Figure 3 The present invention provides the effect of isorhynchophylline on the attention of mice subjected to plantar electric shock stress under the condition of a stimulation duration of 2s; Figure 4 The present invention provides the effect of isorhynchophylline on the attention of mice induced by plantar electric shock stress under the condition of a stimulation duration of 1.8s; Figure 5 The present invention provides the effect of isorhynchophylline on the attention of mice induced by plantar electric shock stress under the condition of a stimulation duration of 1.6s; Figure 6 The present invention provides the effect of isorhynchophylline on the attention of mice under the conditions of stimulation delay time of 2s, 3s, 4s and 5s; Figure 7 The present invention provides an effect of isorhynchophylline on the attention of mice induced by plantar electric shock stress under the conditions of stimulation delay time of 5s, 6s, 7s and 8s respectively. DETAILED DESCRIPTION

[0022] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; however, in the event of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms is non-limiting.

[0023] The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated.

[0024] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0025] The present invention finds that isorhynchophylline has a protective effect on attention impairment, can improve attention impairment and enhance attention.

[0026] In one aspect, the present invention provides a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving attention impairment.

[0027] This study proposes for the first time that isorhynchophylline or its derivatives can be used to improve attentional impairment. Experimental results show that seven consecutive days of intraperitoneal injection of isorhynchophylline significantly improved the accuracy, omission rate, and completion time of foot shock-induced mice. This suggests that isorhynchophylline improves attention by regulating alertness, orientation, and executive control.

[0028] According to another aspect of the present invention, there is also provided a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving vigilance impairment.

[0029] According to another aspect of the present invention, there is also provided a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving orientation impairment.

[0030] According to another aspect of the present invention, there is also provided a use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving executive control impairment.

[0031] In some specific embodiments, the impairment of attention comprises stress-induced impairment of attention.

[0032] Stress and attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression share the following mechanisms: First, hypothalamic-pituitary-adrenal axis (HPA axis) dysregulation Stress activates the HPA axis, leading to elevated levels of glucocorticoids such as cortisol. This imbalance is common in disorders such as ADHD and depression. For example, patients with ADHD exhibit a delayed circadian rhythm of cortisol, while patients with depression often exhibit HPA axis hyperactivation. Long-term HPA axis imbalance can damage the hippocampus and prefrontal cortex, impairing attention and cognitive function.

[0033] Second, neurotransmitter dysfunction Dopamine (DA): Dopamine plays a key role in attention regulation. Dysfunction in dopamine has been linked to a variety of neuropsychiatric disorders, including ADHD, schizophrenia, drug addiction, Parkinson's disease, and Huntington's disease. For example, in ADHD, dysregulation of dopaminergic neurotransmission is thought to be associated with attention deficits and impulsive behavior. In Parkinson's disease, degeneration of dopaminergic neurons leads to impairments in attention and motor function.

[0034] Norepinephrine (NE): Norepinephrine is also involved in attention regulation, and its dysfunction is associated with stress, ADHD, depression, and other diseases. For example, ADHD patients show dysregulation of noradrenergic neurotransmission, leading to inattention.

[0035] Serotonin (5-HT): Serotonin plays an important role in mood and cognitive function, and its abnormal function is associated with diseases such as stress, depression, ADHD and drug addiction.

[0036] Third, neuroinflammation and oxidative stress Neuroinflammation: Neuroinflammation plays an important role in multiple neuropsychiatric disorders, including stress, ADHD, Alzheimer's disease, Parkinson's disease, and depression. For example, patients with ADHD show evidence of neuroinflammation, which may be associated with attention deficits.

[0037] Oxidative stress: Oxidative stress is common in stress and various neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease) and psychiatric disorders (such as ADHD and depression). Oxidative stress can damage nerve cells, affect the synthesis and release of neurotransmitters, and thus lead to attention deficit.

[0038] Fourth, neuroplasticity changes Neurogenesis and synaptic plasticity: Neurogenesis and synaptic plasticity play a crucial role in attention regulation. Stress and various disorders (such as ADHD, depression, and Alzheimer's disease) can lead to changes in neuroplasticity, impairing attention and cognitive function. For example, ADHD patients have reduced volume in the prefrontal cortex and basal ganglia, impairing attention and executive function.

[0039] Fifth, stress and various diseases can lead to dysfunction in brain regions such as the prefrontal cortex, hippocampus, and amygdala: Prefrontal cortex (PFC): The PFC plays a key role in attention and executive function. A variety of disorders (such as ADHD, schizophrenia, and depression) can lead to abnormal PFC function, impairing attention. For example, individuals with ADHD show reduced activation of the PFC during attention tasks.

[0040] Basal ganglia: These organs play an important role in motor control and attention regulation. Disorders such as Parkinson's disease and Huntington's disease can lead to malfunction of the basal ganglia, which in turn affects attention.

[0041] Hippocampus: The hippocampus plays an important role in learning and memory. Stress and diseases (such as Alzheimer's disease and depression) can cause the hippocampus to atrophy, affecting attention and memory.

[0042] Stress and attention deficits caused by various neuropsychiatric diseases (such as ADHD, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression) share common mechanisms, including neurotransmitter dysfunction, neuroinflammation and oxidative stress, changes in neuroplasticity, and abnormal brain region function.

[0043] In some specific embodiments, the attention impairment further comprises attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, or depression.

[0044] Specifically, patients with attention deficit hyperactivity disorder (ADHD) often exhibit symptoms such as inattention, impulsivity, and hyperactivity. Schizophrenia is associated with inattention. Drug addiction has a significant impact on attention and impulse control abilities. Attention and executive control abilities of patients with Alzheimer's disease (AD) are impaired in the early stages of AD. Patients with Parkinson's disease often exhibit inattention and slow reaction. Huntington's disease is associated with attention deficits, particularly the ability to maintain attention in visual-spatial areas. Other studies have also shown that HD patients have deficits in selective attention, shifting and directing attention, and tasks that disengage attention. Patients with depression often exhibit inattention and slow reaction.

[0045] In some specific embodiments, the stress includes trauma and stress-related disorders; according to the classification in DSM-5 Trauma- and Stressor-Related Disorders, in some specific embodiments, the trauma and stress-related disorders include at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specific trauma and stress-related disorder or unspecified trauma and stress-related disorder.

[0046] In some specific embodiments, the drug is administered to a patient to improve impairment of vigilance, orientation, and executive control to improve attention impairment.

[0047] In some specific embodiments, the active ingredient of the drug includes isorhynchophylline.

[0048] In some specific embodiments, the dosage of isorhynchophylline is 20-60 mg / kg, preferably 40 mg / kg.

[0049] In some specific embodiments, the drug further comprises a pharmaceutically acceptable excipient.

[0050] Among them, "pharmaceutically acceptable excipients" are basically synonymous with "pharmaceutically usable excipients" or "excipients commonly used in the pharmaceutical process" understood in the art. Those skilled in the art can select conventional excipients according to actual conditions and preparation requirements.

[0051] In some specific embodiments, the pharmaceutically acceptable excipient includes at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

[0052] Among them, pharmaceutically acceptable excipients may include but are not limited to at least one of lactose, glucose, sucrose, sorbitol, mannose, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.

[0053] In some specific embodiments, the dosage form of the drug includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

[0054] It should be noted that the drug is administered orally, sublingually, transdermally, intramuscularly, subcutaneously, etc. The preparation processes and equipment for various dosage forms of drug preparations are conventional techniques in the pharmaceutical field and are not limited in the present invention.

[0055] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples were prepared according to existing methods or directly purchased from the market.

[0056] Attention deficit / hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, and stress-induced attention impairment all manifest, to varying degrees, as symptoms of inattention (or distractibility), delayed response, impulsivity, and hyperactivity. The 5-CSRT can simulate these symptoms and assess the effects of medication or other interventions on attention impairment by measuring accuracy, omission rate, and completion time.

[0057] Isorhynchophyline (IRN, CAS: 6859-01-4) was purchased from Chengdu Mansite Biotechnology Co., Ltd.

[0058] Example 1.1 Reagents and materials used in the experiment: SPF male C57BL / 6J mice were purchased from Beijing Sibeifu Biotechnology Co., Ltd. and acclimated for one week with free access to food and water. The enclosure temperature was 25 ± 2°C, humidity was 40%–60%, and the light-dark cycle was 7:00 AM to 7:00 PM with a 12-hour light-dark cycle. Two days before and during the experiment, the mice were placed on a restricted diet and water schedule: free access to food and water for one hour each morning or after the experiment, and deprived of food and water for the rest of the time to maintain motivation. Cardboard tubes and ping-pong balls were placed in each cage to provide environmental enrichment for the mice. Animal care, experimental protocols, and experimental procedures strictly adhered to the guidelines of the Animal Care and Use Committee of the National Center for Drug Safety Evaluation, Beijing.

[0059] Touch screen operating platform experimental box (Campden Instruments Limited, UK); Touch screen operating system (Bussey Saksida Touch Screen); Software: Whisker Server for running the experimental environment; 89540-Pairwise (Visual) Discrimination (PD) Task for Mouse Touch Screen Systems for running the experimental program; 5-Choice Serial Reaction Time Task for Mouse Touch Screen Systems (895435); ABET II Touch for data acquisition, export, and analysis.

[0060] 1.2 Experimental Procedure After mice experience acute stress, their attention is damaged to a certain extent. After administering isorhynchophylline, the animals' damaged attention is significantly improved. Figure 1 shown.

[0061] Experimental Example 1: Effect of Isorhynchophylline on Attention in Normal Mice The method used includes the following steps: (1) Environmental adaptation During the 7-day acclimatization period, mice were gently handled for 3 minutes daily to minimize the impact of irrelevant stress stimuli on subsequent experimental procedures. During the experiment, the experimental environment was kept relatively quiet.

[0062] (2) Experimental groups After weighing, the mice were randomly divided into control and drug intervention groups, with 11 animals in each behavioral experiment group. The control group received intraperitoneal injection of normal saline. Three drug intervention groups (isohypnthine) were administered intraperitoneally for seven consecutive days and then underwent attention testing. The monomeric compound doses were 20 mg / kg, 40 mg / kg, and 80 mg / kg.

[0063] (3) Touchscreen paradigm pre-training Two days before the experiment, the subjects were restricted from eating and drinking for one hour each day. Pre-training was also started: Habituation 1: Place the mice in the touch-screen operant chamber for 20 minutes to acclimate them to the chamber for 2 days. Habituation 2: 3 days in total. On the first day, the rats were placed in the operating room for 20 minutes to adapt and eat. On the next two days, the rats were placed in the operating room for 40 minutes to adapt and eat. Initial Touch Training: The touchscreen device was functioning normally, and a pattern stimulus appeared on the screen. The mouse received a triple reward for touching the pattern. If the mouse did not touch the pattern, it would receive a single reward after the pattern disappeared. The food reward was accompanied by a tray light and an audible sound. The training standard was to touch the pattern 30 times within 60 minutes.

[0064] Must Touch Stimuli: During this phase, mice must touch the stimulus pattern (one stimulus at a time, displayed on one side of the screen. The other side is blank. The left or right position is pseudo-randomly chosen; for example, no pattern will appear on the same side more than three times in a row). The mouse must touch the stimulus to elicit a tone / food response. If the mouse touches a blank portion of the screen, there is no response. A tray light illuminates and a tone is played during food delivery. The training criterion is 30 pattern touches within 60 minutes.

[0065] Must Initiate: During this phase, mice were required to initiate the experiment at the start of the experiment by touching the light on the food tray. The screen then displayed a pattern, one at a time, with the other blank. The left and right positions of the patterns were pseudo-randomized. The mice had to touch the pattern to elicit a tone / food response. The training criterion was 30 trials within 60 minutes.

[0066] Punish Incorrect: Training is identical to the previously described training, except that touching a blank stimulus (i.e., a screen without the image) results in the light in the operant chamber turning on (by default, for 5 seconds) and no food reward. After the light turns off, a 20-second delay elapses. The mouse must complete a correction trial. The image and position remain unchanged, and the same trial must be repeated until a correct response is made. The mouse then receives a tone and reward and proceeds to the next trial. The training criterion is 23 / 30 correct touches (77%) within 60 minutes for two consecutive days.

[0067] (4) 5-CSRT attention training and testing 5-CSRT Training to Baseline: Building on touchscreen training, reaction time training began after reaching the "Punish Incorrect" stage. The experiment began with a condensed milk reward, and the first trial began when the mouse left the food tray. After the mouse left the food tray, a 5-second "stimulus delay" began. At the end of the 5-second stimulus delay, a stimulus was presented in one of the five stimulus grid spaces on the touchscreen. The order of stimulus presentation was pseudo-randomized. The mouse had to respond within a specified time period (with a 5-second hold time limit). A correct response, touching the stimulus location, triggered the presentation of a food reward in the food tray. The reward was delivered accompanied by the illumination of the tray light and a tone. The tone lasted 1000 milliseconds. When the mouse left the food tray, the 5-second Interim Time Interval (ITI) began. After the ITI period, the tray light re-illuminated, and the mouse had to enter and exit the food tray before the next trial and the start of the "stimulus delay" began. Incorrect responses, such as touching a location other than the stimulus presentation or failing to respond within the limited stimulus duration (omissions), will result in a timeout (TO, 5 seconds) and the illumination of the house light. After the TO, the house light will turn off, and the "ITI Incorr" will begin (5 seconds). After the "ITI Incorr," the tray light will illuminate, and the mouse must enter and exit the food tray to begin the next trial, which also begins the "stimulus delay." A premature response, recorded when a touch is made in a response grid area during the stimulus delay, will also result in a TO. The 5-CSRT can be run by setting different stimulus durations to require mice to respond within a time limit. Initially, set a longer interval of 32 seconds to allow mice ample time to adapt to the task requirements. Then gradually shorten the interval to a baseline of 4 seconds to train the mice's response speed and accuracy. The training criterion is a >80% accuracy rate (<20% omission rate) for three consecutive days. In the "Execution Manager," set the appropriate touchscreen boxes to run the "5-choice Mouse Touch Basic" schedule and change the Session variable to 9, 10, …, or 12.

[0068] Testing phase: Once performance stabilized at the 4-second baseline, attention function was further assessed by manipulating basic task parameters. Mice were required to recognize and respond to a brief pattern stimulus presented in one of five stimulus grids on an LCD touchscreen.

[0069] Observation indicators: accuracy rate, omission rate, and completion time.

[0070] Experimental Example 2: Effects of Isorhynchophylline on Attention Impairment in Stress-Induced Mice The method used includes the following steps: (1) Environmental adaptation During the 7-day acclimatization period, mice were gently handled for 3 minutes daily to minimize the impact of irrelevant stress stimuli on subsequent experimental procedures. During the experiment, the experimental environment was kept relatively quiet.

[0071] (2) Experimental groups After weighing, mice were randomly divided into control, model (foot shock), and drug intervention groups. Behavioral experiments were conducted with 10 animals per group. The control and model groups received intraperitoneal injections of normal saline. One drug intervention group (isohypnthine) received foot shock 0.5 hours after intraperitoneal injection, followed by an attention test 0.5 hours later. The compound dose was 40 mg / kg.

[0072] (3) Touchscreen paradigm pre-training Same as (3) in “Test Example 1”.

[0073] (4) 5-CSRT attention training and testing 5-CSRT Training to Baseline: Detailed instructions are the same as in "Test Example 1" (4). 5-CSRT can be run by setting different stimulus durations to require mice to respond within a limited time. In the early stages of training, a longer interval of 32 seconds is set to allow mice enough time to adapt to the task requirements. Then, the interval is gradually shortened to the baseline level of 2 seconds to train the mice's response speed and accuracy. The training standard is an accuracy rate of >80% (omission rate <20%) for three consecutive days. Set the appropriate touch screen box in the "Execution Manager" to run the "5-choice Mouse touch basic" schedule and change the Session variable to 9, 10, 11... to 13.

[0074] Testing phase: Once the mice's performance stabilized at the 2-second baseline for three consecutive days, attentional function was further assessed by manipulating basic task parameters. The mice's attentional function was tested by varying the stimulus duration (2.0s, 1.8s, and 1.6s) and stimulus delay (short durations such as 2s, 3s, 4s, and 5s pseudo-randomly appearing or long durations such as 5s, 6s, 7s, and 8s pseudo-randomly appearing). The mice were required to recognize and respond to a brief pattern stimulus in one of five stimulus grid spaces on an LCD touchscreen.

[0075] Observation indicators: accuracy rate, omission rate, and completion time.

[0076] (5) Electric shock stress in mice The drug-treated group received the drug intraperitoneally 30 minutes before each foot shock. The control and model groups received normal saline intraperitoneally. All mice, except the normal control group, were placed in the shock box and allowed to acclimate for 5 minutes before the shocks began. The parameters were: AC current, 1.0 mA, 6 seconds duration, 10 seconds interval, 15 shocks. Mice in the normal control group were placed in the shock box for the same period of time but were not shocked.

[0077] All data are expressed as "mean ± standard error," and all data analysis and graphics were generated using GraphPad Prism 10.3.0 software. Means between the drug-treated and model groups were compared using one-way analysis of variance followed by Dunnett's multiple comparison test. P A value < 0.05 was considered statistically significant.

[0078] Analysis of test results 1. Effects of isorhynchophylline on attention of normal mice In Experimental Example 1, intraperitoneal injection of 20 mg / kg and 80 mg / kg of isorhynchophylline for 7 consecutive days had no significant effect on improving the attention of normal mice, while intraperitoneal injection of 40 mg / kg of isorhynchophylline for 7 consecutive days had a significant effect on improving the attention of normal mice.

[0079] The results are as follows Figure 2 As shown, * P <0.05, compared with the normal control group, one-way analysis of variance and Dunnett's test, mean ± standard error, n = 8-11. A: The correct touch screen rate of mice tested with a stimulation duration of 4 s after 7 consecutive days of administration of 20 mg / kg, 40 mg / kg, and 80 mg / kg of isorhynchophylline; B: The omission rate of touch screen of mice tested with a stimulation duration of 4 s after 7 consecutive days of administration of 20 mg / kg, 40 mg / kg, and 80 mg / kg of isorhynchophylline; C: The time it took for mice to complete 30 touch screen trials with a stimulation duration of 4 s after 7 consecutive days of administration of 20 mg / kg, 40 mg / kg, and 80 mg / kg of isorhynchophylline.

[0080] Compared with the control group, the accuracy rate of the 20mg / kg group showed an upward trend, and the omission rate showed a downward trend; there was no significant change in the accuracy rate and omission rate of the 80mg / kg group. Intraperitoneal injection of 40mg / kg of isorhynchophylline for 7 consecutive days significantly improved the attention of normal mice. Compared with the control group, the accuracy rate of the 40mg / kg group increased significantly, the omission rate decreased significantly, and the completion time was significantly shortened; this suggests that 40mg / kg of isorhynchophylline has a significant improvement on the attention of normal mice. This demonstrates the protective effect of isorhynchophylline on the attention of normal mice. Intraperitoneal injection of isorhynchophylline for 7 consecutive days significantly improved the accuracy rate, omission rate, and completion time of normal mice. This suggests that it may have a beneficial effect on attention. The results of this section indicate that 40mg / kg has the best effect, so subsequent experiments will use a dose of 40mg / kg for research.

[0081] 2. Effects of isorhynchophylline on attention impairment in stressed mice In Experimental Example 2, intraperitoneal injection of 40 mg / kg of isorhynchophylline for 7 consecutive days significantly improved attention impairment induced by foot shock.

[0082] The results are as follows Figures 3 to 5 As shown, * P <0.05,** P <0.01,*** P <0.001, compared with the foot shock group, one-way analysis of variance and Dunnett's test, mean ± standard error, n = 8-11. Figure 3 Figure A shows the plantar electric shock model after administration of 40 mg / kg of isorhynchophylline for 7 consecutive days. The test was performed 0.5 h later. The correct rate of mouse screen touching was under the condition of a stimulation duration of 2 s; B shows the omission rate of mouse screen touching under the condition of a stimulation duration of 2 s; C shows the completion time of the mouse for 30 trials of screen touching under the condition of a stimulation duration of 2 s. Figure 4 A is the correct rate of mouse touch screen under the condition of stimulation duration of 1.8s; B is the omission rate of mouse touch screen under the condition of stimulation duration of 1.8s; C is the completion time of mouse touch screen 30 trials under the condition of stimulation duration of 1.8s. Figure 5 Figure A shows the correct touch accuracy rate of mice under a 1.6-second stimulation duration; B shows the omission rate of mice under a 1.6-second stimulation duration; and C shows the completion time of mice after 30 touch trials under a 1.6-second stimulation duration. This study demonstrates the protective effect of isorhynchophylline against attentional impairment in mice induced by foot shock. Seven consecutive days of intraperitoneal administration of isorhynchophylline significantly improved the correct touch accuracy, omission rate, and completion time of mice induced by foot shock, suggesting that it may have beneficial effects on attention.

[0083] result Figure 6 and Figure 7 As shown, *P <0.05,** P <0.01,*** P <0.001, compared with the foot shock group, one-way analysis of variance and Dunnett's test, mean ± standard error, n = 8-11. Figure 6 Figure A shows the plantar electric shock model established after administration of 40 mg / kg of isorhynchophylline for 7 consecutive days. The test was performed 0.5 h later. The correct rate of screen touching of mice under the condition of short stimulus delay (2s, 3s, 4s, 5s); B shows the screen touching omission rate of mice under the condition of short stimulus delay (2s, 3s, 4s, 5s); C shows the completion time of 30 trials of screen touching of mice under the condition of short stimulus delay (2s, 3s, 4s, 5s). Figure 7 Figure A shows the accuracy rate of touch screens in mice under conditions with long stimulus delays (5s, 6s, 7s, and 8s); Figure B shows the omission rate of touch screens in mice under conditions with long stimulus delays (5s, 6s, 7s, and 8s); and Figure C shows the completion time of 30 touch screen trials in mice under conditions with long stimulus delays (5s, 6s, 7s, and 8s). This study demonstrates the protective effect of isorhynchophylline against attentional impairment in mice induced by foot shock. Seven consecutive days of intraperitoneal administration of isorhynchophylline significantly improved the accuracy rate, omission rate, and completion time of mice induced by foot shock. This suggests that it may have an ameliorative effect on stress-induced attentional impairment.

[0084] The results of the above experiments show that isorhynchophylline can not only improve the attention of normal mice but also improve the attention of mice subjected to plantar electric shock stress, suggesting that it can be used for the prevention / treatment of stress-related attention impairment.

[0085] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving attention impairment.

2. Use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a medicament for treating and / or improving impaired vigilance.

3. Use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving orientation impairment.

4. Use of isorhynchophylline or an isorhynchophylline derivative in the preparation of a drug for treating and / or improving executive control impairment.

5. The use according to claim 1, characterized in that The attention impairment includes attention impairment caused by stress; Preferably, the attention impairment further includes attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease or depression.

6. The use according to claim 5, characterized in that The stress includes trauma and stress-related disorders; Preferably, the trauma and stress-related disorder comprises at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specified trauma and stress-related disorder or unspecified trauma and stress-related disorder.

7. The use according to any one of claims 1 to 4, characterized in that The drug also includes pharmaceutically acceptable excipients.

8. The use according to claim 7, characterized in that The pharmaceutically acceptable excipients include at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

9. The use according to any one of claims 1 to 4, characterized in that The dosage form of the drug includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

10. The use according to claim 9, characterized in that The isorhynchophylline and isorhynchophylline derivatives are obtained by plant extraction or chemical synthesis.

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