Application of Alda-1 in preparation of preparation for improving cognitive function

Abstract

The invention provides application of Alda-1 in preparation of a preparation for improving a cognitive function, and belongs to the technical field of biological medicines. According to the method, the improvement effect of Alda-1 on cognitive competence is evaluated from the perspectives of working memory, suppression control, visual discrimination and the like, and results show that Alda-1 can improve the working memory ability, the suppression control ability and the visual discrimination ability. Therefore, the invention provides a safe and effective solution for developing new application of the Alda-1 medicine, guaranteeing the visual cognition ability of special occupational people and treating early neurological and mental diseases accompanied by visual cognition impairment.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceutical technology, specifically relating to the application of Alda-1 in the preparation of formulations that improve cognitive function. Background Technology

[0002] Executive function is a collection of cognitive elements, primarily including three core components: working memory, cognitive flexibility, and inhibitory control. Inhibitory control and working memory are fundamental cognitive elements, forming the basis for higher-level cognitive functions such as visual information processing. When performing visual manipulation tasks, inhibitory control and working memory are crucial for capturing visual information and maintaining its processing in the brain. Therefore, understanding inhibitory control and working memory is helpful for subsequent screening research of candidate visual cognitive enhancers.

[0003] Vision is one of the most important channels for sensory information in humans. For professionals in specialized professions such as pilots, the need to acquire external reference information and maintain visual load for extended periods places even higher demands on visual discrimination abilities. Furthermore, many neuropsychiatric disorders (such as Parkinson's disease, ischemic stroke, and schizophrenia) share the common characteristic of impaired visual discrimination abilities in their early stages. Therefore, the development of cognitive enhancers focusing on visual discrimination abilities is of great significance for ensuring the operational capabilities of specific occupational groups and for treating neuropsychiatric disorders with early-stage visual cognitive impairment.

[0004] Alda-1 (Alda-1) is an ALDH2 activator that can increase the enzyme activity of ALDH2. Alda-1 is currently mainly used in research to treat mitochondrial dysfunction and improve cardiac function. There are currently no reports on the effects of Alda-1 on working memory, inhibitory control, and visual cognitive processing ability. Summary of the Invention

[0005] In view of this, the object of the present invention is to provide the application of Alda-1 in the preparation of drugs that enhance cognitive function, thereby improving cognitive activity by enhancing working memory, inhibitory control ability, and visual discrimination learning ability.

[0006] This invention provides the use of Alda-1 or Alda-1 derivatives in the preparation of formulations that improve cognitive function.

[0007] Preferably, the cognitive function includes cognitive activity execution function and / or visual discrimination cognitive processing function.

[0008] Preferably, the cognitive activity executive function includes working memory and / or inhibitory control ability.

[0009] Preferably, the visual discrimination cognitive processing function includes visual discrimination learning ability.

[0010] Preferably, the formulation includes at least one of the following: oral preparations, injections, sprays, suppositories, and patches.

[0011] Preferably, the mass percentage of Alda-1 is 1% to 99%.

[0012] This invention improves the use of Alda-1 or its derivatives in the preparation of medicaments for treating cognitive impairment-related diseases or functional formulations for improving cognitive abilities in specific occupational groups.

[0013] Preferably, the cognitive impairment-related diseases include at least one of the following: schizophrenia, Parkinson's disease, and ischemic stroke.

[0014] Preferably, the drug comprises at least one of the following dosage forms: oral, injectable, topical, and mucosal dosage forms.

[0015] Preferably, the oral dosage form includes at least one of the following: tablets, sustained-release tablets, capsules, controlled-release tablets, pellets, and liquid formulations; The injectable preparations include injectable powders and / or injectable solutions.

[0016] This invention provides the application of Alda-1 or its derivatives in the preparation of formulations that improve cognitive function. The visual cognitive-enhancing effects of Alda-1 were investigated using models of working memory, inhibitory control, and visual discrimination. Results showed that Alda-1 can improve working memory in mice, increase inhibitory control in rats, and enhance visual discrimination ability in rats. Therefore, this invention provides a safe and effective solution for developing new uses for Alda-1, ensuring visual cognitive abilities in specific occupational groups, and treating early-stage neuropsychiatric diseases accompanied by visual cognitive impairment. Attached Figure Description

[0017] Figure 1 A represents the effect of Alda-1 on working memory in mice; B represents the effect of Alda-1 on the rate of continuous spontaneous alternation in mice; C represents the effect of Alda-1 on the number of arm insertions in mice; Control group: n=13; Alda-1 10 mg / kg group: n=13; Alda-1 20 mg / kg group: n=12; Alda-1 40 mg / kg group: n=12; * P <0.05, compared with the Control group; Figure 2The results show the effect of Alda-1 on the inhibitory control ability of rats; A represents the number of impulsive responses; B represents the latency of correct responses; C represents the latency of incorrect responses; Control group: n=10; Alda-1 10 mg / kg group: n=11; Alda-1 20 mg / kg group: n=11; Alda-1 40 mg / kg group: n=11; * P <0.05, Alda-1 40 mg / kg group compared with Control group; Figure 3 The results show the effect of Alda-1 on visual discrimination ability in rats; A represents the visual discrimination accuracy rate. * P <0.05, Alda-1 20 mg / kg group compared with Control group; # P <0.05, comparison between Alda-1 40 mg / kg group and Control group; B is the visual discrimination achievement rate curve; Control group: n=12; Alda-1 10 mg / kg group: n=11; Alda-1 20 mg / kg group: n=12; Alda-1 40 mg / kg group: n=12; * P <0.05, Alda-1 20 mg / kg group compared with Control group. Detailed Implementation

[0018] This invention provides the use of Alda-1 or Alda-1 derivatives in the preparation of formulations that improve cognitive function.

[0019] In this invention, Alda-1 is an ALDH2 activator with the structural formula shown in Formula I. It is purchased from MCE Corporation, catalog number HY-18936.

[0020] Formula I.

[0021] In this invention, the cognitive function preferably includes cognitive activity execution function and / or visual discrimination cognitive processing function. The cognitive activity execution function preferably includes working memory and / or inhibitory control ability. The visual discrimination cognitive processing function preferably includes visual discrimination learning ability.

[0022] In one embodiment of the present invention, the spontaneous alternation rate of Y-maze continuity was used as an indicator to evaluate the effect of Alda-1 on working memory. The results showed that, compared with the control group, Alda-1 (40 mg / kg, ip) significantly increased the percentage of spontaneous alternation in mice, indicating that Alda-1 can improve the working memory ability of mice.

[0023] In another embodiment of the invention, a five-choice continuous reaction time task experiment was used to evaluate the effect of Alda-1 on improving inhibitory control. The results showed that, compared with the control group, Alda-1 (40 mg / kg, ip) significantly reduced the number of impulsive responses in rats. This indicates that Alda-1 can improve the inhibitory control ability of rats.

[0024] In one embodiment of this invention, a two-choice visual discrimination task was used to assess the effect of Alda-1 on improving visual discrimination ability. The results showed that the visual discrimination accuracy of rats in the 20 mg / kg and 40 mg / kg Alda-1 groups on day 8, and in the 20 mg / kg Alda-1 group on day 12, was significantly higher than that of the control group at the same time point. The visual discrimination task achievement curves showed a significant difference between the Alda-1 20 mg / kg group and the control group (Figure 3B), indicating that Alda-1 can significantly improve the achievement rate and shorten the achievement time of the visual discrimination task in rats. In summary, these results suggest that Alda-1 can improve the visual discrimination ability of rats.

[0025] In this invention, the formulation further includes excipients, such as carriers or excipients. Depending on the choice of excipients, the formulation preferably includes at least one of the following dosage forms: oral dosage form, injection, spray, suppository, and patch. The mass percentage of Alda-1 is preferably 1% to 99%, but can be 2% to 90%, 5% to 85%, 10% to 70%, further 20% to 60%, further 30% to 50%, and even more preferably 40%. This invention does not impose any particular limitation on the preparation method of the formulation; any preparation method well known in the art can be used.

[0026] Given that Alda-1 has the property of enhancing cognitive function, the present invention provides the use of Alda-1 or Alda-1 derivatives in the preparation of medicaments for treating cognitive impairment-related diseases or functional formulations for improving the cognitive abilities of specific occupational groups.

[0027] In this invention, the cognitive impairment-related diseases preferably include at least one of the following: schizophrenia, Parkinson's disease, and ischemic stroke.

[0028] In this invention, the formulation for improving cognitive function is preferably a cognitive enhancer. The cognitive enhancer is suitable for specific occupational groups or patients with early-stage neuropsychiatric disorders accompanied by visual cognitive impairment. The specific occupational groups preferably include pilots, drivers, astronauts, etc.

[0029] In this invention, the route of administration of the drug includes administration via the digestive tract or non-digestive tract. The digestive tract route preferably includes formulations administered orally or through the gastrointestinal tract. Non-digestive tract administration preferably includes administration via the respiratory tract, muscle, vein, skin, mucous membrane, vagina, or rectum.

[0030] In this invention, the drugs are classified according to their route of administration, preferably including at least one of the following dosage forms: oral preparations, injections, topical preparations, and mucosal delivery preparations. The oral preparations preferably include at least one of the following: tablets (including sublingual tablets), sustained-release preparations, capsules, controlled-release preparations, droplets, and liquid preparations. The injections preferably include injectable powders and / or injectable solutions, specifically categorized as intramuscular injection, intravenous injection, and intravenous infusion. The drugs are classified according to their physical state, preferably including liquid dosage forms, fixed dosage forms, and semi-solid dosage forms. The liquid dosage forms preferably include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and combined emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments. The solid dosage forms preferably include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays. The semi-solid dosage forms preferably include ointments, gels, and pastes. The tablets can also be formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

[0031] In this invention, the tablets preferably also include medically acceptable excipients. The excipients preferably include any one of the following: diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, carboxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and flow aid may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0032] In this invention, the preparation of the capsules preferably involves mixing a diluent and a gliding agent, and then placing the mixture directly into hard or soft capsules. Alternatively, the active ingredient, the compound of this invention, can be first mixed with a diluent, a binder, and a disintegrant to form granules or microspheres, which are then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and gliding agents used to prepare the tablets of this invention can also be used to prepare capsules of the compounds of this invention.

[0033] In this invention, the preparation of the injection is preferably carried out by using the active ingredient and water, ethanol, isopropanol, propylene glycol, or a mixture thereof as solvents, and adding appropriate amounts of solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators well known in the art. Solubilizers or co-solvents may be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters may be phosphates, esters, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators may be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing a lyophilized powder injection, mannitol, glucose, etc., may also be added as a support agent.

[0034] In this invention, the drug may also contain at least one of the following excipients as needed: colorant, preservative, flavoring agent, taster or other additive.

[0035] To enhance therapeutic efficacy, the medicaments or pharmaceutical compositions of the present invention can be administered using any known method of administration. The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the cognitive ability to be improved, the individual circumstances of the patient or animal, the route of administration, and the dosage form. Generally, the appropriate daily dose range for the compounds of the present invention is 0.001-100 mg / kg body weight. The above dosage can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0036] The compounds of this invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of this invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0037] The following examples illustrate the application of Alda-1 provided by this invention in the preparation of drugs that enhance cognitive function, but these examples should not be construed as limiting the scope of protection of this invention.

[0038] Example 1 The effect of Alda-1 on working memory in mice was assessed using a Y-maze continuous spontaneous alternation task experiment. Male C57BL / 6J mice, SPF grade, weighing 22-25 g, were used in the experiment. Mice were divided into a solvent control group and Alda-1 (10 mg / kg, 20 mg / kg, and 40 mg / kg) groups. The test began 30 minutes after intraperitoneal injection (ip). During the experiment, mice were randomly placed into one arm of a Y-maze (A, B, C arms) as the starting arm. The order in which mice entered each arm within 5 minutes was recorded. Three consecutive entries into different arms were counted as one spontaneous alternation (e.g., ABCABCBA, a total of 5 spontaneous alternations). The total number of spontaneous alternations and the total number of arm entries within 5 minutes were recorded. The total number of arm entries and the percentage of spontaneous alternations were analyzed using one-way ANOVA combined with Dunnett's t-test.

[0039] Spontaneous alternation percentage = Total number of spontaneous alternations / (Total number of arm advances - 2) × 100% Formula I.

[0040] The spontaneous alternation rate reflects the animal's working memory, while the total number of arm advances reflects the animal's basic activity level.

[0041] Table 1. Effects of Alda-1 on the continuous spontaneous alternation task in the Y-maze in mice.

[0042] Note: Mean ± standard error; * P <0.05, compared with the Control group.

[0043] Results: In the continuous spontaneous alternation experiment in the mouse Y-maze, Alda-1 (40 mg / kg, ip) significantly increased the percentage of spontaneous alternation in mice compared with the control group. Figure 1 (A), but had no significant effect on the total number of arm advances ( Figure 1 (B) suggests that Alda-1 can improve working memory in mice.

[0044] Experiment Example 2 The effect of Alda-1 on inhibitory control in rats was assessed using a five-choice continuous reaction time task. Male SD rats, SPF grade, with an initial weight of 180-220 g, were used in the experiment. After one week of acclimatization feeding, food restriction was initiated, with the rat's weight reduced to 85%-90% of its normal weight. Training began after this period. The training consisted of eight phases (two pre-training phases and six formal training phases). The pre-training phase aimed to quickly establish an operant conditioned reflex of nose-touching light activation in response to a food pellet reward. In the formal training phase, the rats touched the food bowl nose-to-nose. After a 5-second inter-trial interval (ITI), one of the five lights was randomly illuminated. The stimulus duration (SD) of the lights varied across different training phases. After the lights were illuminated, there was a 5-second effective nose-touching time. Rats that correctly touched the illuminated light during this period were considered to have a correct response, receiving a food pellet reward and initiating the next training session. Rats that did not touch the illuminated light were considered to have an incorrect response and did not receive a food pellet reward. If a rat does not touch any of the five semaphore lights within its nose, it is recorded as a missing response and will not receive the pill reward. Both incorrect and missing responses are followed by a 5-second ITI (Initial Time Interval). If a rat fails to control its behavior and touches one of the five semaphore lights within the ITI, it is recorded as an impulsive response. The baseline parameters for rats to reach the training standard are: 1 s-SD (Short Detection Time), 5 s-ITI (Initial Time Interval), and 100 tests. After rats achieve a nose-touching accuracy rate of over 80% under these parameters, drug administration is initiated, and the ITI parameters are changed to simulate a high-impulsive task environment (7 s-ITI).

[0045] Rats were divided into a solvent control group and Alda-1 (10 mg / kg, 20 mg / kg, 40 mg / kg) groups, and the test began 30 minutes after intraperitoneal injection (ip). The test parameters were the number of impulsive responses, the latency of correct responses, and the latency of incorrect responses. Data were analyzed using one-way ANOVA combined with Dunnett's t-test. A decrease in the number of impulsive responses indicated enhanced inhibitory control in the rats, while unchanged latency of correct and incorrect responses indicated no central excitation or inhibition and normal motor function.

[0046] Table 2 Effects of Alda-1 on inhibitory control in rats

[0047] Note: Mean ± standard error; * P <0.05, compared with the Control group.

[0048] Results: In the inhibitory control paradigm (7 s-ITI, 1 s-SD), Alda-1 (40 mg / kg, ip) significantly reduced the number of impulsive responses in rats compared with the control group. Figure 2 (A), while the correct reaction latency ( Figure 2 (B) and the latency period of incorrect response ( Figure 2 The results showed no significant effect on C, suggesting that Alda-1 can improve the inhibitory control ability of rats.

[0049] Experimental Example 3 The effect of Alda-1 on visual discrimination ability in rats was assessed using a two-choice visual discrimination task. Male SD rats, SPF grade, with an initial weight of 180-220 g, were used in the experiment. After one week of acclimatization feeding, food restriction was initiated, with the rats' weight reduced to 85%-90% of their normal weight before training began. A rat touchscreen behavioral test chamber was used. Through approximately two weeks of acclimatization and formal training (the purpose of which was to establish an operant conditioned reflex between visual stimulus patterns and food rewards), the rats ultimately achieved a training pass rate of ≥80% accuracy in touching the visual stimulus pattern within 60 minutes for two consecutive days during the punishment phase. Then, a two-choice visual discrimination task phase was introduced, in which two paired visual stimulus patterns, "airplane" and "spider," were presented on the screen (not appearing three times consecutively in the same position). Based on the average accuracy rate achieved over the two consecutive days of the punishment phase, the rats were evenly divided into two groups: one group treated the "airplane" pattern as the correct stimulus (CS+), and the other group treated the "spider" pattern as CS+. If the rat touched the correct stimulus, the visual stimulus pattern disappeared, a reward food particle appeared in the food trough, and the food trough light illuminated. When rats enter the feeding trough to eat, the trough light is turned off, and a 20-second inter-trial interval (ITI) begins. After each ITI, the rat must trigger a new round of experiments on its own. If the wrong touch is made, the visual stimulus pattern disappears, the box light turns on for 5 seconds, and after the 20-second ITI, a correction step begins until the correct touch is made. The two-choice visual discrimination task phase lasts for 23 days.

[0050] Rats were divided into a solvent control group (2% DMSO + 1% Tween 80 + 30% hydroxypropyl-β-cyclodextrin) and an Alda-1 group (10, 20, 40 mg / kg). Visual discrimination tasks were performed 30 minutes after daily intraperitoneal injection (ip). The test indicators were visual discrimination accuracy and target achievement rate. The target achievement rate was ≥ 80% visual discrimination accuracy within 60 minutes.

[0051] Results: In the rat two-choice visual discrimination task paradigm, a two-way ANOVA with one repeated measure showed a significant drug treatment × time interaction effect on visual discrimination accuracy. Therefore, a simple effects analysis was further performed, which showed that the drug treatment effect was significant on days 8 and 12. Specifically, the visual discrimination accuracy of rats in the Alda-1 20 mg / kg and 40 mg / kg groups on day 8, and the Alda-1 20 mg / kg group on day 12, was significantly higher than that of the control group at the same time point. Figure 3 (A)

[0052] The visual discrimination task achievement curves showed that the visual discrimination achievement rate of rats continued to improve with the extension of Alda-1 administration and training time. Log-Rank test showed that the achievement curve of the Alda-1 20 mg / kg group was significantly different from that of the control group. Figure 3 (Figure B) indicates that Alda-1 significantly improves the success rate and shortens the time required to achieve the visual discrimination task in rats. In summary, these results suggest that Alda-1 can improve the visual discrimination ability of rats.

[0053] This invention employs a rodent behavioral model to investigate the effects of Alda-1 on continuous spontaneous alternation behavior in a mouse Y-maze, a five-hole continuous reaction time task in rats, and two selective visual discrimination tasks. The results show that intraperitoneal administration of Alda-1 can improve working memory, inhibitory control, and visual discrimination ability in rodents. Therefore, Alda-1 has a cognitive-enhancing effect. Using Alda-1 as the active substance, it can be used alone or in combination with other pharmacologically active compounds and / or extracts to formulate various dosage forms of cognitive-enhancing drugs according to conventional pharmaceutical formulation methods. Alternatively, it can be combined with other active ingredients with cognitive-enhancing effects to form compound preparations. These formulations can reduce adverse drug reactions while maintaining efficacy, providing a safe, effective, and economical solution for protecting the visual cognitive abilities of specific occupational groups and for the prevention and treatment of early-stage neuropsychiatric diseases with visual cognitive impairment (such as schizophrenia, Parkinson's disease, and ischemic stroke).

[0054] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Application of Alda-1 or its derivatives in the preparation of formulations that improve cognitive function.

2. The application according to claim 1, characterized in that, The cognitive functions include cognitive activity execution functions and / or visual discrimination cognitive processing functions.

3. The application according to claim 2, characterized in that, The cognitive executive functions include working memory and / or inhibitory control abilities.

4. The application according to claim 2, characterized in that, The visual discrimination cognitive processing function includes visual discrimination learning ability.

5. The application according to claim 1, characterized in that, The formulation includes at least one of the following: oral preparations, injections, sprays, suppositories, and patches.

6. The application according to claim 1, characterized in that, The mass percentage of Alda-1 is 1% to 99%.

7. The use of Alda-1 or its derivatives in the preparation of drugs for treating cognitive impairment-related diseases or functional formulations for improving cognitive abilities in specific occupational groups.

8. The application according to claim 7, characterized in that, The cognitive impairment-related diseases include at least one of the following: schizophrenia, Parkinson's disease, and ischemic stroke.

9. The application according to claim 7, characterized in that, The drug includes at least one of the following dosage forms: oral, injectable, topical, and mucosal dosage forms.

10. The application according to claim 9, characterized in that, The oral dosage form includes at least one of the following: tablets, sustained-release tablets, capsules, controlled-release tablets, pellets, and liquid preparations; The injectable preparations include injectable powders and / or injectable solutions.

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