CN115813917A - Compound with function of rapidly improving cognitive function and application - Google Patents
Compound with function of rapidly improving cognitive function and application Download PDFInfo
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- CN115813917A CN115813917A CN202211362836.7A CN202211362836A CN115813917A CN 115813917 A CN115813917 A CN 115813917A CN 202211362836 A CN202211362836 A CN 202211362836A CN 115813917 A CN115813917 A CN 115813917A
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Abstract
The invention belongs to the field of medicines, and discloses a compound for improving cognitive impairment, which can rapidly increase the activity of neurons and enhance the plasticity of nerve synapses, thereby rapidly improving cognitive functions.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a compound with a function of quickly improving cognitive function and application thereof.
Background
Alzheimer's Disease (AD) causes a decline in memory and other cognitive abilities, which accounts for over 60% of dementia cases. Most of the existing marketed drugs aim at a single target point to serve as a brain metabolism improving agent or a neuroprotective agent, but the effect is very little. In recent years, with the research on pharmacological activity, therapeutic studies on improving cognitive functions of AD patients by using hallucinogens are increasing, and the alleviation of AD symptoms and cognitive impairment show a considerable trend. Since alzheimer's disease cannot be cured at present, improvement of cognitive impairment, which is a major symptom, becomes a major treatment option, and drugs related thereto also become in demand.
Therefore, how to provide a compound for improving cognitive functions is a problem that needs to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the present invention provides a compound having a fast cognitive function improvement effect, which can rapidly improve spatial memory and cognitive function.
In order to achieve the purpose, the invention adopts the following technical scheme:
the chemical formula of the compound with the function of rapidly improving cognitive function provided by the invention is as follows:
the invention relates to a drug dimethyl tryptamine which is a first class of mental drugs and belongs to tryptamine hallucinogens. Structurally similar to neurotransmitters, serotonin and other hallucinogens, nudiflozin, and the like. Dimethyltryptamine was initially found primarily in plants and also in trace amounts in the mammalian brain. This drug was also synthesized in the laboratory thereafter.
The compound capable of rapidly improving cognitive function and improving senile dementia can be prepared into preparations such as injection, spray and the like.
The preparation for rapidly improving memory and cognitive ability and improving senile dementia can be added with pharmaceutically acceptable conventional auxiliary materials.
Indications for the above compounds: a decline in memory; impairment of cognitive function; alzheimer's disease.
The pharmacological and medicinal properties of the invention are as follows: can rapidly increase the activity of neurons and enhance the plasticity of nerve synapses, thereby rapidly improving cognitive functions.
The compound can be prepared into pharmaceutically acceptable salts, and has obvious repair effect on neurons damaged by neurotoxin.
In the invention, the raw material medicinal physiological saline with the functions of improving cognitive function and protecting nerves by express delivery is dissolved to 0.25-1mg/ml.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the invention discloses a new application of a dimethyltryptamine compound in preparing a neuroprotective medicament, which can quickly improve cognitive impairment and is used for preparing the neuroprotective medicament.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a graph of the effect of a drug on LTP in the hippocampus of mice for rapid improvement of cognitive function.
FIG. 2 is a graph of the effect of a fast cognitive function improving drug on mouse hippocampal calcium activity and neuronal ATP.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The drugs used in the examples were approved by the hong kong special district health administration and purchased from sigma, usa. The drug used in the comparative example was purchased from sigma, usa.
In the embodiment, the raw material medicinal normal saline for improving cognitive function and neuroprotection by express delivery is dissolved to 1mg/ml.
The comparative example is donepezil, and the preparation method of the comparative example comprises the following steps: the donepezil raw material is dissolved to 0.5mg/ml by using the physiological saline.
The following experiments show that the compound of the chemical formula has the effects of quickly improving cognitive function and protecting nerves, and can be applied to the medicines for treating or preventing senile dementia.
Example 1
(1) Test materials
The experimental medicine is a compound with the effects of rapidly improving cognitive function and neuroprotection in the examples and the comparative example donepezil.
Experimental animals were transgenic mice for Alzheimer's disease (3 TG-AD;5 XFAD) purchased from Jackson laboratories, USA; SPF grade C57BL/6 mice were purchased from the university of hong kong comparative medical research center, license number: 5345-20. All mice were housed in an environment with a temperature of 23 + -1 deg.C and a humidity of about 55%. The lighting time is kept for 12 hours, natural light is uniformly radiated, 6 mice/cage can freely take food and water.
(2) Test method
Grouping and administration of mice: mice were divided into control (C57 BL/6), model group (3 TG-AD or 5 XFAD mice), treatment group (compounds described in the present invention). The drugs of the treatment group were dissolved in normal saline to an appropriate concentration, and the mice were administered by single-dose intraperitoneal injection, with the administration dose of 12mg/kg for the example group and 5mg/kg for the comparative example group.
Animal behavioral testing: the Y maze test is carried out on a mouse by a single intraperitoneal injection of the medicine for about 30min, and the effect of the medicine for quickly improving the space memory and cognitive ability of the mouse is detected.
And (3) Y labyrinth: the Y-maze consists of three identical arms, each at 120 degrees, each with dimensions 30cm x 8cm x 15cm (length x width x height), with a movable partition in the center. The three arms of each Y maze were randomly set to: a new arm, a starting arm, and other arms. A new different arm: blocking in the first stage of experiment, namely training stage, and opening in the second stage of test period; a starting arm: the mouse entered the arm where the maze was located. During the whole experiment, the initial arm and other arms are always opened, and the animals can freely come in and go out. After each training or test, the animal excreta are cleared with alcohol to prevent interference from residual odors of the animals.
The Y maze detection animal space recognition memory capacity comprises two stages at an interval of 1h, the first stage is an acquisition stage, a new arm is closed, and the animal freely explores for 5min in other two arms. A second experiment (recall phase) was performed after 1 hour, all arms were opened and the animals were free to move for 5min on three arms. The time and distance of the animal's exploration at each arm was recorded using a SMART video tracking system.
Mouse hippocampal Long Term Potentiation (LTP) assay: the mice to be detected are rapidly decapitated, and the scalp is cut to remove the skull and the dura mater. Quickly taking out whole brain, standing at 0-4 deg.C with 95% O 2 And 5% of CO 2 Slightly cooled in saturated artificial cerebrospinal fluid (ACSF). The cerebellum and 1/3 of forebrain are cut off, the brain is divided into two parts along the median line, and the brain tissue containing the hippocampus is fixed on a carrying bath dish by glue. The coronal section of the brain was cut to a thickness of 350 microns using a vibrating microtome. Placing brain slices in an incubation groove, soaking the brain slices on a nylon net below the liquid level, continuously filling mixed gas, placing the brain slices in a constant-temperature water bath at 34 ℃ for incubation for 0.5h, and then placing the brain slices at room temperature for incubation for standby. In the laboratory, a recording point is placed on the vertebral body cell layer in the CA1 area under an operation microscope, and the recorded signals can be simultaneously displayed on a memory oscilloscope and a computer display screen. The excitatory postsynaptic potential (fEPSP) and its change in slope were monitored every 20s for 60min.
Mouse hippocampal intracellular calcium activity and hippocampal ATP levels: and detecting calcium signals of hippocampal regions and ATP levels of neurons of the mice by adopting optical fiber photometry. The anesthetized mice were fixed on a stereotaxic apparatus. Cutting the scalp of the mouse along the midline, cleaning the soft tissue on the surface of the mouse, and positioning the surface of the skull: AP is taken as a reference mouse spectrum bregma, and the diameter is-1.85 mm; ML, ± 1.10mm; DV,2.04mm. A quantity of virus is extracted using a microinjection pump. Mice were craniotomed and stopped for 5min before virus (AAV 9-syn-RCaMP; AAV9-syn-ATP 1.0) was injected at 50nL/min with a microinjection pump at 200nL. After the injection is finished, the injection is stopped for 10min and then is slowly withdrawn. Cleaning the injection site and surrounding impurities and suturing the scalp. And (5) putting the mice back into the rearing cage after the mice are awake. After the mice are continuously raised for 2 weeks after the injection of the virus, the optical fiber is implanted into the hippocampal region of the mice, and the mice are continuously raised for 1 week until the virus infects neurons and fully expresses Ca 2+ Fluorescence indicator protein (RCaMP) and ATP fluorescent protein (ATP 1.0), record hippocampal Ca after mice injected with drug in conscious free state 2+ And (3) synchronously acquiring the behavioral data by adopting a video camera according to the level and the ATP level of the hippocampal neurons, and recording for about 30min.
The data processing method comprises the following steps: experimental data are expressed as mean ± standard deviation (mean ± s.e.). Statistically significant differences the differences between groups were examined according to the one-way ANOVA analysis of graphpadpristm 9.0 software (Tukey's test performed afterwards), P <0.05 considered significant and statistically significant.
(3) The experimental results are as follows:
y maze test results: the experimental results of the time in the neoarm of each group of mice are shown in table 1, the treatment group is the drug treatment group of the present invention, the time in the neoarm of the mice is significantly increased (P < 0.05) when tested 30min after single dose injection administration.
TABLE 1 Effect of drugs for fast improvement of cognitive function on mouse Y maze experiment
| Group of | Number of animals | New different arm time (%) | P value |
| |
10 | 24.85±2.781 | |
| Model set | 10 | 5.48±2.98 | P＜0.0001 |
| Group of examples | 10 | 17.86±2.47 | P＜0.01 |
| |
10 | 2.54±2.00 | P＞0.05 |
Note: data are presented as mean ± standard deviation (n = 10/group). P <0.01, P-woven cloth 0.0001 represents extremely significant.
Mouse hippocampal Long Term Potentiation (LTP) assay: the treatment group (drug of the invention) takes brain slices to test mouse hippocampal LTP within 1 hour after single injection of mice, and the result shows that the treatment group remarkably enhances excitatory postsynaptic potential (fEPSP) of AD mice (P < 0.0001) (figure 1), the average fEPSP recorded 50-60 minutes after theta pulse stimulation (TBS) is treated by the drug, the fEPSP of AD mice is also remarkably increased by the drug, and the treatment group is remarkably higher than a blank control group, which indicates that the drug of the invention can rapidly change LTP and improve the synaptic function of mouse hippocampus.
As shown in FIG. 1, FIG. 1 shows the effect of a drug for rapidly improving cognitive function on LTP in mouse hippocampus. The excitatory postsynaptic potential (fEPSP) of the hippocampus of each group of mice 15 minutes before and 60 minutes after theta pulse stimulation is shown.
TABLE 2 Effect of fast improving cognitive drugs on mouse Hippocampus LTP
Note: data are mean fepsps recorded 50-60 minutes after theta pulse stimulation (TBS), expressed as mean ± standard deviation (n = 10/group). P <0.01, P-woven cloth 0.0001 represents extremely significant.
Mouse hippocampal intracellular calcium ions and hippocampal ATP levels: and (3) recording calcium activity and ATP change of hippocampal regions of each group of mice in a waking free activity state of the mice by adopting an optical fiber system. The results show that after a single injection of the drug of the invention, the treatment group induced Ca significantly 2+ Change in calcium (FIG. 2), calcium signal rapidly increased from 5 minutes after injection of the drug of the present invention, and Ca was found in hippocampus of treated mice 2+ The signal increased significantly (P < 0.05). The medicine of the present invention can raise the activity of mouse hippocampal neuron obviously.
The ATP level of mouse hippocampal neurons after single injection of the drug is recorded by adopting an optical fiber system, and the result shows that the drug can remarkably increase the ATP release (P is less than 0.05) of mouse hippocampal compared with a control group (injected with normal saline).
FIG. 2 is a graph of the effect of a fast cognitive function improving drug on mouse hippocampal calcium activity and neuronal ATP. AD mice were injected with saline and the drug of the invention, respectively, and mouse hippocampal calcium activity and neuronal ATP signals were recorded and compared (n = 4-5). P <0.05, representing significant difference.
Example 2
(1) Test materials
The experimental drug is a compound with the effects of rapidly improving cognitive functions and neuroprotection in the examples. The experiment adopts primary hippocampal neurons of a mouse, the mouse is provided by a comparative medicine center of hong Kong university, and the license number is as follows: 5369-20.
(2) Test method
Examination of drug pairs for A β in the above examples 25-35 Protective effect of induced primary hippocampal neuronal damage in mice. Cells were cultured at 8X 10 3 Density of individual/well inoculated in 96-well plates, 5% CO 2 Incubation at 37 ℃ for 7 days in a constant temperature incubator, pretreatment of the drug at a concentration of 2. Mu.M for 1 hour for observation of the cell state, and then treatment with 10. Mu.M of A.beta. 25-35 Cells were modeled and blanks were left untreated and incubated for 24 hours. Adding CCK-8 solution into 96-well plate in dark, incubating in dark for 2 hr, detecting absorbance at 450nm, and calculating cell activity changeAnd (4) transforming.
Survival rates of each group were calculated with the viability of the blank group as 100%. Experimental data are expressed as mean ± standard error (mean ± s.e.). Statistically significant differences the differences between groups were examined according to the one-way ANOVA analysis of graphpadprism9.0 software (Tukey's test performed afterwards), P <0.05 considered significant and statistically significant.
(3) Test results
Table 3 shows the effect of the drugs with the effects of rapidly improving cognitive function and neuroprotection on the viability of primary hippocampal neurons in mice in the examples. Abeta to blank 25-35 The cell viability was reduced to 70.53% (P < 0.01) (final concentration of 10. Mu.M), and was significantly increased in the example group (P < 0.001) at the administration concentration of 2. Mu.M. Pretreatment of Ass with drugs to demonstrate rapid improvement in cognitive function 25-35 Induced cell damage plays a significant neuroprotective role.
TABLE 3 neuroprotective Effect of drugs with fast cognitive improvement on Primary hippocampal neurons in mice
| Group of | Cell survival rate (%) | P value |
| Blank group | 100.00±0.00 | |
| Control group | 70.53±0.63 | P＜0.01 |
| Group of embodiments | 109.00±0.63 | P＜0.001 |
The compound with the function of quickly improving cognition can obviously increase the time of a mouse in a new arm in a test 30min after administration, improve the spatial memory of an AD mouse, and simultaneously can quickly enhance the intracellular calcium ion level, the hippocampal neuron ATP level and the mouse hippocampal long-term time-course enhancement (LTP), thereby quickly increasing the hippocampal synaptic transmission.
The above experiments demonstrate that, compared with the control group and the model group, the treatment group shows good and rapid improvement of cognitive function and spatial memory ability, and can rapidly enhance the ATP level and the neuron activity of the hippocampal neurons. In vitro experiments show that the medicine for rapidly improving the cognitive function has a certain neuroprotective effect. In conclusion, the compound can be used as a compound for rapidly improving cognitive and memory abilities and preventing and treating the Alzheimer disease.
In the present specification, the embodiments are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed in the embodiment corresponds to the method disclosed in the embodiment, so that the description is simple, and the relevant points can be referred to the description of the method part.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (2)
1. A compound having a rapid cognitive improvement, characterized by the chemical structure:
2. use of a compound according to claim 1 for the manufacture of a medicament for improving cognition.
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