CN104473926A - Medicament for improving synaptic function - Google Patents
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- CN104473926A CN104473926A CN201410697626.2A CN201410697626A CN104473926A CN 104473926 A CN104473926 A CN 104473926A CN 201410697626 A CN201410697626 A CN 201410697626A CN 104473926 A CN104473926 A CN 104473926A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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Abstract
The invention relates to a medicament for improving synaptic function. The effective component of the medicament is bi(3)-tacrine, the molecular formula of which is C29H32N4, the molecular weight is 436 and the structural formula is shown in the description. The medicament can be used for improving synaptic function, increasing the quantity of synapsis and adjusting synaptic plasticity. The medicament can be used for effectively relieving symptoms of Alzheimer disease, relieving the memory function decline of Alzheimer disease, alleviating the cognition impairment of Alzheimer disease and preventing the impairment of synaptic function caused by Alzheimer disease, and has a high efficiency for treating Alzheimer disease.
Description
Technical field
The present invention relates to and improve synaptic function technical field, specifically a kind of medicament for improving synaptic function.
Background technology
Synapse is the position functionally occurring between neuron to contact, and is also the key position that information is transmitted.Synaptic plasticity comprises the plasticity that plasticity, synaptic development plasticity and Synaptic Morphology are transmitted in synapse, long term potentia￣tion (long-term potentiation, LTP) belongs to synapse and transmits the Basic of Biology that plasticity is the cellular level being acknowledged as learning and memory activity.Have now found that plasticity that synapse transmits is except in close relations with learning and memory function, also take part in other important physiology or the pathological processes such as sensation, Cardiovascular regulation.Therefore synapse number and plastic change can cause a series of disease.Such as, in Alzheimer (Alzheimer ' s disease, AD), it is its a typical pathological change that synapse is lost.
Amyloid-beta (amyloid-β, A β) by amyloid beta-protein precursor (β-amyloid precursor protein, APP) be hydrolyzed, by emiocytosis, after cellular matrix precipitation is built up, there is very strong neurotoxic effect, A β can be combined with synapse, thus causes the damage of synaptic function, further causes neuronal degeneration and death.
Two (3)-tacrine (Bis (3)-cognitin) a kind ofly derives from tacrine and with the novel dimer of 3 methylene.Tacrine is first and is applied to clinical AD medicine by FDA approval, but due to the serious liver toxicity of its lower bioavailability and gastrointestinal side effect, inactive at present.Two (3)-tacrine, as the derivant of tacrine, not yet finds that it has the side effect of tacrine at present.Two (3)-tacrine is be synthesized as a kind of acetylcholinesterase (acetylcholinesterase, AChE) inhibitor at first, finds that it is also a kind of non-competing nmda receptor antagonist afterwards.The combination of it and nmda receptor has fast speed of dissociating (IC
50, 0.52 μM).Nearest research shows the Spatial learning ability damage that two (3)-tacrine can improve scopolamine and causes to improve the motor capacity damage in parkinson disease.Two (the 3)-tacrine of above research prompting may be a kind of potential medicine improving synapse number and function, and then improves synaptic function and damage the disease such as AD caused.But there is no relevant report at present.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned prior art present situation, and provide a kind of medicament for improving synaptic function, this medicament can increase synapse number, regulates synaptic plasticity.It can be applied to and improve the hypofunction of Alzheimer spatial memory, and that slows down Alzheimer distinguishes dysmnesia.
The present invention solves the problems of the technologies described above adopted technical scheme:
For improving a medicament for synaptic function, the effective ingredient of described medicament is two (3)-tacrine, and the molecular formula of described two (3)-tacrine is C
29h
32n
4, its molecular weight is 436, and structural formula is:
。
Above-mentioned medicament is oral formulations or injection.
Above-mentioned medicament is tablet or capsule.
Above-mentioned medicament is aqueous injection or lyophilized injectable powder.
Above-mentioned medicament is as the alleviation Memory Impairment of Alzheimer and the drug use of cerebral damage.
Above-mentioned medicament is as the drug use improving the damage of Alzheimer synaptic function.
Medicament for improving synaptic function of the present invention, its effective ingredient is two (3)-tacrine, and it can improve synaptic function, increase synapse number, regulate synaptic plasticity, slow down the Memory Impairment of Alzheimer, slow down the cognitive dysfunction of Alzheimer.
Accompanying drawing explanation
Fig. 1 is that two (3)-tacrine process is to the protective effect of synapse function damage;
Fig. 2 is the protective effect that two (3)-tacrine process damages neuronal synaptic plasticity;
Fig. 3 is for two (3)-tacrine process is to the improvement result of the learning memory injury that amyloid-beta causes;
Fig. 4 is for two (3)-tacrine process is to the improvement result of the cerebral damage that amyloid-beta causes.
Detailed description of the invention
Below in conjunction with accompanying drawing embodiment, the present invention is described in further detail.
Of the present invention is a kind of medicament for improving synaptic function, and the effective ingredient of described medicament is two (3)-tacrine, and the molecular formula of described two (3)-tacrine is C
29h
32n
4, its molecular weight is 436, and structural formula is:
。
Two (3)-tacrine involved in the present invention and pharmaceutically useful salt thereof as raw material, can add pharmaceutically acceptable adjuvant and make oral formulations or injection; Suitable excipient can be added and make tablet or capsule, also can be mixed with aqueous injection or lyophilized injectable powder by its pharmaceutical salts.
Described medicament both can as the alleviation Memory Impairment of Alzheimer and the drug use of cerebral damage, again can as the drug use improving the damage of Alzheimer synaptic function.
Medicament for improving synaptic function of the present invention, its effective ingredient is two (3)-tacrine, and it can improve synaptic function: increase synapse number, regulates synaptic plasticity, slow down the Memory Impairment of Alzheimer, slow down the cognitive dysfunction of Alzheimer.
In following experiment, n is sample size, and P is probability, and P<0.05 indicates statistical significance.
1, laboratory animal:
Experiment adopts male ICR mouse, body weight 25 to 30g.Be divided into following several groups: Normal group, amyloid beta (A β) group, two (3)-tacrine (1.5 μm of ol/kg, 2 μm of ol/kg, the 2.5 μm of ol/kg) group of variable concentrations, A β and two (the 3)-tacrine administration group of variable concentrations, often organize 8.The test period of every day is fixed on 9:00AM-4:30PM.Experimental implementation follows NIH laboratory animal guide for use (NIH publications No.80-23,1996).
2, administration:
To injected in mice chloral hydrate, dosage 10mg/kg, is anaesthetized, and is fixed on stereotaxic instrument, cut head hair, expose skin, with the mid point of two lines for starting point, the mid point of two ear trailing edge lines is that terminal cuts off one otch, and exposing bregma, take bregma as zero, retreat 1.5 mm, left and right is other opens 1.2mm, and these two points are the coordinate of Hippocampal CA 1, boring, inserting needle 1.5mm, injection oligomer A β 1 ug, skin suture, sterilization, puts back in cage and raises.
After 24 h set up by model, intraperitoneal injection of saline or two (the 3)-tacrine (1.5 μm of ol/kg, 2 μm of ol/kg, 2.5 μm of ol/kg) of variable concentrations, once a day, continuous 21 days.
3, behavioristics's inspection (water maze laboratory) of learning and memory ability:
Adopt water maze laboratory test mouse memory ability, water maze is made up of round pool, safety island (platform) and recording system three part.Water maze pool diameter 180 cm that this experiment adopts, high 50 cm, the depth of water 30 cm, water temperature (22 ± 1) DEG C.Pond is divided into four quadrants with 4 equidistant points by pool wall, and diameter is that the circular non-opaque platform of 10 cm is placed in third quadrant, is hidden in cm place, underwater 2.Video camera is placed in pond overcentre 200 cm place and is connected with computer.The support of peripheral pool posts the different mark of painted color, as labyrinth ectosuggestion.Black is dyed with the water in food coloring pond.Keep environment quiet during training, object of reference immobilizes, and avoids direct light, adopts reflected light.Pond water is changed in order to avoid water is putrid and deteriorated every day.Train six days altogether, the first five sky is constant-bearing navigation experiment (place navigation test), train four every day, respectively mice is put into from four different quadrantal points successively gently towards pool wall at every turn, test index is incubation period and swimming rate, each testing time is 90s, does not find the rat of platform guide bar to be guided on platform yet, stop 15 s in 90 s.Last day is space exploration experiment (spatial probe test), and withdrawn from by platform, experiment mice is faced the wall and meditated and put into water by an optional place of entry, and test once, records its swimming time at each quadrant and platform traversing times.
4, cognitive function inspection (new object identification):
This experiment is main at 60 × 60 × 15cm
3spacious case in carry out, experiment is divided into 3 days, tests and starts after animal injectable drug or normal saline 1 h, and after every zoopery terminates, cleans experimental assembly, prevent the identification of abnormal smells from the patient to animal from causing interference with the ethanol of 10%.First day, is placed on free movable adaptation 5 min in spacious case by animal.Second day, two identical objects are placed in symmetrical position near adjacent angle in spacious case, and animal head direction, apart from tank wall 10 cm, is deviated from object by object, between two articles, center line is put into, record its time to two object enquiry learnings in 5 min.Animal is defined as animal nose is initiatively less than 2 cm close to the distance of object to probing into of object, if animal squats, motionless on object or total Inquiry Learning time is less than 3s, then reject.3rd day, one of them object is changed into color and the diverse new object of shape, continues to allow animal explore 5 min, and record new object and past heritage body respectively probe into the time, be recorded as Tn and Tf respectively.And calculate the discrimination index (descrimination index) of animal to new object, i.e. Tn/ (Tn+Tf) × 100.In training period, the discrimination index of animal to object is close, and animal is to the discrimination index of new object generally higher than 50%, and discrimination index higher explanation ability of learning and memory is stronger, otherwise poorer.
5, number of synapses visual inspection checking method:
The hippocampal tissue of getting newborn rat does primary neuronal culture.Newborn rat is separated Hippocampus, puts into trypsin solution, and the DMEM culture medium added after 37 DEG C of incubators digest 12 minutes containing 10% serum stops digestion.Be inoculated in batch cultur ware after piping and druming gently and cultivate in cell culture incubator in 37 DEG C.Inoculate and entirely change liquid after 3 hours, after 24 hours, Neurobasal culture medium changes liquid, and within the 5th day, adding final concentration is that the cytosine arabinoside of 5 μMs is to suppress glial growth.Hippocampal neuron In vitro culture, to the 5th day, carries out transfection with marking cytoskeleton with GFP-actin and F-GFP plasmid.At DIV14, model group gives neuron 500nM amyloid-beta and hatches 3h, and two (3)-tacrine processed group gives two (the 3)-tacrine of variable concentrations simultaneously and hatches 5h.
6, synaptic function detection method
Insert dentate gyrus intermediate layer with bipolar metal electrode as stimulating electrode, with glass microelectrode record field excitatory postsynaptic potential (fEPSP), frequency is 0.033 Hz, and intensity is cause maximum fEPSP intensity 1/3.Whether observe fEPSP to stablize, stablize after 15 min, then carry out high frequency stimulation (high frequency stimulation, HFS), 200 Hz until it, 8 strings, often string 8 pulses, intensity is cause maximum reaction 75%.Again giving testing stimulus (test stimulation, TS) afterwards immediately, observe fEPSP amplitude, as increased by more than 20%, continuing 1 more than h, be considered as LTP and form index.0.5 μM of amyloid-beta, B3C (0.1 μM, 0.3 μM, 0.5 μM, 1 μM) is used to process respectively.A β 42 45 min before HFS start to hatch altogether with brain sheet.B3C 1 h and brain sheet before HFS are hatched altogether.The Picrotoxin (picrotoxin) adding 100 μMs in perfusate blocks GABA
areceptor-mediated depression effect.
Above-mentioned B3C i.e. two (3)-tacrine.
7, statistical analysis process
The data of this part all represent with the form of mean ± SEM (mean ± standard error).The variance analysis (one-way ANOVA) of the multilevel design quantitative data of data single factor test.P < 0.05 is decided to be significant difference statistical significance.
Experimental result:
One, the neuron dendritic spine density that two (3)-tacrine process reversing B-amyloid causes loses (as shown in Figure 1):
In Fig. 1, (A-E) the neuronic cell imaging of each experimental group is represented respectively: matched group (A), amyloid-beta processed group (B), amyloid-beta+bis-(3)-tacrine (0.1 μM) group (C), amyloid-beta+bis-(3)-tacrine (0.5 μM) group, (D) amyloid-beta+bis-(3)-tacrine (1 μM) group (E).(F) the dendritic spine density ratio of each experimental group comparatively.All data mean ± standard error represents.
Compared with Normal group (A), amyloid-beta processed group (B) obviously reduces the density of dendritic spine, shows that amyloid-beta causes synapse early development to damage.Compared with amyloid-beta processed group (B), neuron dendritic spine density in amyloid-beta+bis-(3)-tacrine (0.1 μM) group (C) is without obvious increase, difference not statistically signigicant (P>0.05, Fig. 1), after showing 0.1 μM of two (3)-tacrine pretreatment, the dendritic spine density of amyloid-beta induction is reduced without impact.Amyloid-beta+bis-(3)-tacrine (0.5 μM) group (D) significantly increases respectively with the dendritic spine density in amyloid-beta+bis-(3)-tacrine (1.0 μMs) group (E) compared with amyloid-beta processed group (B), difference has remarkable statistical significance (P<0.0001, Fig. 1), illustrate that two (the 3)-tacrine of 0.5 μM and 1.0 μMs can the dendron silk density of effective reversing B-amyloid minimizing.In addition, amyloid-beta+bis-(3)-tacrine (0.5 μM) group (D) and amyloid-beta+bis-(3)-tacrine (1.0 μMs) group (E) are respectively compared with amyloid-beta+bis-(3)-tacrine (0.1 μM) group (C), and difference all has remarkable statistical significance (P<0.0001).
Two, two (3)-tacrine protective effect (as shown in Figure 2) that neuronal synaptic plasticity is damaged:
At normal rat brain slice in vitro, the long term potentia￣tion (long term poteitiation, LTP) that HFS can induce nmda receptor to rely on.After HFS, the LTP test value of 60 minutes records is 150.11 ± 5.65% (n=6; Fig. 2 A).The amyloid-beta of 500 nM is selected in this experiment, adds make it perfusion when first 45 minutes of high frequency stimulation (High freqeuency stimulation, HFS).Compared with Normal group, amyloid-beta does not affect basic synapse transmission, but the generation of hippocampal dentate district LTP after obviously suppressing HFS, after HFS, the LTP test value of 60 minutes records is 112.54 ± 2.43% (n=6, P<0.001
vsmatched group; Fig. 2 A).In order to study the inhibiting impact of LTP that two (3)-tacrine is induced amyloid-beta, first we select 0.1 μM of two (3)-tacrine within first 15 minutes, to add at HFS, the amyloid-beta of 500 nM adds at HFS for first 45 minutes, our research finds that 0.1 μM of two (3)-tacrine does not affect LTP, he also can not reversing B-amyloid to the inhibitory action (Fig. 2 B) of LTP.And 0.5 μM of two (3)-tacrine independent role does not affect LTP, but two (3)-tacrine (0.5 μM)+amyloid-beta group can completely reversing B-amyloid induction LTP suppress (145.95 ± 7.73%, n=5, P<0.001; Fig. 2 C).Two (3)-tacrine (1 μM) independent roles of higher concentration also can cause LTP to strengthen, and (n=5, compares P<0.05 with matched group; Fig. 2 D)
Three, the process of two (3)-tacrine improves mice Spatial learning and memory damage (as shown in Figure 3) that amyloid-beta causes:
In Fig. 3, "
*" represent P < 0.001, represent that difference has remarkable statistical significance compared with matched group."
#" represent P <0.05, "
##" representing P <0.01, both represent that difference has statistical significance compared with amyloid-beta processed group respectively.
Training period, respectively organizes laboratory animal escape latency there were significant differences (P<0.01; Fig. 3 A).Animal is after 16 training, compared with matched group, the animal escape latency of hippocampus injection amyloid-beta obviously extends (P<0.001), animal needs the time more grown to find stealthy platform, illustrates that amyloid-beta can the Spatial memory impairment of induced animal.And compared with amyloid-beta processed group, the escape latency that amyloid-beta+bis-(3)-tacrine (1.5 μm of ol/kg) is organized does not shorten, and the escape latency that amyloid-beta+bis-(3)-tacrine (2.0 μm of ol/kg) group and amyloid-beta+bis-(3)-tacrine (2.5 μm of ol/kg) are organized all significantly shortens, illustrate that two (3)-tacrine improves the damage of amyloid-beta to animal Spatial memory ability in the mode of concentration dependant.
In experiment probe phase, found by statistical analysis, the difference of the distance explored at target quadrant of each group of laboratory animal when platform traversing times has statistical significance (Fig. 3 B, Fig. 3 C), result shows, compared with matched group, the distance ratio that amyloid-beta processed group is explored at target quadrant is less.Compared with amyloid-beta processed group, find after two (3)-tacrine process of variable concentrations, the distance ratio that amyloid-beta+bis-(3)-tacrine (2.5 μm of ol/kg) group is explored at target quadrant significantly improves (P<0.01).Platform traversing times index shows, and compared with matched group, amyloid-beta processed group traversing times significantly reduces (P<0.05); Compared with amyloid-beta processed group, the spanning platform number of times that amyloid-beta+bis-(3)-tacrine (2.5 μm of ol/kg) is organized significantly increases (P<0.05).And respectively organize the no significant difference (Fig. 3 D) of laboratory animal average swim speed.
Four, the process of two (3)-tacrine improves amyloid-beta and causes cerebral damage (as shown in Figure 4):
In Fig. 4, "
*" represent P < 0.001, represent that difference has remarkable statistical significance compared with matched group."
##" represent P <0.01, represent that difference has remarkable statistical significance compared with amyloid-beta 1-42 processed group.
The time scale of new and old object is explored by new object identification experiment test mice.Resolving index=recognition object 1 time/(1 time of recognition object+recognition object 2 time), Fig. 4 A representative to be familiar with in the phase mice to the resolving index of same object (object 1 and 2 is two identical objects) with always explore the time, respectively organize the time that mice explores two same object add up being familiar with the phase, the resolving index that discovery mice explores two same object is substantially equal, compares there was no significant difference (Fig. 4 A) between each group.Fig. 4 part B represents testing period mice to the resolving index of new object (object 1 changes new object not contacted before into, and object 2 is constant).In the testing period, discovery compared with matched group, the discrimination index of amyloid-beta group to new object significantly reduces (P<0.001), and display A β 1-42 can cause animal cognition ability to decline.Contrast with amyloid-beta processed group, two (3)-tacrine (2.5 μm of ol/kg)+amyloid-beta treated animal can significantly improve the discrimination index to new object, illustrates that two (3)-tacrine of this concentration can improve the cognitive dysfunction of amyloid-beta induction.
Conclusion: two (3)-tacrine effectively can improve Memory Impairment and the cerebral damage of Alzheimer, and has protective effect to the neuronal damage of Alzheimer.Therefore, the present invention may be used for Alzheimer for the medicament improving synaptic function, and it has significant clinical meaning and using value.
Most preferred embodiment of the present invention is illustrated, and the various change made by those of ordinary skill in the art or remodeling all can not depart from the scope of the present invention.
Claims (6)
1. for improving a medicament for synaptic function, it is characterized in that: the effective ingredient of described medicament is two (3)-tacrine, and the molecular formula of described two (3)-tacrine is C
29h
32n
4, its molecular weight is 436, and structural formula is:
。
2. a kind of medicament for improving synaptic function according to claim 1, is characterized in that: described medicament is oral formulations or injection.
3. a kind of medicament for improving synaptic function according to claim 2, is characterized in that: described medicament is tablet or capsule.
4. a kind of medicament for improving synaptic function according to claim 2, is characterized in that: described medicament is aqueous injection or lyophilized injectable powder.
5. a kind of medicament for improving synaptic function according to claim 1, is characterized in that: described medicament is as the alleviation Memory Impairment of Alzheimer and the drug use of cerebral damage.
6. a kind of medicament for improving synaptic function according to claim 1, is characterized in that: described medicament is as the drug use improving the damage of Alzheimer synaptic function.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101658522A (en) * | 2008-08-26 | 2010-03-03 | 普尔药物科技开发（深圳）有限公司 | Application of tacrine short-chain dimer in preparation of medicament for treating neurodegenerative diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101658522A (en) * | 2008-08-26 | 2010-03-03 | 普尔药物科技开发（深圳）有限公司 | Application of tacrine short-chain dimer in preparation of medicament for treating neurodegenerative diseases |
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Application publication date: 20150401 |