CN103816143A - Medicine for preventing and treating senile dementia - Google Patents
Medicine for preventing and treating senile dementia Download PDFInfo
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- CN103816143A CN103816143A CN201410082815.9A CN201410082815A CN103816143A CN 103816143 A CN103816143 A CN 103816143A CN 201410082815 A CN201410082815 A CN 201410082815A CN 103816143 A CN103816143 A CN 103816143A
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Abstract
The invention provides a medicine for preventing and treating senile dementia. The medicine is acetyl-L-carnitine (ALC). The invention shows that ALC can relieve anomalous excessive phosphatation in brain mantle and hippocampus skeleton albumen tau of mice with senile dementia, can reduce starch albumen sediment, and can improve animal learning and dysmnesia; ALC can be used for preventing and treating senile dementia.
Description
Technical field
Invention belongs to field of medicaments, relates to the medicine of preventing and treating senile dementia, and the medicine that is specifically related to a kind of easy absorption and sees through blood brain barrier is in the new application preventing and treating in alzheimer disease.
Background technology
Alzheimer disease (Alzheimer Disease, AD) is a kind of common neurodegenerative diseases, and its cardinal symptom shows as hypomnesis, low and the bradyphrenia of cognitive competence, and carrying out property increases the weight of, finally can't take care of oneself and death, general 8～10 years of the course of disease.Along with the quickening of social senilization's process, the number of patients of AD sharply rises, and has become and has threatened the particularly able-bodied serious disease of population at advanced age of old-age group, and brought serious society, economy and domestic problem.
The main brain pathological change of patient AD is to form a large amount of neurofibrillary tangleses (neurofibrillary tangles, NFTs) and in a large number senile plaque, its molecular marker are respectively Protein tau and the amyloid-beta (A-beta) of Abnormal Phosphorylation.Foreign scholar has adopted transgenic technology, successfully copies the senile plaque sample pathological changes of amyloid-beta formation of deposits mice, thereby makes following AD treatment become possibility using reducing A-beta deposition as the target of pharmaceutical intervention.The quantity of NFTs and AD clinical dementia degree positive correlation.Therefore, intervention NFTs is particularly important to the control of AD.Since finding that the main component of NFTs has been that since Protein tau abnormal, Hyperphosphorylationof is assembled the Double helix silk forming, Chinese scholars is generally generally acknowledged, abnormal, the Hyperphosphorylationof of skelemin tau are the committed steps that NFTs forms.The gathering of Hyperphosphorylationof Protein tau not only exists with the form of tangling, and it is also the main component of the malnutrition projection in neuropil fibril and senile plaque.
Still not for specific treatment medicine and the method for alzheimer disease pathology feature, the conventional senile dementia outbreak medicine that slows down has: (1) improves choline neurotransmission medicine: a main cause of senile dementia is that choline deficiency causes amnesia at present.Therefore acetylcholinesterase (AchE) inhibitor acts on senile dementia treatment aspect by enhancing cholinergic and has brought into play important function; (2) improve the medicine of cerebral blood circulation and brain cell metabolism: this type of medicine can expansion of cerebral vascular to improve the dysbolismus such as the sugar, albumen, nucleic acid, lipid of old dementia patients; (3) calcium antagonist: this type of medicine is easy to by blood brain barrier, selectivity expansion of cerebral vascular, thus improve memory and cognition function; (4) hormone medicine: the symptom of mainly alleviating female patient.But these medicines only dementia symptom of centering late stage of Alzheimer disease to some extent slightly improve or delay dull-witted progress.Therefore research and develop the new medicine for alzheimer disease pathology feature, become global expectation.
Acetyl-L-carnitine (ALC), as a kind of important food enrichment, is widely applied and comprises in many aspects: infant food, diet food and arsenic etc.The ability of infant synthesis of acetyl L-carnitine only has adult's 15%, on market take soybean protein as basic dispensed food for baby with take corn in main ablactational food, almost there is no carnitine.At present existing 22 countries add acetyl-L-carnitine in baby milk powder.A large amount of research datas also prove in brain and nervous tissue, there is the acetyl-L-carnitine (ALC) of high concentration, and it can pass blood brain barrier, provides brain cell enough energy.Along with old and feeble association, its content also reduces significantly.
Summary of the invention
Task of the present invention is to provide a kind of for prevention and treatment alzheimer disease medicine.
For realizing task of the present invention, technical scheme provided by the invention is:
Provided by the invention is acetyl-L-carnitine for the medicine preventing and treat alzheimer disease medicine, and the left-handed meat poisoning of acetyl is cried out can be for the preparation of the medicine of prevention and treatment alzheimer disease.
The present invention has disclosed acetyl-L-carnitine (ALC) and can extenuate the abnormal Hyperphosphorylationof of alzheimer disease rat cerebral cortex and hippocampus skelemin tau, can reduce amyloid beta deposition and improve animal learning, dysmnesia.Acetyl-L-carnitine (ALC) can be used for prevention and the treatment of alzheimer disease.
Experimental data:
The present invention, by rat injection acetyl-L-carnitine (ALC), finds that it can improve the senile plaque of AD sample animal model, Protein tau Hyperphosphorylationof and study, dysmnesia.
Concrete operation step is as follows:
1. experimental subject
Male wistar rat (Tongji Medical College, Huazhong Science and Technology Univ.'s laboratory animal experimental center provides), SPF level, 250～320 grams of body weight, 45, conventional environment is raised.Be divided at random three groups: 1. normal group (nor); 2. modeling group (con); 3. treatment group (ALC); Every group 15.
2. experimental model preparation
1. normal group: do not process.
2. modeling group: give homocysteine (homocystin, Hcy) by tail vein injection, once a day, continue 14 days, dosage is 400 μ g/kg, builds presenile dementia animal model.
3. treatment group: inject homocysteine (homocystin, Hcy) by rat tail vein, dosage is 400 μ g/kg, every day 1 time, continues 14 days; Then rat oral gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and profit amount is 50mg/kg.
3. research method
The ability of learning and memory in rats: Morris water maze training and test
The demonstration of Hippocampus phosphorylation tau positive cell: immunoblotting
The content of Hippocampus phosphorylation tau: SABC
The toxic Segment A β content of Hippocampus: enzyme linked immunosorbent assay
4. experimental result
* P<0.05, with normal group comparison
* P<0.01, with normal group comparison
# P<0.05, with the comparison of modeling group
## P<0.01, with the comparison of modeling group
(1) Morris water maze training and test result: see Fig. 1.There is obvious learning memory disorder (Fig. 1) in modeling group (con), statistical result shows obviously to extend the incubation period of water maze test, the time lengthening (Fig. 1) of study compared with normal group.Modeling group obviously reduces (Fig. 2) at the number of times of the target quadrant time of staying and distance and spanning platform, and going down of memory ability is described, modeling success.Treatment group (ALC) time incubation period compared with modeling group (con) shortens, and target quadrant stops number of times and spanning platform number of times increases, and its learning and memory ability has all obtained good improvement.
(2) Tau protein phosphorylation group result: see Fig. 3.Normally (nor) group hippocampal neuron is arranged fine and close, layering is clear, in good order, modeling group (con) is positive painted minimizing not only, and hippocampal neuron arrangement is mixed and disorderly, acetyl-L-carnitine (ALC) processed group positive cell is arranged neat compared with modeling group (con).The tau site serine 214 (pS214) of three phosphorylations in modeling group (con) brain, serine 262 (pS262), the painted obvious enhancing of serine 396 (pS396) cell, the phosphorylation of tau strengthens.After acetyl-L-carnitine (ALC) is processed, the Hyperphosphorylationof level in these sites for the treatment of group (ALC) reduces.
(3) Tau phosphorylation immunoblotting result: see Fig. 4.Compare with normal group (nor), in the cerebral hippocampus of modeling group (con) rat, Protein tau is at serine 198/199/202, threonine 205, serine 212, serine 214, serine 262, serine 396, serine 404 sites, phosphorylation level obviously increases, after acetyl-L-carnitine (ALC) is processed, tau phosphorylation level obviously declines.
(4) euzymelinked immunosorbent assay (ELISA) detects rat layer A β content: enzyme linked immunosorbent assay (ELISA) detects to be found, compare with normal group (nor), in the cerebral cortex of modeling group (con) group rat, A β content raises, after acetyl-L-carnitine (ALC) is processed, A β content obviously declines.
5. conclusion and usage suggestion:
Above result demonstration gives homocysteine (homocystin, Hcy) in the mouse water maze training of tail vein injection and testing process, increase the incubation period of platform, spanning platform number of times obviously reduces the learning and memory ability damage of explanation rat, after detecting presenile dementia index of correlation Protein tau phosphorylation and A β content, find, the phosphorylation level of Protein tau significantly rises, A β content is also increased significantly, the change of the correlated characteristic of these presenile dementia, illustrates rat presenile dementia modeling success.
Compare with modeling group, to after processing with acetyl-L-carnitine (ALC), detect mouse water maze behavioristics, its learning and memory ability is effectively improved; Simultaneously, presenile dementia index of correlation Protein tau phosphorylation and A β content and modeling group more also have obvious reduction, illustrate that acetyl-L-carnitine (ALC) can extenuate the abnormal Hyperphosphorylationof of alzheimer disease rat cerebral cortex and hippocampus skelemin tau, can reduce amyloid beta deposition and improve animal learning, dysmnesia.Acetyl-L-carnitine (ALC) can be used for prevention and the treatment of alzheimer disease.
" pharmacological experimental methodology, " with reference to professor Xu Shuyun chief editor has a table in its appendix, listed between humans and animals by the dose,equivalent ratio of body surface area conversion.We can calculate rat dosage and people's ratio:
Rat Shape Coefficient: 0.09 standard body weight: 200g=0.2kg
Conversion factor=(Shape Coefficient rat * W rat 2/3)/(Shape Coefficient people * W people 2/3) of rat
=(0.09*0.22/3)/0.1*702/3)*70X/0.4
=0.018
After theory converts, we recommend people's using dosage is clinically 1mg/d, and treatment stage recommend adoption cycle therapy is taken 21 days continuously, and stopping using 7 days is a course for the treatment of; Take prevention and health care as main, the dosage that can reduce by half is to 0.5mg/d, long-term taking.
Accompanying drawing explanation
Fig. 1 is water maze test mouse device for exercising swim trajectory diagram and statistical result incubation period.In figure: * * p<0.01 and normal group comparison; ##p<0.01 and the comparison of modeling group.Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
Male wistar rat is divided into three groups of 1. normal group at random: do not process; 2. modeling group: homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model, once a day, continues 14 days, and dosage is 400 μ g/kg; 3. treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg; Carry out respectively Morris water maze training and test.
The experiment Morris water maze test macro that adopts comprises round pool diameter 120cm, high 60cm; Cylindrical lucite platform diameter 10cm, high 40cm.The high about 45cm of the water surface in pond, room temperature and water temperature all remain on 26 ± 2 ℃, and platform is positioned over the center of a certain quadrant, not the about 2cm in underwater.When training, rat is put down gently in water to pool wall from arbitrary quadrant 1/2 radian women's head-ornaments, detect its incubation period (being that rat plays the time of finding platform used from place of entry), path as the index of weighing learning and memory in rats and test result.Every rat is trained 4 times altogether at 4 quadrants every day, is limited to 60s while swimming at every turn, and person's system stops record automatically in 60s, not find platform, is designated as 60s incubation period, guides it to appear on the stage by tester, after rest 30s, trains next time.The first trained time is 6 days, in the 7th day, records rat and finds plateau required time, records rat and finds platform required incubation period.
Result shows with normal group compares modeling group rats'swimming track confusion; find required time incubation period of platform the longest; illustrate that rat learning capacity sustains damage; giving after acetyl-L-carnitine (ALC); treatment group rat is compared track with modeling group and again recovers simple; shorten incubation period, learning capacity be improved significantly.(* * P<0.01, with normal group comparison; ##P<0.01, with the comparison of modeling group)
Fig. 2 is water maze test mouse spanning platform number of times and time and distance statistics result.In figure: * p<0.05 and normal group comparison; * p<0.01 and normal group comparison; #p<0.05 and the comparison of modeling group; ##p<0.01 and the comparison of modeling group.Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
Morris water maze test macro was through training in 6 days, and how rat association is found after platform.Take a day off, remove platform, calculate rat in 3 minutes in the time of staying of target quadrant and analyze its traversing times in platform position, to evaluate its memory ability.
Result shows the time of modeling group rat spanning platform and apart from the shortest, least number of times, illustrates that the memory ability of modeling group mouse suffers damage, and forgets the position of platform; The time that treatment group rat is compared spanning platform with modeling group, spanning platform number of times is corresponding increase also with range recovery to normal consistent, and its memory ability is obviously recovered after acetyl-L-carnitine (ALC) giving.(* P<0.05, with normal group comparison; * P<0.01, with normal group comparison; #P<0.05, with the comparison of modeling group; ##P<0.01, with the comparison of modeling group)
Fig. 3 is three phosphorylation site pS396 of Protein tau in rat hippocampus, pS214, pS262 phosphorylation ImmunohistochemistryResults Results.
Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
In alzheimer's disease patient's brain, be often accompanied by the Hyperphosphorylationof of Tau, can reflect the difference of normal mouse and alzheimer's disease model mouse by the phosphorylation situation that detects Protein tau phosphorylation site.
Male wistar rat is divided into three groups of 1. normal group at random: do not process; 2. modeling group: homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; 3. treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.After water maze training completes, carry out the fixing cerebral tissue of heart perfusion by 4% paraformaldehyde phosphate buffered saline(PBS) (PB), after cerebral tissue to be removed again in above-mentioned fixative after fixing 6h, can do vibration section.SABC adopts ABC method, benzidine ammonia (diaminobezidin, DAB) colour developing.
Normally (nor) group hippocampal neuron is arranged fine and close, layering is clear, in good order, modeling group (con) is positive painted minimizing not only, and hippocampal neuron arrangement is mixed and disorderly, acetyl-L-carnitine (ALC) processed group positive cell is arranged neat compared with modeling group (con).The tau site serine 214 (pS214) of three phosphorylations in modeling group (con) brain, serine 262 (pS262), the painted obvious enhancing of serine 396 (pS396) cell, the phosphorylation of tau strengthens.After acetyl-L-carnitine (ALC) is processed, the Hyperphosphorylationof level in these sites for the treatment of group (ALC) reduces.
Fig. 4 is Protein tau phosphorylation site phosphorylation level immunoblotting result in rat hippocampus.Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
After water maze training completes, cervical vertebra dislocation sacrificed by decapitation rat, take out rapidly brain cerebral tissue and be placed in 0-4 ℃ of 0.05M Tris buffer salt solution (TB, pH7.0) in, sharp separation bilateral hippocampus, makes 10% albumen homogenate, at 1000rmp centrifugal 5 minutes, get supernatant, for subsequent use after mensuration protein content.
The phosphorylation level that detects respectively Protein tau different loci, comprises pS396, pS404, pS212, pS205; Detect the level of non-phosphorylating site tau1 and the level variation of total tau R134d.DM1A is internal reference band, proves the concordance of albumen applied sample amount.By with total tauR134d comparison, modeling group non-phosphorylating site taul phosphorylation level obviously reduces, phosphorylation site pS396, pS404, pS212, pS205 phosphorylation level obviously increases, there is Hyperphosphorylationof in tau; After treatment group administration acetyl-L-carnitine (ALC), the Hyperphosphorylationof of tau is relaxed, and recovers level close to normal group.
Fig. 5 euzymelinked immunosorbent assay (ELISA) is measured rat layer A β level result.In figure: * * p<0.01 and normal group comparison; ##p<0.01 and the comparison of modeling group.Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
The same immunoblotting of sample preparation, is coated with post rinse with the antibody of A β 1-40 or A β 1-42, adds sample, with tetramethyl benzidine (3,3 ', 5,5'-tetramethylbenzidine, TMB) colour developing, and on spectrophotometer wavelength 450nm reading.
Another pathological characteristics of alzheimer's disease patient is the gathering of A β in brain, and the generation of A β is due to the shearing mistake of its precursor APP is caused, and can produce two kinds and shear Segment A β 1-40 and A β 1-42.Wherein, A β 1-42 has higher toxic action.Experimental result shows, the release showed increased of A β 1-42 fragment in modeling group mouse, after acetyl-L-carnitine (ALC) treatment, treatment group A β 1-42 gets back to normal group A β 1-42 emission levels, further proves that acetyl-L-carnitine (ALC) can improve the pathological characters that alzheimer's disease model mouse occurs.(* * P<0.01, with normal group comparison; ##P<0.01, with the comparison of modeling group)
Fig. 6 is that silver dyes Cortical Neurons of Rat result.Normal group, is left intact; Modeling group, homocysteine (homocystin, Hcy) tail vein injection builds alzheimer disease ageing mouse model; Treatment group: alzheimer disease varying model mouse gavage gives acetyl-L-carnitine (ALC), once a day, continues 14 days, and dosage is 50mg/kg.
The same Immunohistochemical Method of sample preparation, 2%-4% silver nitrate is hatched 30min, with 10 & formaldehyde reduction colour developings.
Silver dyes result and shows, compares with normal group, and silver-colored painted enhancing appears significantly having a liking in modeling group Cortical Neurons of Rat cell space, and prompting has protein abnormal deposition, neuronic regression; And gavage is processed after acetyl-L-carnitine (ALC), treatment group is had a liking for painted the weakening of silver, and neuronal degeneration reduces.
Claims (3)
1. acetyl-L-carnitine is in the application for the preparation of in prevention and treatment alzheimer disease medicine.
2. for prevention and a treatment alzheimer disease medicine, it is characterized in that containing active component acetyl-L-carnitine.
3. for preventing and treat a pharmaceutical preparation for alzheimer disease, it is characterized in that, it is made up of the acetyl-L-carnitine as active component and pharmaceutically acceptable carrier and/or additive.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114617865A (en) * | 2022-03-14 | 2022-06-14 | 北京脑血管病产业技术创新战略联盟 | Application of acetyl L-carnitine in preparing medicine for preventing or treating venous outflow obstruction diseases |
-
2014
- 2014-03-07 CN CN201410082815.9A patent/CN103816143A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| G.A.LIVINGSTON ET AL.: "ACETYL-L-CARNITINE IN DEMENTIA", 《INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY》 * |
| 王涛等: "乙酰化左旋肉碱与神经系统疾病", 《河北医药》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114617865A (en) * | 2022-03-14 | 2022-06-14 | 北京脑血管病产业技术创新战略联盟 | Application of acetyl L-carnitine in preparing medicine for preventing or treating venous outflow obstruction diseases |
| CN114617865B (en) * | 2022-03-14 | 2024-02-13 | 北京脑血管病产业技术创新战略联盟 | Use of acetyl l-carnitine for the preparation of a medicament for the prevention or treatment of venous outflow disorders |
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