CN103417547B - Applications of medicine prepared from ceftriaxone and used for curing and/or preventing dementia caused by Parkinson's disease - Google Patents
Applications of medicine prepared from ceftriaxone and used for curing and/or preventing dementia caused by Parkinson's disease Download PDFInfo
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Abstract
The invention discloses applications of medicine prepared from ceftriaxone and used for curing and/or preventing dementia caused by Parkinson's disease.
Description
Technical field
The invention relates to use ceftriaxone (ceftriaxone) treat and/or prevent Parkinson's disease lose intelligence (Parkinson ' s disease dementia, PDD), the dosage range of this ceftriaxone drops on from about 1.5mg/kg/ days in about 35mg/kg/ days.
Background technology
Dementia can be divided into 2 large types below according to the affected position of brain: (1) cortex dementia (cortical dementia): such as, Alzheimer (Alzheimer ' s disease, AD), Lewy body loses intelligence (dementia with Lewy body, and volume temporal lobe dementia (Frontal-temporal dementia, FTD) etc. DLB); And dementia (subcortical dementia) under (2) cortex: such as, Parkinson's disease mistake intelligence (Parkinson ' s disease dementia, and Heng Tingdunshi chorea (Huntington ' s disease, HD) etc. PDD).
Parkinson's disease (Parkinson ' s disease, PD) be a kind of common neurodegenerative disease (neurodegenerative disease), its clinical symptoms comprises nature static and trembles (resting tremor), stiff (rigidity), bradykinesia (bradykinesia) and body posture shakiness (postural instability), and its pathomechanism may with at black substance body dense area (substantia nigra pars compacta, the degeneration of the dopamine neuron (dopaminergic neuron) SNc) and the generation of Lewy body (Lewy body) relevant.With the sufferer of Parkinson's disease except there will be main motor symptoms (cardinal motor symptoms), there is the sufferer of about 25-50% also can develop cerebral damage (impairments of cognitive function) and cause dementia (dementia) (namely Parkinson's disease loses intelligence (Parkinson ' s disease dementia, PDD)).The damage that cerebral damage that the sufferer of intelligence has comprises attention (attention), working memory (working memory), n-back test (executive function), architectural competence (constructional abilities) and visual space function (visuospatial function) is lost with Parkinson's disease.
The pattern of the difference, particularly cerebral damage of sufferer on neuropsychological (neuropsychological) of intelligence is lost in existing many research and inquirement with Alzheimer or Parkinson's disease.Such as, the initial loss of memory (primacy of memory loss) is the classical symptom of Alzheimer, but is not the classical symptom that Parkinson's disease loses intelligence.And attention, motivation (motivation) and access and the interference (disturbance) of operative knowledge (accessing and manipulating knowledge) and psychomotor slow (psychomotor slowing) are all classical symptom (the Song I.U.et al. (2008) that Parkinson's disease loses intelligence, Eur.Neurol., 59:49-54).Separately there is reported in literature: compare down with the sufferer with Alzheimer, instrumental function (instrumental functions) in the sufferer losing intelligence with Parkinson's disease, the damage of (such as language and utilization (praxis)) is lighter, and the damage of language fluency (verbal fluency), obstacle and the hallucination (hallucination) of visual space function (such as visual perception (visual perception)) are then comparatively serious, and common have personality changes and melancholic features (depressive symptom) (Emre M. (2003), Lancet Neurology, 2:229-237).
The medicine being often used to treat Parkinson's disease mistake intelligence at present is clinically that (trade name is Rivastigmine (rivastigmine)
but Rivastigmine can only treat Parkinson's disease mistake intelligence that is slight or moderate, and the deterioration of Parkinson's disease symptom (particularly trembling) may be caused.On the other hand, often be used to the levodopa (Levodopa of the motor symptoms improving Parkinson's disease at present clinically, L-dopa) therapeutic effect on cerebral damage is quite limited (Emre M. (2003), with above-mentioned) also.Therefore, current the world of medicine has needs to go to develop effectively to treat Parkinson's disease mistake intelligence and the medicine that can not produce un-desired side effect.
Ceftriaxone (ceftriaxone) is a kind of beta-Lactam antibiotic (β-lactam antibiotic) of wide acting type, is often used to the infection for the treatment of Gram-positive and gram negative bacteria (Gram-positive and Gram-negative bacteria) clinically.In recent years, have about utilizing ceftriaxone to start to receive publicity to treat neurodegenerative disease (such as Parkinson's disease and dementia).Such as, Hong Kong Baptist University (Hong Kong Baptist University) Leung Cheuk Hung in 2007 show in thesis for the doctorate (title: " Glutamate Antagonism as a Potential Treatment of Parkinson ' s Disease:A Study in a Rat Model "), Leung Cheuk Hung uses ceftriaxone to process the rat [6-hydroxydopamine (6-OHDA)-lesioned rat] (a kind of animal model of Parkinson's disease) of 6-OHDA-damage, and experimental result display: ceftriaxone is conducive to the improvement of motor symptoms and the neuroprotective (neuroprotection) of dopamine neuron.
US 2004/0191803 A1 discloses the method for cognitive function through damage of a kind for the treatment of in a kind of mammal, and it includes offers medicine necessarily treating the ceftriaxone of effective dose or its a kind of analog or derivant to the step of this mammal.This through damage cognitive function may with disease below or obstacle relevant: mild cognitive impairment (mild cognitive impairment, MCI), relevant with age cognitive deterioration (age related cognitive decline, ARCD), the loss of memory, aging (senility), dementia (such as, Lewy body loses intelligence, vascular dementia (vascular dementia), Alzheimer and the dementia relevant with HIV (HIV associated dementia)).Especially, in the embodiment of this application for a patent for invention, rat (aged-impaired (AI) rats) through Aging Damage is processed lasts 7 days with ceftriaxone (dosage is for 200mg/kg/ days), and experimental result display: ceftriaxone can improve the cognitive impairment of the rat through Aging Damage.
At Hota S.K.et al. (2008), Neurobiology of Learning and Memory, in 89:522-532, the people such as Hota S.K. use ceftriaxone to process the rat being exposed to hypobaric hypoxia (hypobaric hypoxia) for a long time, and experimental result display, ceftriaxone can improve the cognitive impairment caused by hypobaric hypoxia, and the oxidative stress (oxidative stress) be reduced in hippocampal gyrus (hippocampus) and reduce deterioration of neurons (neuronal degeneration) with Chromatin condensation (chromatin condensation).Therefore, ceftriaxone be expected can be used for treatment Alzheimer and with excitatory toxicity (excitotoxicity) related ischemic and the conditions associated with hypoxia patient's condition (ischemic and hypoxic conditions).
Known to applicant, not yet there are document or the Patent Case before the application's day once to disclose ceftriaxone at present and can be used to treatment Parkinson's disease mistake intelligence.After deliberation, applicant is surprised to find that the cognitive function (such as working memory and identification capability (recognition ability)) using and can improve the rat losing intelligence with Parkinson's disease in a dosage range ceftriaxone dropped in 10 to 200mg/kg/ sky.Applicant is inference accordingly: the ceftriaxone with a given dose scope is available for the Parkinson's disease treated and/or prevented in a human individual and loses intelligence.
Summary of the invention
So the invention provides and be a kind ofly used for the treatment of and/or prevent the Parkinson's disease of human individual to lose the pharmaceutical compositions of intelligence, it includes and drops on from about 1.5mg/kg/ days to the ceftriaxone in about 35mg/kg/ days in a dosage range.
The present invention also provides a kind of being used for the treatment of to have or the method with the human individual of Parkinson's disease mistake intelligence under a cloud, and it comprises this human individual dispensing to drop on from about 1.5mg/kg/ days to the ceftriaxone in about 35mg/kg/ days in a dosage range.
Accompanying drawing explanation
Come below in conjunction with drawings and Examples that the present invention is described in detail, so the present invention is in above-mentioned and other objects and feature, by with reference to following description, to examine attached claims and accompanying drawing with literary composition and become more obvious, wherein:
Fig. 1 is the axonometric chart in a T-shaped labyrinth;
Fig. 2 is the top view of open space case, is placed with object 41,42 and 43 in display open space case;
Fig. 3 is the top view of open space case, and display open space case is placed with object 41,42 and 5;
Fig. 4 is presented at the 10th day after MPTP-HCl injection, and each group rat is by the correct response rate measured by T-shaped maze test, and wherein " * * * " represents: when comparing with sham operated rats 1, p < 0.001; " # " represents: when comparing with pathology comparison group, p < 0.05; And " ## " represents: when comparing with pathology comparison group, p < 0.01;
Fig. 5 is presented at the 14th day after MPTP-HCl injection, each group of rat tested by article identification measured by object 43 and the percent value of exploration time of object 5, wherein " # " represents: the percent value when the exploration time with object 43 compares, p < 0.05; And " ### " represents: the percent value when the exploration time with object 43 compares, p < 0.001;
Fig. 6 is presented at the 15th day after MPTP-HCl injection, the black substance body dense area of each group of acquired rat by immunohistochemical staining by the density of activated microgliacyte recorded, wherein " * * * " represents: when comparing with sham operated rats 1, p < 0.001; And " ### " represents: when comparing with pathology comparison group, p < 0.001;
Fig. 7 is presented at the 15th day after MPTP-HCl injection, the hippocampal gyrus CA1 region of each group of acquired rat by Nissl's staining by the area percentage value of cone neurone recorded, wherein " * * * " represents: when comparing with sham operated rats 1, p < 0.001; And " ### " represents: when comparing with pathology comparison group, p < 0.001;
Fig. 8 is presented at the 10th day after MPTP-HCl injection, and each group rat is by the correct response rate measured by T-shaped maze test, and wherein " * * * " represents: when comparing with sham operated rats, p < 0.001; And " # " represents: when comparing with pathology comparison group, p < 0.05; And
Fig. 9 is presented at the 14th day after MPTP-HCl injection, each group of rat tested by article identification measured by object 43 and the percent value of exploration time of object 5, wherein " ## " represents: the percent value when the exploration time with object 43 compares, p < 0.01; And " ### " represents: the percent value when the exploration time with object 43 compares, p < 0.001.
Detailed description of the invention
Can be used for treating and/or preventing Parkinson's disease in exploitation to lose on the medicine of intelligence, applicant is surprised to find that: ceftriaxone has the industry application potential of this respect.So announcement ceftriaxone of the present invention prepares the purposes that a kind of Parkinson's disease being used for treating and/or preventing human individual loses the pharmaceuticals of intelligence.
Especially, applicant by experiment result confirms: to losing the rat dispensing of intelligence with Parkinson's disease to drop on the ceftriaxone in 10 to 200mg/kg/ sky in a dosage range, effectively can improve their cognitive function (such as movable memory and identification ability).And this dosage range being applicable to rat can refer to Shannon R.S.et al. (2007), FASEB J., the dosage based on body surface area (body surface area, BSA) described in 22:659-661 works as is changed the formula of (dose translation) and is scaled the dosage range being applicable to the mankind or other animals.
Therefore, the invention provides and be a kind ofly used for the treatment of and/or prevent the Parkinson's disease of human individual to lose the pharmaceutical compositions of intelligence, it includes and drops on from about 1.5mg/kg/ days to the ceftriaxone in about 35mg/kg/ days in a dosage range.
In a preferred embodiment of the present invention, the dosage range of this ceftriaxone drops on from about 1.62mg/kg/ days in about 32.4mg/kg/ days.In another preferred embodiment of the present invention, the dosage range of this ceftriaxone drops on from about 1.62mg/kg/ days in about 16.2mg/kg/ days.In another preferred embodiment again of the present invention, the dosage range of this ceftriaxone drops on from about 1.62mg/kg/ days in about 8.1mg/kg/ days.
As used herein, term " treatment (treating or treatment) " () means to reduce (reducing), alleviate (alleviating), improve (ameliorating), alleviate one or more clinical symptom (clinical sign) of (relieving) or control (controlling) a kind of disease (disease) or obstacle (disorder), and reduce (lowering), stop (stopping) or reverse the progress (progression of severity) of seriousness of (reversing) a kind of patient's condition (condition) of being treated or symptom (symptom).
As used herein, term " Parkinson's disease mistake intelligence (Parkinson ' s disease dementia, PDD) " a kind of dementia developed in the sufferer of Parkinson's disease is meant, the symptom of this dementia comprises following cerebral damage: attention (attention), working memory (working memory), impermanent memory (short-term memory), n-back test (executive function), identification ability (recognition ability), architectural competence (constructional abilities), the damage of visual space function (visuospatial function) and language fluency (verbal fluency).
According to the present invention, the technology that this pharmaceutical compositions can utilize those of ordinary skill in the art to know in detail and be manufactured into one and be suitable for the dosage form (dosage form) that parenteral genuine (parenterally) or oral (orally) offer medicine, this comprises, but be not limited to: injection product (injection) is (such as, aseptic aqueous solution (sterile aqueous solution) or dispersion liquid (dispersion)), aseptic powder (sterile powder), lozenge (tablet), tablet (troche), suck ingot (lozenge), pill (pill), capsule (capsule), Dispersible powders (dispersible powder) or fine grained (granule), solution, suspension (suspension), Emulsion (emulsion), syrup (syrup), elixir (elixir), underflow (slurry) and analog.
Can be selected from according to pharmaceutical compositions of the present invention and be offerd medicine by the parenteral approach (parenteral routes) in following formed group: peritoneal injection (intraperitoneal injection), intrapleural injection (intrapleural injection), intramuscular injection (intramuscular injection), intravenous injection (intravenous injection), intra-arterial injection (intraarterial injection), intra-articular injection (intraarticular injection), injection (intrasynovial injection) in synovial fluid, injection through vertebral canal (intrathecal injection), intracranial injection (intracranial injection) and sublingual administration (sublingual administration).
In a preferred embodiment of the present invention, this pharmaceutical compositions is made into be suitable for peritoneal injection by the dosage form of offeing medicine.
A kind of pharmaceutically acceptable supporting agent be widely used in medicine producing technology can be included further according to pharmaceutical compositions of the present invention.Such as, this pharmaceutically acceptable supporting agent can comprise one or more and be selected from by the reagent in following formed group: solvent (solvent), emulsifying agent (emulsifier), suspending agent (suspending agent), distintegrant (decomposer), binding agent (binding agent), excipient (excipient), tranquilizer (stabilizing agent), chelating agen (chelating agent), diluent (diluent), gellant (gelling agent), antiseptic (preservative), lubricant (lubricant), absorption delay agent (absorption delaying agent), liposome (liposome) and analog.About these reagent select and quantity be drop on be familiar with technique personage Specialized Quality and routine technology category in.
According to the present invention, this pharmaceutically acceptable supporting agent includes and is a kind ofly selected from by the solvent in following formed group: water, normal saline (normal saline), phosphate buffered saline (phosphate buffered saline, PBS), sugary soln, aqueous solution (aqueous solution containing alcohol) containing alcohol, and their combination.
The present invention also provides a kind of being used for the treatment of to have or the method with the human individual of Parkinson's disease mistake intelligence under a cloud, and it comprises this human individual dispensing to drop on from about 1.5mg/kg/ days to the ceftriaxone in about 35mg/kg/ days in a dosage range.
According to the present invention, the dosage of ceftriaxone can change depending on following factors with dispensing number of times: the seriousness of the disease that be treated, dosing way, and the age of the individuality that will be treated, health and reaction.Generally speaking, according to pharmaceutical compositions of the present invention can in single dose or be divided into several dosage form and by oral ground or the genuine dispensing of parenteral.
The present invention will be described further with regard to the following examples, but it is to be understood that these embodiments are for illustrating, and should not be interpreted as the restriction in enforcement of the present invention.
< embodiment >
Experiment material:
1. laboratory animal:
(12 weeks large for the male Wistar rat (male Wistar rats) used in embodiment below, body weight is about 419.5 ± 7.5g) be purchased from National Laboratory Animal center (National Laboratory Animal Center, R.O.C.).All laboratory animals individually raised in an illumination be respectively 12 hours (light is 7 unlatchings in the morning), room temperature maintains 24 ± 1 DEG C and relative humidity maintains in the transparent cage of 60 ± 5%, and moisture and feedstuff are supplied fully.
During starting the 2nd to the 4th day after raising, each animal is pacified (handled) and lasted 5 minutes every day, to lower the stress reaction of animal for experimental implementation person and experimental situation.All experimental arrangements of regarding assay animal approved by the care of animal committee of middle mountain medical university (Animal Care Committee of Chung Shan Medical University), and the experimental animal feeding management of foundation NIH (National Institutes of Health, NIH) and operating specification (Guide for the Care and Use of Laboratory Animals) carry out.
1.T type labyrinth (T-maze):
The structure in the T-shaped labyrinth used in embodiment is below shown in Fig. 1.This T-shaped labyrinth is made by the polyethylene plastic cement of black (polyvinyl plastic), and T-shapedly this T-shaped labyrinth is made up of 1 initial arm 1 (start arm 1) (60cm length × 15cm wide × 30cm is high), 2 opposed selection arms 2 (opposed choice arms 2) (40cm length × 10cm wide × 30cm is high) and 1 middle section 3 (central square 3) (long × 10 wide cm × 30cm of 15cm are high) being positioned at center.This initial arm 1 has an initiating terminal 11 (start end 11) away from this middle section 3, and these select arm 2 to have a terminal 21 (terminal end 21) away from this middle section 3 respectively.In addition, these select arm 2 to have a slide 22 (sliding door 22) respectively, when these select one of them slide 22 of arms 2 to be closed, laboratory animal can move from this initiating terminal 11 and select slide 22 of arm 2 and incoming terminal 21 through another.Alternatively, these select the slide 22 of arm 2 can be unlocked to allow that laboratory animal moves from this initiating terminal 11 and passes through these slides 22 of any one selecting arms 2 and incoming terminal 21 simultaneously.Before each laboratory animal is tested, this T-shaped labyrinth is cleaned up hill and dale with 20% ethanol, then gives dry up hill and dale.
1. open space case (open box):
The structure of the open space case that uses in embodiment below (60cm length × 60cm wide × 60cm is high) is shown in Fig. 2 and Fig. 3.This open space case is made by the polyethylene plastic cement of black, and be placed in 3 corners of the bottom of this open space case 3 all identical and without the object of special odor in size, color, shape and material, they be denoted as 41,42 and 43 respectively and separately and the corner 61,62 and 63 of this open space case there is the distance (see Fig. 2) of 27cm, and any object is not placed in corner 64.In addition, object 43 replacedly can neither be same as object 43 with 1 and without the object 5 (see Fig. 3) of special odor in size, color, shape and material.On pretreatment, all objects are unfamiliar for laboratory animal.And before each laboratory animal is tested, this open space case and all objects all clean up hill and dale with 20% ethanol, then give dry up hill and dale.
Embodiment 1. ceftriaxone (ceftriaxone) is for the assessment for the treatment of effectiveness of rat of losing intelligence (Parkinson ' s disease dementia, PDD) with Parkinson's disease
In this experiment, applicant uses 1-methyl 4-phenyl-1,2,3,6,-tetrahydropyridine hydrochlorate (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, MPTP-HCl) bring out rat and produce Parkinson's disease mistake intelligence, and assess the treatment effectiveness of ceftriaxone for Parkinson's disease mistake intelligence by the performance testing (behavioral test) of rat and the histopathological analysis of brain.Experiment is below with reference to Ho Y.J.et al. (2011) substantially, and the method described in Behav.Brain Resi., 219:280-290 work as is carried out.
Experimental technique:
A. Parkinson's disease loses bringing out of intelligence:
Male Wistar rat is divided into randomly 1 pathology comparison group (n=48), 2 prevention groups (namely prevention group 1 (n=12) and prevention group 2 (n=12)), 3 treatment group (namely treatment groups 1 (n=15), treatment group 2 (n=12) and treatment group 3 (n=12)) and 3 sham operated rats (namely sham operated rats 1 (n=38), sham operated rats 2 (n=7) and sham operated rats 3 (n=8)), wherein pathology comparison group, the rat of prevention group and treatment group is by free from worries (zoletil, Virbac, Carros, France) (20mg/kg) peritoneal injection (intraperitoneal injection) and anaesthetized.Then, 0.5M 1-methyl 4-phenyl-1 in normal saline will be assigned in, 2,3,6,-tetrahydropyridine hydrochlorate (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, MPTP-HCl) (dosage be 0.21mg/ side/only) is injected in the bilateral black substance body dense area (bilateral substantia nigra pars compacta, bilateral SNc) of the midbrain (mesencephalon) of rat lentamente, produces Parkinson's disease lose intelligence to bring out rat.
Afterwards, each rat is injected with penicillin-G procaine (Penicillin-G procaine) (0.2mL, 20,000IU) immediately, to lower the chance of postoperative infection (post-operative infection).Then, each rat is put into individually plastic cement cage (plastic cages) and raise and allow them carry out wound healing and last about 7 days, then they are transferred in rearging cage (home cages).
In addition, the rat of sham operated rats is brought carries out identical experiment, difference be in: the bilateral black substance body dense area of the midbrain of these rats is injected with isopyknic normal saline.
B. the dispensing of ceftriaxone:
In MPTP-HCl injection before (MPTP-HCl injection) 5 days, the rat of prevention group 1 and 2 respectively by peritoneal injection with ceftriaxone (purchased from sigma) (dosage be respectively 100 and 200mg/kg/ days).After MPTP-HCl injection, the rat for the treatment of group 1, sham operated rats 2 and 3 respectively immediately by peritoneal injection with ceftriaxone (dosage is respectively 200mg/kg/ days, 100mg/kg/ days and 200mg/kg/ days), and the rat of pathology comparison group and sham operated rats 1 respectively immediately by peritoneal injection with normal saline (dosage is all 1mL/kg/ days).In addition, the 3rd day after MPTP-HCl injection, the rat for the treatment of group 2 and 3 respectively by peritoneal injection with ceftriaxone (dosage be respectively 100 and 200mg/kg/ days).Each group of rat is offerd medicine once every day, until MPTP-HCl injection after the 14th day at the end of.
The 8th day after MPTP-HCl injection, each group of rat is carried out to the analysis of C item below; The 12nd day after MPTP-HCl injection, each group of rat is carried out to the analysis of D item below; And MPTP-HCl injection after the 15th day, the rat for the treatment of group 1, sham operated rats 1 and pathology comparison group is carried out to the analysis of E item below.
C.T type maze test (T-maze test):
In order to understand the impact of ceftriaxone for activity memory (working memory) of the rat with Parkinson's disease mistake intelligence, the 8th day after MPTP-HCl injection, difference random choose 11,32 and 36 rats from the rat for the treatment of group 1, sham operated rats 1 and pathology comparison group, and carry out T-shaped maze test to all rats of these rats and all the other each groups, whole experimentation lasts 3 days altogether.Relevant T-shaped maze test mainly carries out according to following manner:
(1) at first 1 day that carries out testing, the fasting (fasting) making rat experience 23 hours, and after test all tests on the same day terminate, make rats eating last 1 hour.
The training period (training session) of (2) the 1st days and the 2nd day: rat is placed on the position of the initiating terminal 11 in T-shaped labyrinth to carry out 9 groups of tests (trials), often group test sequentially comprises 1 pressure route (forced run) and 1 selection schemer (choice run), and the interval forcing the test of route and selection schemer is all 30 seconds.In the test forcing route, one of them slide 22 of arms 2 is selected to be closed at 2, and select the terminal 21 of arm 2 to be placed the food appreciating (reward) as reward at another, when rat obtains reward reward, this time forces the test of route to be namely moved to end.In the test of selection schemer, the slide 22 of arm 2 is selected all to be unlocked for 2, wherein slide 22 is placed by the terminal 21 of the selection arm 2 (namely the pent selection arm 2 of slide 22 in the test forcing route) reopened the food appreciated as reward, when rat enters any one of 2 selection arms 2, namely the test of this selection schemer is moved to end.In the test of selection schemer, if rat enter slide 22 by reopen selection arm 2 (namely the pent selection arm 2 of slide 22 in the test forcing route) time, this rat is defined as making correct response (correct response).
The duration of test (test session) of (3) the 3rd days, rat is placed on the position of the initiating terminal 11 in T-shaped labyrinth to carry out 3 groups of tests, often group test sequentially comprises 1 pressure route and 2 continuous print selection schemers, and records the number of times that rat makes correct response in the test of 6 selection schemers.
The activity memory of rat assesses with the correct response rate of the duration of test of the 3rd day (the 10th day namely after MPTP-HCl injection), and this correct response rate (correct response rate) is calculated by the number of times of the correct response measured by the 3rd day is substituted into following formula (1):
Formula (1): A=(B/6) × 100
Wherein: A=correct response rate (%)
The number of times of B=correct response
The experimental data obtained represents with meansigma methods ± SEM.All data are by single-factor analysis of variance (one-way analysis of variance, ANOVA), then with least significant difference (least-significant difference, LSD) perform an analysis, to assess the diversity between sham operated rats 2 or 3 and sham operated rats 1, the diversity between pathology comparison group and sham operated rats 1 and each treatment group or the diversity between prevention group and pathology comparison group.If the statistics comparison result obtained is p < 0.05, representative has significance,statistical (statistical significance).
D. article identification test (object recognition test):
In order to understand ceftriaxone for the identification of rat and/or the impact of memory ability of losing intelligence with Parkinson's disease, the 12nd day after MPTP-HCl injection, carry out article identification test to all rats of each group, whole experimentation lasted 3 days altogether.
First, rat is placed in open space case and tests (trials) near the position in corner 64 (see Fig. 2) to carry out 4 times, wherein the 1st time with to test for the 2nd time be respectively after MPTP-HCl injects the 12nd day with within the 13rd day, carried out, and to test with the 4th for the 3rd time be being carried out for the 14th day after MPTP-HCl injects.Each testing time lasts 5 minutes altogether, and with regard to the test of the 1st, 2 and 3 time, interval of each test is 1 day, is then 5 minutes as the interval to test with the 4th for the 3rd time.In the test of the 1st, 2 and 3 time, be placed object 41,42 and 43 in open space case and explored for rat, in the test of the 4th, then carried out alternative object 43 (see Fig. 3) with object 5.During whole test, use one to be placed on camera above open space case to monitor the behavior of rat, and record rat during each test, explore the time that each object spends.The exploration (exploration) of an object is defined as rat close to an object has Body contact (physical contact) with its nose (snout) and/or half sole (forepaw) with this object.The difference that rat spends in the percent value of the time explored on object 43 and object 5 is used as the index of assessment rat for the memory ability of object be familiar with and the identification ability for the difference between new object and past heritage part.And the percent value of the exploration time of object 43 and object 5 (exploration time) substitutes into following formula (2) total time respectively by what spent by the measured each object of exploration during the 3rd test and the 4th test and be calculated:
Formula (2): C=(D/E) × 100
Wherein: the object of C=object 43 or object 5 explores the percent value (%) of time
The time that D=exploration object 43 or object 5 spend
E=explores the total time that all objects spend
The experimental data obtained represents with meansigma methods ± SEM.All data test (paired-samples t-tests) by paired sample t-to perform an analysis, to assess the difference of each group of rat in the percent value of the exploration time of object 43 and object 5.If the statistics comparison result obtained is p < 0.05, representative has significance,statistical.
E. histopathological analysis:
In order to understand ceftriaxone, whether there is the neuroinflammatory (neuroinflammation) of rat and the effectiveness of nerve degeneration (neurodegeneration) improving and lose intelligence with Parkinson's disease, the 15th day after MPTP-HCl injection, from the rat for the treatment of group 1, sham operated rats 1 and pathology comparison group, random choose 4 rats carried out histopathological analysis respectively.
First, CO is passed through
2sacrifice rat, then give perfusion with 4% metaformaldehyde (paraformaldehyde) be assigned in phosphate buffered saline (phosphate buffered saline, PBS).Then, rapidly take out brain and at 4 DEG C, give immersion with 30% aqueous sucrose solution containing 4% metaformaldehyde last at least 3 days.Afterwards, brain is placed on freezing microtome (Reserch Cryostst Lecia CM3050S, Leica) and carries out coronal section (coronal section) (thickness about 30 μm).
Then, the tissue slice with black substance body dense area is selected, then by using OX-6 antibody (anti-MHC class II OX-6 antibody) (the BD Biosciences Pharmingen of anti-MHC class II, CA) as Primary antibodies and use biotinylated horse anti-mouse IgG antibody (biotinylated horse anti-mouse IgG antibody) (Vector Laboratory, CA) to know in detail and usual technology carries out immunohistochemical staining (immunohistochemistry stain) to these tissue slices according to person skilled in the art person as secondary antibody.Dyed tissue slice is by using optical microscope (AXioskop2, and observe under being the amplification of 200X one ZEISS), then using Image Pro Plus Software 6.0 software (Media Cybernetics) to calculate at one is 18,769 μm
2area under the density of activated microgliacyte (activated microglia).
In addition, the tissue slice with hippocampal gyrus CA1 region (hippocampal CA1 area) out selected and know in detail according to person skilled in the art person and usual technology to carry out Nissl's staining (Nissl staining).Dyed tissue slice is by using optical microscope and observing under an amplification of 200X, then Image Pro Plus Software 6.0 software is used and reference Xavier L.L.et al. (2005), Brain Research protocols, semi-quantitative method (semi-quantitative method) described in 16:58-64 works as is estimated 2,354 μm
2area under an area percentage value of cone neurone (pyramidal neuron).
The experimental data obtained represents with meansigma methods ± SEM.All data are by single-factor analysis of variance, then perform an analysis with least significant difference, to assess the diversity between pathology comparison group and sham operated rats 1 and the diversity between treatment group 1 and pathology comparison group.If the statistics comparison result obtained is p < 0.05, representative has significance,statistical.
Result:
A.T type maze test:
Fig. 4 is presented at the 10th day after MPTP-HCl injection, and each group rat is by the correct response rate measured by T-shaped maze test.As seen from Figure 4, the correct response rate of the rat of sham operated rats 2 and 3 and the rat institute tool person of sham operated rats 1 compare and all do not present statistical significance, and this represents that ceftriaxone can not affect the activity memory of normal rat.In addition, compare down with the rat of sham operated rats 1, the correct response rate of the rat of pathology comparison group has and declines significantly, and this represents that MPTP-HCl successfully can bring out rat and produce Parkinson's disease and lose intelligence and the defect causing them in activity memory.And compare down with the rat of pathology comparison group, the correct response rate of the rat for the treatment of group 1 to 3 and prevention group 1 to 2 all has the trend of rising.Especially, comparing that the correct response rate of the rat for the treatment of group 1 to 3 and the rat of pathology comparison group have all presents statistical significance, or even the rat being similar to sham operated rats 1 has.This experimental result shows: ceftriaxone can be treated Parkinson's disease and lost intelligence and improve the activity memory of losing the rat of intelligence with Parkinson's disease.
B. article identification test:
Fig. 5 is presented at the 14th day after MPTP-HCl injection, each group rat tested by article identification measured by object 43 and the percent value of exploration time of object 5.As seen from Figure 5, with regard to the rat of sham operated rats 1 to 3, the percent value of the exploration time of object 5 and object 43 tool persons compare and all present statistical significance, and this represents that ceftriaxone can not affect identification and/or the memory ability of normal rat.And with regard to the rat of pathology comparison group, comparing that the percent value of the exploration time of object 5 and object 43 have does not present statistical significance, and this represents that MPTP-HCl successfully can bring out rat and produces Parkinson's disease mistake intelligence and cause them in the defect identified and/or on memory ability.On the contrary, with regard to the rat for the treatment of group 1 to 3 and prevention group 1 to 2, comparing that the percent value of the exploration time of object 5 and object 43 have all presents statistical significance.This experimental result shows: ceftriaxone can prevent Parkinson's disease to lose intelligence and improve to lose the rat of intelligence for the memory ability of past heritage part be familiar with and the identification ability for the difference between new object and past heritage part with Parkinson's disease.
C. histopathological analysis:
Fig. 6 is presented at the 15th day after MPTP-HCl injection, the black substance body dense area of each group of acquired rat by immunohistochemical staining by the density of activated microgliacyte recorded.As seen from Figure 6, compare down with the rat of sham operated rats 1, the density of the activated microgliacyte in the black substance body dense area of the rat of pathology comparison group has to be increased significantly, and this represents that MPTP-HCl successfully can bring out rat and produce Parkinson's disease mistake intelligence and the activation and the neuroinflammatory that cause their microgliacyte.And compare down with the rat of pathology comparison group, the density of the activated microgliacyte in the black substance body dense area of the rat for the treatment of group 1 has and declines significantly.This experimental result shows: ceftriaxone has the activation of microgliacyte and the effectiveness of neuroinflammatory that suppress to lose the rat of intelligence with Parkinson's disease.
Fig. 7 is presented at the 15th day after MPTP-HCl injection, the hippocampal gyrus CA1 region of each group of acquired rat by Nissl's staining by the area percentage value of cone neurone recorded.As seen from Figure 7, compare down with the rat of sham operated rats 1, the area percentage value of the cone neurone in the hippocampal gyrus CA1 region of the rat of pathology comparison group has and declines significantly, and this represents that MPTP-HCl successfully can bring out rat and produce Parkinson's disease and lose intelligence and the hippocampal gyrus nerve degeneration causing them.And compare down with the rat of pathology comparison group, the area percentage value of the cone neurone in the hippocampal gyrus CA1 region of the rat for the treatment of group 1 has to be increased significantly.This experimental result shows: ceftriaxone has the neurodegenerative effectiveness of hippocampal gyrus improving the rat losing intelligence with Parkinson's disease.
Comprehensive above experimental result, applicant thinks: ceftriaxone has the effectiveness of prevention and treatment Parkinson's disease mistake intelligence.
The ceftriaxone of embodiment 2. low dosage is for the assessment for the treatment of effectiveness of rat of losing intelligence with Parkinson's disease
For whether the ceftriaxone understanding low dosage further also has the effectiveness that treatment Parkinson's disease loses intelligence, experiment is below carried out.
Experimental technique:
Male Wistar rat is divided into randomly 1 pathology comparison group (n=23), 2 treatment groups (namely treatment group 1 (n=15) and treatment group 2 (n=13)) and 1 sham operated rats (n=27), and according to " experimental technique " of embodiment 1 above A item " Parkinson's disease loses bringing out of intelligence " when described in method each group of rat is processed.
After MPTP-HCl injection, the rat for the treatment of group 1 and 2 respectively immediately by peritoneal injection with ceftriaxone (dosage be respectively 10 and 50mg/kg/ days), and the rat of pathology comparison group and sham operated rats respectively immediately by peritoneal injection with normal saline (dosage is for 1mL/kg/ days).Each group of rat is offerd medicine once every day, until MPTP-HCl injection after the 14th day at the end of.
The 8th day after MPTP-HCl injection, random choose 12 and 19 rats respectively from the rat for the treatment of group 2 and pathology comparison group, and according to " experimental technique " of embodiment 1 above C item " T-shaped maze test " when described in all rats of method to these rats and all the other each groups carry out T-shaped maze test and calculate the correct response rate of each group of rat, to assess the diversity between pathology comparison group and sham operated rats and the diversity between each treatment group and pathology comparison group.
In addition, the 12nd day after MPTP-HCl injection, random choose 23 rats from the rat of sham operated rats, and according to " experimental technique " of embodiment 1 above D item " article identification test " when described in all rats of method to these rats and all the other each groups carry out article identification test, to assess the difference of each group of rat in the percent value of the exploration time of object 43 and object 5.
Result:
A.T type maze test:
Fig. 8 is presented at the 10th day after MPTP-HCl injection, and each group rat is by the correct response rate measured by T-shaped maze test.As seen from Figure 8, compare down with the rat of sham operated rats, the correct response rate of the rat of pathology comparison group has and declines significantly.And compare down with the rat of pathology comparison group, the correct response rate of the rat for the treatment of group 1 and 2 all has and rises significantly, or even the rat being similar to sham operated rats has.This experimental result shows: the ceftriaxone of low dosage can be treated Parkinson's disease and lost intelligence and improve the activity memory of losing the rat of intelligence with Parkinson's disease.
B. article identification test:
Fig. 9 is presented at the 14th day after MPTP-HCl injection, each group rat tested by article identification measured by object 43 and the percent value of exploration time of object 5.As seen from Figure 9, with regard to the rat of pathology comparison group, the percent value of the exploration time of object 5 and object 43 tool persons compare and do not present statistical significance.On the contrary, with regard to the rat for the treatment of group 1 and 2, comparing that the percent value of the exploration time of object 5 and object 43 have all presents statistical significance.This experimental result shows: the ceftriaxone of low dosage can be treated Parkinson's disease mistake intelligence and improve and be lost the rat of intelligence for the memory ability of past heritage part be familiar with and the identification ability for the difference between new object and past heritage part with Parkinson's disease.
Comprehensive above experimental result is known: use and drop in a dosage range rat can effectively treating and prevent to lose with Parkinson's disease intelligence from about 10mg/kg/ days to the ceftriaxone in about 200mg/kg/ days.Applicant is according to this result and utilize Shannon R.S.et al. (2007), FASEB J., 22:659-661 when described in based on body surface area (body surface area, the formula of dosage conversion (dose translation) BSA) calculates the dosage being applicable to human individual further, and thinks accordingly: drop on the Parkinson's disease mistake intelligence being available for treating and/or preventing human individual from about 1.5mg/kg/ days to the ceftriaxone in about 35mg/kg/ days in dose scope.
The all patents be quoted in this description and document are merged in the application as reference data using its entirety.If when conflicting to some extent, the detailed description of the application will be got the upper hand (comprising in being defined in).
Although the present invention is described with reference to above-mentioned specific concrete example, a lot of modifications and variations can be made not deviating under scope and spirit of the present invention significantly.Therefore the present invention is only by the restriction as examined the scheme shown in attached claims with literary composition.
Claims (6)
1. treat and/or prevent with ceftriaxone preparation the purposes that Parkinson's disease loses the pharmaceuticals of intelligence, it is characterized in that:
The dosage range of this ceftriaxone drops on from 1.5mg/kg/ days in 35mg/kg/ days.
2. purposes as claimed in claim 1, is characterized in that:
The dosage range of this ceftriaxone drops on from 1.62mg/kg/ days in 32.4mg/kg/ days.
3. purposes as claimed in claim 2, is characterized in that:
The dosage range of this ceftriaxone drops on from 1.62mg/kg/ days in 16.2mg/kg/ days.
4. purposes as claimed in claim 3, is characterized in that:
The dosage range of this ceftriaxone drops on from 1.62mg/kg/ days in 8.1mg/kg/ days.
5. purposes as claimed in claim 1, is characterized in that:
These pharmaceuticals are in a kind of dosage form for parenteral dispensing.
6. purposes as claimed in claim 1, is characterized in that:
These pharmaceuticals are in a kind of dosage form for oral administration medicine supplying.
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| The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of Aβ1-42;Christopher M. Lauderback et al.;《Journal of Neurochemistry》;20111231(第78期);413-416 * |
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