CN103656685A - Application of micro RNA-219 in preparing antiepileptic drug - Google Patents
Application of micro RNA-219 in preparing antiepileptic drug Download PDFInfo
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Abstract
The invention relates to an application of micro RNA-219 in preparing an antiepileptic drug, and relates to the micro RNA-219. The antiepileptic drug is a drug for preventing or treating epilepsy and the nervous system diseases characterized by epileptic seizure. The drug consists of nucleic acid of a sequence number indicated by an effective quantity sequence table and a carrier or auxiliary materials acceptable on the medicine. The drug can be made into injection preparation, oral preparation, spray preparation and soft cream preparation or stickers. The invention provides an application of micro RNA-219 and agonist thereof inn preventing and treating the epilepsy and the nervous system disease characterized by the epileptic seizure, and the micro RNA-219 is used for treating and preventing the epilepsy and the nervous system disease characterized by the epileptic seizure.
Description
Technical field
The present invention relates to microRNA-219, especially relate to the application of microRNA-219 in preparing antiepileptic.
Background technology
Epilepsy is a kind of serious nervous system disease of chronic repeatability that the electric discharge of the abnormal synchronization of cerebral neuron is feature of take, and the whole world approximately 5,000 ten thousand patients are disturbed by it deeply.Antiepileptic is only controlled approximately 2/3rds patients' epilepsy, and can not fundamentally improve its pathological and physiological condition.The ion channel that relates to of epilepsy changes, synaptic remodeling, inflammation, gliosis and neuronal death etc.Yet, up to now, for the intervening measure of these processes, seldom showing clinically enough curative effects, cell and molecular mechanism that we occur epilepsy still lack complete understanding.
MicroRNA is that a class length is the endogenous non-coding RNA of 19～23 nucleotide; it is induced silencing complex (RISC by RNA; by Dicer; Argonaute and other protein group become) be written into after can with 3 ' untranslated region (UTR) pairing of said target mrna; cause the degraded of said target mrna or suppress its translation efficiency; and then regulate gene expression (Vasudevan S; Tong Y; Steitz J A.Switching from repression to activation:miRNAs can up-regulate translation.Science, 2007; (5858): 1931-1934; Lewis B P, Burge C B, Bartel D P.Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are miRNA targets Cell2005 (1): 15-20).MiRNA participates in organism physiological process in the mode of complex network regulation and control, miRNA in physiological condition hyponeural system system is distributed, the research of expression and function shows, miRNA is by regulating the expression of several genes, wide participation is to neuronal development, cell maturation and migration, myelin forms, synapse is reached maturity and plasticity, colloid cicatrization, neuropathic pain, the multiple pathological processes such as neural reparation and again domination, miRNA generates abnormal or its function path generation obstacle at neurodegenerative diseases, in the developing of psychosis and the cerebral tumor etc., bring into play pivotal role (Hebert S S, De Strooper B.Alterations of the miRNA network cause neurodegenerative disease.Trends Neurosci, 2009, (4): 199-206, Saugstad JA.MiRNAs effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration.J Cereb Blood Flow Metab.2010, 30 (9): 1564-1576).
MiRNA-219 is one of people and the peculiar miRNA of rodent cerebral tissue (Dostie J; Mourelatos Z; Yang M, Sharma A, Dreyfuss G.Numerous microRNPs in neuronal cell containing novel miRNAs.RNA.2003; 9 (2): 180-6); growth and closely related (the Okabe M of higher nerve function with cerebral tissue; Imai T; Kurusu M; Hiromi Y; Okano H, Translational repression determines a neuronal potential in Drosophila asymmetric cell divison.Nature.2001; 411 (6833): 94-98; Miller S; Yasuda M; Coats JK; Jones Y; Martone ME, Mayford M.Disruption of dendritic translation of CaMK II alpha impairs stabilization of synaptic plasticity and memory consolidation.Neuron.2002; 36 (3): 507-19).The further investigation of its physiological function is progressively demonstrated to the potential dependency of miRNA-219 and epilepsy generation.As the discovery N-methyl-D-aspartate function of receptors such as nearest Jannet Kocerha go down relevant to miRNA-219 down-regulated expression, miRNA-219 is by regulating NMDAR signal downstream effect PROTEIN C aMK II γ to participate in behavioral disorder (Kocerha J due to NMDAR dysfunction, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, Sales N, Willoughby D, Elmen J, Hansen HF, Orum H, Kauppinen S, Kenny PJ, Wahlestedt C.MiRNA-219modulates NMDA receptor-mediated neurobehavioral dysfunction.Proc Natl Acad Sci USA.2009, 106 (9): 3507-12), in addition, research is found, miRNA-219 is at cell space, the dendron region high expressed of hippocampal neuron, in aixs cylinder district, also there is expression (Okado H, Ohtaka-Maruyama C, Sugitani Y, Fukuda Y, Ishida R, Hirai S, Miwa A, Takahashi A, Aoki K, Mawano H, Kasai M.The transcriptional repressor RP58is crucial for cell-division patterning and neuronal survival in the developing cortex.Dev Biol.2009, 331 (2): 140-51), show that it plays a significant role in synaptic plasticity.More than research prompting, the generation of miRNA-219 and epilepsy is closely related, and it may participate in the pathogenic process of epilepsy.
Summary of the invention
The object of the present invention is to provide the application of microRNA-219 in preparing antiepileptic.
MicroRNA-219 can apply in preparing antiepileptic.
Described antiepileptic is for prevention or treat epilepsy and the medicine of the nervous system disease that the epilepsy outbreak of take is feature, and the nucleic acid that described medicine comprises sequence shown in sequence table by effective dose and pharmaceutically acceptable carrier or adjuvant form.
The common method that described medicine can be prepared according to medicine is made ejection preparation, oral formulations, spray agent, ointment formulation or patch etc.
Those skilled in the art can suitably modify the nucleotide sequence of microRNA-219 of the present invention; described modification comprises one or more combination or increase and decrease, the replacement of nucleotide arbitrarily in ribose modification, base modification and the phosphoric acid backbone modification of any nucleotide, as long as the nucleotide sequence after modifying still has within the activity identical with microRNA-219 just should belong to invention which is intended to be protected.
The invention discloses microRNA-219 and agonist thereof the purposes in preventing, treat the nervous system disease that epilepsy and the epilepsy outbreak of take are feature.By a large amount of experiments, confirm, in bringing out the mouse model of epilepsy, in mouse brain hippocampal tissue, microRNA-219 level significantly reduces.The antagonist (antagomir) that gives mice intracerebroventricular injection microRNA-219 can cause mice epilepsy symptom.The agonist (agomir) that gives epilepsy model mice intracerebroventricular injection microRNA-219 can significantly improve its epilepsy symptom; mean that microRNA-219 plays key effect in the pathogenesis of epilepsy, it is the important protectiveness micromolecule nucleic acid of antagonism epilepsy and relevant disease morbidity thereof.The present invention is intended to the purposes of the open biological preparation based on microRNA-219 and agonist/analog/trim thereof, in order to treat and to prevent the generation of the nervous system disease that epilepsy and the epilepsy outbreak of take are feature.
Accompanying drawing explanation
Fig. 1 is mouse brain electrograph waveform after mice intracerebroventricular injection 1.5ug KA.
Fig. 2 is that in KA induction epilepsy model hippocampus of mice, microRNA-219 expresses situation of change.
Fig. 3 is microRNA-219 expression in Cerebrospinal Fluid of Epilepsy Patients.
Fig. 4 is mouse brain electrograph waveform after mice intracerebroventricular injection 0.2nmol antagomir-219.
Fig. 5 is mouse brain electrograph waveform after mice intracerebroventricular injection 0.2nmol negative control agent antagomir-NC.
Fig. 6 is that after mice intracerebroventricular injection 0.2nmol antagomir-219, the interior microRNA-219 of hippocampus of mice expresses situation of change.
Fig. 7 is mouse brain electrograph waveform after epilepsy model mice intracerebroventricular injection 0.2nmol agomir-219.
Fig. 8 is mouse brain electrograph waveform after epilepsy model mice intracerebroventricular injection 0.2nmol negative control agent agomir-NC.
Fig. 9 is mouse brain electrograph waveform after mice intracerebroventricular injection 0.2nmol agomir-219.
Figure 10 is that after epilepsy model mice intracerebroventricular injection 0.2nmol agomir-219, the interior microRNA-219 of hippocampus of mice expresses situation of change.
Figure 11 is that in epilepsy cell model (former culture hippocampus neurons in mice), to add 0.8nmol agomir-219(final concentration be 400nM) after microRNA-219 express situation of change.
Figure 12 is that in epilepsy cell model (former culture hippocampus neurons in mice), to add 0.8nmol antagomir-219(final concentration be 400nM) after microRNA-219 express situation of change.
The specific embodiment
Below in conjunction with specific embodiment, further describe the present invention, all embodiment only, for illustration the present invention, never limit the scope of the invention.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
With bull ICR mice (30-35g), intracerebroventricular injection classics cause epilepsy agent digenic acid (Kainic acid, KA) 1.5ug and bring out mice epilepsy, set up mice animal epileptic model.After injection digenic acid mice show eyes stare, must moving increase, rapid breathing, the action that washes one's face repeatedly, with Head And Face, twitch, develop into gradually the epilepsy symptom with the complete tetanus Myoclonic seizures of standing and falling down, outbreak grade reaches Racine classification IV～V level, mouse brain electrograph is shown as the epilepsy waveform of volume high-amplitude spike, respectively lead and see every s5～6 time, the epilepsy sample discharge sustain of 30～80 μ V is provided (referring to Fig. 1).After 24h, broken end is got brain, takes out bilateral hippocampus, extracts RNA, and fluorescent quantitative PCR experiment shows, KA group mice compared with normal control group mice, and in Hippocampus, microRNA-219 level significantly reduces (reducing by 70%) (referring to Fig. 2).Collect clinical epileptic's samples of CSF, in detection display Cerebrospinal Fluid of Epilepsy Patients, the more non-epileptic of microRNA-219 level significantly reduces (referring to Fig. 3).This means that the expression variation of microRNA-219 and the generation of epilepsy development are closely related.
Further give the specific antagonists (antagomir-219) of bull ICR mice intracerebroventricular injection microRNA-219, mice shows epilepsy symptom, outbreak grade reaches Racine classification IV level, electroencephalogram is shown as abnormal spike waveform, respectively lead and see every s1 time, the epilepsy sample discharge sustain of 10～60 μ V is provided (referring to Fig. 4).Epilepsy resting stage, part mice easily enrages, irritability, has aggressive behavior.Fluorescent quantitative PCR experiment shows, after injection microRNA-219 antagonist, in hippocampus of mice, microRNA-219 level significantly reduces (referring to Fig. 6), means that antagonism microRNA-219 can bring out mice epilepsy, and microRNA-219 plays an important role in epilepsy invasion mechanism.
Simultaneously, ICR mice KA brings out after epilepsy 6h, give the agonist (agomir-219) of its intracerebroventricular injection microRNA-219, mice epilepsy symptom is clearly better, outbreak prolongation of latency, the outbreak persistent period shortens greatly, only occurs staring, Head And Face is twitched, and two forelimbs lift the slight outbreaks such as clonic spasm.Then having no mice repeatedly shows effect.Mouse brain electrograph shows that the electric discharge of cortex epilepsy sample is obviously suppressed, and basic fluctuation is the theta rhythm of 4～6HZ, and epilepsy sample electric discharge (referring to Fig. 7) by a narrow margin appears once in interval 5～7s.Fluorescent quantitative PCR experiment demonstration, in hippocampus of mice, microRNA-219 level returns to normal level, means that microRNA-219 is the important protectiveness micromolecule nucleic acid (referring to Figure 10) of antagonism epilepsy and relevant disease morbidity thereof.
By a large amount of experiments, confirm, in mice epilepsy model cerebral hippocampus tissue, microRNA-219 level significantly reduces.The antagonist (antagomir) that gives mice intracerebroventricular injection microRNA-219 can bring out mice epilepsy outbreak.The agonist (agomir) that gives epilepsy model mice intracerebroventricular injection microRNA-219 can significantly improve its epilepsy symptom; prompting microRNA-219 plays key effect in the pathogenesis of epilepsy, and it is the important protectiveness micromolecule nucleic acid of antagonism epilepsy and relevant disease morbidity thereof.This result has further obtained confirmation (participating in Figure 11 and 12) in epilepsy cell model.Meanwhile, collected clinical epileptic's cerebrospinal fluid, detected wherein microRNA-219 level, confirmed that itself and epilepsy invasion have dependency (referring to Fig. 3).
The present invention is on the basis of a large amount of animals and cell experiment, in conjunction with clinical epileptic's examination of cerebrospinal fluid result, is intended to the biological preparation of the nervous system disease that in order to treatment and prevention epilepsy and take epilepsy outbreak be feature of exploitation based on microRNA-219.Specific as follows:
MicroRNA219 biological preparation: the medicine of preparation can only contain nucleotide sequence or its analog/agonist/trim of microRNA219, also can be made into a kind of pharmaceutical composition, nucleotide sequence or its analog and the pharmaceutically acceptable carrier of the microRNA219 that it is characterized in that comprising effective dose; Wherein, described carrier can be nano-particle, liposome, cholesterol, chitosan, virus etc.Nucleotide sequence or its analog/agonist of synthetic microRNA219, and be connected to form medicine with above-mentioned carrier, can be made into ejection preparation or oral formulations, by vein or intramuscular injection or oral mode, be used for the treatment of epilepsy or take the nervous system disease that epilepsy outbreak is feature.
Embodiment 1. mouse brain electrographic recordings
Adopt Nicolet Buddhist nun's high-tensile strength digitized electroencephalograph to trace, with scalp electrode, trace mouse brain electrograph, adopt 4 to lead, at mice left and right volume (F3, F4), left and right is pushed up on the scalp that (P3, P4) is relative and is respectively placed a needle electrode, and reference electrode is put left ear ground connection.Sensitivity: 10 μ V/mm, chart speed: 30mm/sec, High frequency filter: 70HZ, low frequency filtering: 1.6Hz.
The detection of microRNA-219 expression in embodiment 2. epilepsy model hippocampus of mices
1, this experiment adopts male ICR mouse in 6～8 week age, is specifically divided into 2 groups: epilepsy model mice group and matched group.Epilepsy model mice group mice is placed and is fixed on mouse brain stereotaxic instrument, gives Injected into Cerebral Ventricle digenic acid (KA) 1.5ug(1ug/ μ L), bring out mice epilepsy, manufacture little Epiletic model.Control group mice gives homonymy Injected into Cerebral Ventricle normal saline 1.5 μ L.
2, after 24h, the conventional mice bilateral hippocampus RNA that extracts:
In every 100mg tissue, add 1mL TRIZOL reagent, electric homogenizer homogenate.Under room temperature, place after 5min, add 0.2mL chloroform, mix under rear room temperature and place 5min, 4 ℃ 12, the centrifugal 15min of 000r.Upper strata water liquid is transferred in new EP pipe, adds equal-volume (0.5mL) isopropyl alcohol, mix under rear room temperature and place 10min, 4 ℃ 12, the centrifugal 10min of 000r.Abandon supernatant, add 1mL75% ethanol, mix latter 4 ℃ 9, the centrifugal 5min of 000r.Abandon supernatant, air drying precipitation 10min, adds 20 μ L DEPC to process water, in 55～60 ℃ of water-bath 10min, dissolves RNA.The RNA solution obtaining is stored in-80 ℃.
3, ultraviolet absorption method is measured RNA concentration and purity:
According to microplate reader operation instruction, operate the DEPC water zeroing of first using with dissolving RNA before measurement.According to the 260nm place value of reading, obtain RNA concentration, with the ratio of A260/A280, judge RNA purity.
4, degeneration agarose gel electrophoresis:
1g agarose is dissolved in 72mL water, is cooled to 60 ℃, adds 37% formalin of 10 * MOPS electrophoretic buffer and the 18mL of 10mL.Get 3ugRNA, add the formaldehyde loading dye liquor of 3 times of volumes, add EB in formaldehyde loading dye liquor to final concentration be 10ug/mL.Being heated to 70 ℃ hatches 5min and makes sample degeneration.Be splined in glue hole, under 5～6V/cm voltage, electrophoresis to bromophenol blue indicator enters glue at least 2～3cm, observes and take pictures under ultraviolet transmission light.
5, adopt the PrimeScript miRNA qPCR of TaKaRa company detection kit to detect the expression of has-miR-219:
MiRNAs reverse transcription:
Reverse transcription reaction system (20 μ L):
After above system mixes, instantaneous centrifugal, hatch after 60min 85 ℃ of inactivation reactions of hatching 5sec(enzyme for 37 ℃).Stop rear 4 ℃ standby, product is stored in-20 ℃.
MiRNAs real-time PCR:(PCR reagent source is in TaKaRa company, miR-219, the primers such as U6 are synthetic by the sharp rich biological company limited in Guangzhou)
Reaction system (20 μ L):
Response procedures:
95℃30sec--（95℃3sec--65℃30sec）×40cycles—Melting?Curve
Result shows: mice epilepsy modeling success (Fig. 1).In epilepsy model hippocampus of mice, microRNA-219 content contrasts normal group mice obvious decline, and microRNA-219 expression decline (Fig. 2) is described in hippocampus of epileptic mouse.
The expression of embodiment 3. Cerebrospinal Fluid of Epilepsy Patients microRNA-219
1, collect 5 routine epileptics and 5 routine normal control's CSF sample (take from Zhongshan Hospital Xiamen University's Department of Neurology in 2013, each case is made a definite diagnosis classification by two or more clinicists).According to method described in embodiment 2, extract RNA, and detect the expression of microRNA-219.
2, result shows: in Cerebrospinal Fluid of Epilepsy Patients, microRNA-219 expression obviously reduces (Fig. 3).The prompting expression variation of microRNA-219 and the generation of epilepsy development are closely related.
The specific antagonists of embodiment 4.microRNA-219 (antagomir-219) can bring out mice epilepsy
1, this experiment adopts male ICR mouse in 6～8 week age, is specifically divided into 2 groups: antagomir-219 processes and intervenes mice group and negative control group.Antagomir-219 processes the placement of intervention group mice and is fixed on mouse brain stereotaxic instrument, gives antagonist (antagomir-219) the 0.2nmol(0.2nmol/2.5 μ L of Injected into Cerebral Ventricle microRNA-219).Control group mice gives the negative control agent antagomir-NC0.2nmol of homonymy Injected into Cerebral Ventricle antagomir-219.
2, observe the behavior performance of mice: antagomir-219 processes intervention group mice and shows as obvious epilepsy symptom, and Racine classification reaches IV level.The demonstration of mouse brain electrograph, intervention group mice presents abnormal spike waveform, respectively leads and sees every s1 time, and the epilepsy sample discharge sustain of 10～60 μ V is provided (Fig. 4).Control group mice shows as normal behaviour, and electroencephalogram is also without abnormal epilepsy waveform (Fig. 5).
3,, after 24h, two groups of hippocampus of mice RNA of conventional extraction, as the step of embodiment 2 detects respectively two groups of microRNA-219 expressions in hippocampus of mice.Result shows that antagomir-219 processes microRNA-219 expression in intervention group hippocampus of mice and obviously reduces (Fig. 6) compared with matched group.
These results show that the antagomir-219 expression in antagonism hippocampus of mice can bring out mice epilepsy, illustrate that microRNA-219 plays pivotal role in the pathogenesis of epilepsy.
Embodiment 5.microRNA-219 and agonist thereof (agomir-219) therapeutical effect in mice epilepsy
1, this experiment adopts 6-8 male ICR mouse in age in week, specifically be divided into 4 groups: Normal group (intracerebroventricular injection normal saline), epilepsy model mice agomir-219 processes intervention group (KA bring out mice epilepsy 6h after intracerebroventricular injection agomir-2190.2nmol), intervention group (KA bring out mice epilepsy 6h after intracerebroventricular injection agomir-NC0.2nmol) is processed in epilepsy model mice agomir-219 negative control agent (agomir-NC), and agomir-219 processes intervention group (intracerebroventricular injection agomir-2190.2nmol).
2, observe the behavior performance of mice: the epilepsy symptom that epilepsy model mice agomir-219 processes intervention group mice has clear improvement, and has no thereafter repeatedly epilepsy outbreak.Do mouse brain electrograph and show, after epilepsy injected in mice agomir-219, the electric discharge of mouse cortex epilepsy sample is obviously suppressed, and basic fluctuation is the theta rhythm of 4～6HZ, and epilepsy sample electric discharge (referring to accompanying drawing 7) by a narrow margin appears once in interval 5～7s.Epilepsy model mice agomir-219 negative control agent (agomir-NC) is processed intervention group mice epilepsy symptom and is not improved, mice Racine classification reaches IV level, electroencephalogram shows abnormal spike waveform, visible every s3～4 time of respectively leading, and 30-60 μ V spike continues to provide (Fig. 8).And agomir-219 processing intervention group mice is acted normally, electroencephalogram is also without extraordinary wave.Illustrate that agomir-219 does not affect the normal physiological function of mice, to mice harmless (Fig. 9).
3,, after 24h, four groups of hippocampus of mice RNA of conventional extraction, as the step of embodiment 2 detects respectively the microRNA-219 expression of respectively organizing in hippocampus of mice.Result shows that epilepsy model mice agomir-219 processes microRNA-219 expression in intervention group hippocampus of mice and returns to normal level (Figure 10).
These results show that microRNA-219 is the important protectiveness micromolecule nucleic acid of antagonism epilepsy and relevant disease morbidity thereof, can become the medicine of the nervous system disease that prevention and treatment epilepsy and the epilepsy outbreak of take are feature.
The expression situation of change that adds microRNA-219 after the agonist/antagonist of microRNA-219 in embodiment 6. epilepsy cell models
1, this experiment adopts the embryo of conceived 18 days mices, takes out the wherein former culture of Hippocampal Neuron Cells and, after 7 days, is divided into following group: Normal group (adding normal saline); Epilepsy cell model group (add KA, final concentration is 50 μ M); Epilepsy cell model agomir-219 processes intervention group (add KA6h to wait, adding agomir-2190.8nmol to make final concentration is 400nM); Intervention group (processing method is with agomir-219 processed group) is processed in epilepsy cell model agomir-219 negative control agent (agomir-NC); Agomir-219 processes intervention group (adding 0.8nmol agomir-219 to make final concentration in neuron is 400nM); Antagomir-219 processes intervention group (adding 0.8nmol Antagomir-219 to make final concentration in neuron is 400nM); Antagomir-NC processes intervention group (processing method is with antagomir-219 processed group).
2,, after 24h waits, the conventional RNA that respectively organizes cell that extracts, as the step of embodiment 2 detects respectively the microRNA-219 expression of respectively organizing cell.Result as shown in FIG. 11 and 12.
Claims (3)
- The application of 1.microRNA-219 in preparing antiepileptic.
- 2. application as claimed in claim 1, it is characterized in that described antiepileptic for prevention or treat epilepsy and the medicine of the nervous system disease that the epilepsy outbreak of take is feature, the nucleic acid that described medicine comprises sequence shown in sequence table by effective dose and pharmaceutically acceptable carrier or adjuvant form.
- 3. application as claimed in claim 2, is characterized in that the common method that described medicine is prepared according to medicine makes ejection preparation, oral formulations, spray agent, ointment formulation or patch.
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| US10087443B2 (en) | 2013-10-28 | 2018-10-02 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for modulating neuronal excitability and motor behavior |
| CN115998879A (en) * | 2023-01-09 | 2023-04-25 | 广东医科大学附属医院 | Application of miR-92b-3p inhibitor in preparation of epilepsy treatment drugs |
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| WO2009026576A1 (en) * | 2007-08-23 | 2009-02-26 | Keren Pharmaceuticals | Targeting rna with external guide sequences |
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| US10087443B2 (en) | 2013-10-28 | 2018-10-02 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for modulating neuronal excitability and motor behavior |
| US10870853B2 (en) | 2013-10-28 | 2020-12-22 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for modulating neuronal excitability and motor behavior |
| CN115998879A (en) * | 2023-01-09 | 2023-04-25 | 广东医科大学附属医院 | Application of miR-92b-3p inhibitor in preparation of epilepsy treatment drugs |
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