KR102336701B1 - A pharmaceutical composition for treating cognitive decline due to stroke containing sildenafil and Rho-associasted kinase inhibitor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating cognitive decline due to stroke, comprising sildenafil and GSK429286A.
The present inventors studied to use sildenafil and a ROCK inhibitor in combination for the treatment of sequelae due to stroke based on clinical knowledge related to stroke treatment. When administered, it was confirmed for the first time that the decrease in cognitive function due to stroke is significantly improved or that cognitive function is improved compared to the normal control. It is expected to be usefully used in research related to treatment or research and cognitive function enhancement.

Description

A pharmaceutical composition for treating cognitive decline due to stroke containing sildenafil and Rho-associasted kinase inhibitor }

The present invention relates to a pharmaceutical composition for the treatment of sequelae due to ischemic cerebrovascular disease comprising a phosphodiesterase type 5 inhibitor and a ROCK inhibitor (Rho-associasted kinase inhibitor), more specifically It relates to a pharmaceutical composition for treating cognitive decline due to stroke, comprising sildenafil and GSK429286A.

Stroke is defined as a condition in which consciousness and neurological symptoms appear rapidly due to cerebrovascular disorders represented by cerebral hemorrhage and cerebral infarction. 5000 new stroke cases are reported.

Stroke is a temporary brain disease caused by blockage or rupture of blood vessels to the brain. It is a disease that leaves serious sequelae, and hemorrhage such as loss of motor function, sensory abnormality, cognition, speech impairment, loss of consciousness, and impaired swallowing function due to damage to cranial nerve cells. and various neurological symptoms depending on the site of occlusion.

In addition, the causes of brain nerve cell damage caused by stroke include excessive release of excitatory neurotransmitters, generation of free radicals, inhibition of protein synthesis, abnormal gene expression, and activation of immune response. Therefore, no treatment has been developed that can protect the brain nerve cells from damage.

However, there are a number of studies on the prevention or treatment of stroke sequelae of the pharmaceutical composition containing other compounds (Korea Patent Publication No. 10-1869322), but phosphodiesterase type 5 activity inhibitors and ROCK inhibitors There are no studies on the therapeutic use of a pharmaceutical composition comprising a stroke-related motor function loss.

The present inventors studied to use sildenafil and a ROCK inhibitor in combination for the treatment of sequelae due to stroke based on clinical knowledge related to stroke treatment. When administered, it was confirmed for the first time that the decrease in cognitive function due to stroke was significantly improved or cognitive function was improved compared to the normal control group, and the present invention was completed based on this.

Accordingly, the present invention is a phosphodiesterase type 5 activity inhibitor (phosphodiesterase type 5 inhibitor); and

An object of the present invention is to provide a pharmaceutical composition for the treatment of cognitive decline due to ischemic cerebrovascular disease, including a ROCK inhibitor (Rho-associated kinase inhibitor).

In addition, the present invention is a phosphodiesterase type 5 activity inhibitor (phosphodiesterase type 5 inhibitor); and

It is another object to provide a pharmaceutical composition for enhancing cognitive function, including a ROCK inhibitor (Rho-associated kinase inhibitor).

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention as described above, the present invention

phosphodiesterase type 5 inhibitors; and

It provides a pharmaceutical composition for the treatment of cognitive decline due to ischemic cerebrovascular disease, including a ROCK inhibitor (Rho-associasted kinase inhibitor).

In one embodiment of the present invention, the ischemic cerebrovascular disease may be any one selected from the group consisting of ischemic stroke (cerebral infarction), thrombosis, embolism, transient ischemic attack, leukodystrophy and small infarction.

In another embodiment of the present invention, the phosphodiesterase type 5 activity inhibitor is mirodenafil (mirodenafil), sildenafil (sildenafil), vardenafil (vardenafil), tadalafil (tadalafil), udenafil (udenafil) ), dasantafil, avanafil, and pharmaceutically acceptable salts, solvates and hydrates thereof may be any one selected from the group consisting of.

In another embodiment of the present invention, the ROCK inhibitor is Fasudil (Fasudil), Ripasudil (Ripasudil), RKI-1447, Y-27632, GSK429286A, Y-30141 and pharmaceutically acceptable salts, solvates thereof And it may be any one selected from the group consisting of hydrates.

In another embodiment of the present invention, the pharmaceutical composition may be administered before, simultaneously with, or after reperfusion after occlusion of a cerebral blood vessel.

The present invention also provides a method for treating cognitive decline due to ischemic cerebrovascular disease, comprising administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for the treatment of cognitive decline due to ischemic cerebrovascular disease.

In addition, the present invention is a phosphodiesterase type 5 activity inhibitor (phosphodiesterase type 5 inhibitor); and

It provides a pharmaceutical composition for enhancing cognitive function, including a ROCK inhibitor (Rho-associated kinase inhibitor).

The present invention also provides a method for enhancing cognitive function, comprising administering the pharmaceutical composition to a subject.

In addition, the present invention provides a use for enhancing cognitive function of the pharmaceutical composition.

The present inventors studied to use sildenafil and a ROCK inhibitor in combination for the treatment of sequelae due to stroke based on clinical knowledge related to stroke treatment. When administered, it was confirmed for the first time that the decrease in cognitive function due to stroke is significantly improved or cognitive function is improved compared to the normal control. It is expected to be usefully used in research related to treatment or research and cognitive function enhancement.

1 shows an escape hole used in the Barnes maze test.
Figure 2 shows the tracing figures for confirming the cognitive function of the control group, the stroke (cerebral infarction) animal model, the drug alone treatment group, and the drug combination treatment group. Here, MCAo30 represents a stroke (cerebral infarction) animal model, SIL represents a group treated with sildenafil alone, ROCK-I represents a group treated with a Rho-associasted kinase inhibitor alone, and SR represents a group treated with sildenafil alone. ) and ROCK inhibitor (Rho-associasted kinase inhibitor), pre represents the group administered before reperfusion after middle cerebral artery occlusion, and post represents the group administered after reperfusion after middle cerebral artery occlusion.
3 is a graph showing the results of confirming the level of improvement in cognitive function decline in the control group, the stroke (cerebral infarction) animal model, the drug alone treatment group, and the drug combination treatment group. Here, MCAo30 represents a stroke (cerebral infarction) animal model, SIL represents a group treated with sildenafil alone, ROCK-I represents a group treated with a Rho-associasted kinase inhibitor alone, and SR represents a group treated with sildenafil alone. ) and ROCK inhibitor (Rho-associasted kinase inhibitor), pre represents the group administered before reperfusion after middle cerebral artery occlusion, and post represents the group administered after reperfusion after middle cerebral artery occlusion.
4 shows the results of confirming whether the reduction in neuroplasticity due to stroke was improved by measuring the fEPSP slope in the control group, the stroke (cerebral infarction) animal model, and the sildenafil alone treatment group. Here, MCAo30 represents the stroke (cerebral infarction) animal model, SIL represents the group treated with sildenafil alone, pre represents the group administered before reperfusion after occlusion of the middle cerebral artery, and post represents the group administered after reperfusion after middle cerebral artery occlusion. it has been shown
5 is a graph showing the improvement in neuroplasticity reduction due to stroke by measuring the fEPSP slope in a control group, a stroke (cerebral infarction) animal model, and a group treated with sildenafil alone. Here, MCAo30 represents the stroke (cerebral infarction) animal model, SIL represents the group treated with sildenafil alone, pre represents the group administered before reperfusion after occlusion of the middle cerebral artery, and post represents the group administered after reperfusion after middle cerebral artery occlusion. it has been shown

Hereinafter, the present invention will be described in detail.

The present inventors studied to use sildenafil and a ROCK inhibitor in combination for the treatment of sequelae due to stroke based on clinical knowledge related to stroke treatment. When administered, it was confirmed for the first time that the decrease in cognitive function due to stroke was significantly improved or cognitive function was improved compared to the normal control group, and the present invention was completed based on this.

Accordingly, the present invention is a phosphodiesterase type 5 activity inhibitor (phosphodiesterase type 5 inhibitor); And ROCK inhibitor (Rho-associasted kinase inhibitor), including, provides a pharmaceutical composition for the treatment of cognitive decline due to ischemic cerebrovascular disease.

The term “ischemic cerebrovascular disease” according to the present invention refers to a general term for a disease that occurs because blood vessels in the brain are blocked for some reason and the necessary blood is not supplied to the brain, and is also called cerebral ischemic disease, and the ischemic cerebrovascular disease is It refers to a disease caused by the death of nerve cells in tissues known to be sensitive to cerebral ischemia among brain cells because the blood flow of the brain is reduced and oxygen and glucose are not supplied normally. For example, ischemic cerebrovascular disease is ischemic stroke (cerebral infarction), thrombosis, embolism, transient ischemic attack, leukoplakia and small infarction, etc., preferably may be ischemic stroke, but is not limited thereto.

The symptoms of “cognitive function decline due to ischemic cerebrovascular disease”, a disease targeted by the present invention, are very complex and comprehensive symptoms related to perception, analysis, language, memory, and judgment, and vary depending on the location and degree of brain damage. It indicates a decrease in cognitive function, and includes, but is not limited to, learning ability, spatial neglect, spatial-temporal perception, attention, memory, and the like.

In the present invention, the “phosphodiesterase type 5 inhibitor (PDE inhibitor)” is an enzyme found in various tissues. The PDE inhibitors provide potent inhibition of selected isoenzymes without the side effects resulting from non-selective inhibitors, and PDE-5 inhibitors are known to be used in the treatment of primary pulmonary hypertension and erectile dysfunction. Examples include mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil. and the like, and preferably sildenafil, but is not limited thereto.

In the present invention, "ROCK inhibitor (Rho-associasted kinase inhibitor)" is a substance that inhibits apoptosis, and action-induced Ca ^{2 in neurite regeneration, myosin phosphorylation and smooth muscle contraction +} sensitization (agonist-induced Ca ²⁺ sensitization) is known to function, such as inhibition. More specifically, it is reported that the ROCK inhibitor relieves the abnormal structure of muscle cells causing hypertension and asthma, and has the function of increasing the blood flow of the optic nerve papilla and continuously reducing the intraocular pressure, for example, Fasudil , Ripasudil, RKI-1447, Y-27632, GSK429286A, Y-30141, etc., preferably GSK429286A (N-(6-Fluoro-1H-indazol-5-yl) represented by the following Chemical Formula 1 )-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide), but is not limited thereto.

[Formula 1]

In addition, the pharmaceutical composition may be for administration before, simultaneously with, or after reperfusion after occlusion of a cerebral blood vessel, and preferably for administration before, simultaneously with, or after reperfusion after occlusion of the middle cerebral artery. In the present invention, “reperfusion” refers to when blood flow is temporarily cut off in an organ or tissue, so that when the supply of oxygen and nutrients to the cells is cut off, surgery or a thrombolytic agent is used to resume blood flow. say action.

As described above, in one embodiment of the present invention, sildenafil (phosphodiesterase type 5 activity inhibitor) and GSK429286A (ROCK inhibitor) were co-administered to treat cognitive decline that occurred in an acute stage stroke (cerebral infarction) animal model. In this case, when it was observed that the escape hole was reached at a level similar to the escape time of the normal control group, it was confirmed that the cognitive decline was significantly improved, and some individuals in the combined administration group had a higher probability of reaching the escape hole compared to the normal control group. In short, it was confirmed that it exhibited improved cognitive function (memory enhancement) compared to a normal control group that did not have a stroke (see Example 2).

In addition, the results of the above Examples showed that when sildenafil or GSK429286A was administered alone, when sildenafil (phosphodiesterase type 5 activity inhibitor) and GSK429286A (ROCK inhibitor) were administered in combination, the escape time was shortened compared to that of the normal control group. This means that cognitive function is improved when compared, suggesting that the pharmaceutical composition comprising sildenafil and GSK429286A according to the present invention can be usefully used as a cognitive function enhancing agent.

The pharmaceutical composition according to the present invention includes a phosphodiesterase type 5 inhibitor; And ROCK inhibitor (Rho-associated kinase inhibitor) as an active ingredient, and may also include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is commonly used in formulation, and includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, and the like. It does not, and may further include other conventional additives such as antioxidants and buffers, if necessary. In addition, diluents, dispersants, surfactants, binders, lubricants, etc. may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules, or tablets. Regarding suitable pharmaceutically acceptable carriers and formulations, formulations can be preferably made according to each component using the method disclosed in Remington's literature. The pharmaceutical composition of the present invention is not particularly limited in the formulation, but may be formulated as an injection, an inhalant, an external preparation for skin, or an oral intake.

The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, dermally, nasally, applied to the respiratory tract) according to a desired method, and the dosage may vary depending on the patient's condition and body weight, disease Although it varies depending on the degree, drug form, administration route, and time of administration, it may be appropriately selected by those skilled in the art.

The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drugs, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs, and other factors well known in the medical field. The composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, is administered daily or every other day, or 1 It can be administered in 1 to 3 divided doses per day. However, the administration route, cognitive decline due to ischemic cerebrovascular disease, preferably the severity of cognitive decline due to ischemic stroke, gender, weight, age, etc. It is not limiting.

On the other hand, as another aspect of the present invention, the present invention provides a method for controlling or treating cognitive decline due to ischemic cerebrovascular disease comprising administering the pharmaceutical composition to an individual, preferably according to ischemic stroke Provided is a method for controlling or treating cognitive decline, but is not limited thereto.

As used herein, the term “treatment” means that the symptoms of cognitive decline due to ischemic cerebrovascular disease, preferably cognitive decline due to ischemic stroke, are improved or beneficial by administration of the pharmaceutical composition according to the present invention. Any action that changes.

In the present invention, "individual" means a subject in need of a method for controlling or treating a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, It means mammals such as horses and cattle.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1. Experimental materials and methods

1-1. Experimental animals

Male rats, Sprague-Dawley, 8 weeks old and 260-280 g of experimental animals were used, and the experimental animals were obtained from Soonchunhyang University Laboratory Animal Center (Cheonan). All experimental animals were provided with commercial feed and water ad libitum under specific temperature, humidity and lighting conditions (light-dark cycle 12:12, 22 ± 2 °C, 55 ± 5%). All animal protocols were approved by the Administrative Panel for Laboratory Animal Care, Soonchunhyang University (Permission No. SCH16-0024). In carrying out the experiments related to the present invention, it was attempted to avoid the suffering of the experimental animals and to minimize the number of experimental animals used in the experiments.

1-2. Induction of Middle Cerebral Artery occlusion (MCAo)

Rats were anesthetized with 2% isoflurane (2% isoflurane in mixed gas of oxygen and nitrous oxide, 0.3: 0.7), and body temperature was maintained at 37 °C using a heating pad during surgery.

All micro-forceps were sterilized. The tips of 4-0 monofilaments (Nylon suture, Medtronic plc.) were coated with dental silicone to a thickness of 0.37±0.02 mm, and the filament pieces were coated with 0.01% (w/v) poly-L-lysine (Sigma, USA). coated.

The monofilament was inserted into the left common carotid artery (CCA) and proceeded toward the internal carotid artery (ICA) at 18 mm to block the origin of the Middle Cerebral Artery MCA.

Next, a laser Doppler probe (Millwey, Axminste, UK) was fixed to the parietal bone to measure the local cortical blood flow supplied by the middle cerebral artery during surgery. When the baseline focal cortical blood flow was reduced by 20%, the occlusion was reduced. was considered successful.

Then, transient focal ischemia was induced for 30 min by left middle cerebral artery occlusion. Thirty minutes after the onset of ischemia, the rats recovered from anesthesia and the middle cerebral artery was reperfused from transient ischemia.

In order to verify the induction of middle cerebral artery ligation (occlusion), all rats after surgery were checked to see if the following behaviors were possible:

① Inability to extend the opposite front leg

② Inability to rotate toward contralateral to infarct after neurological deficit

The pharmaceutical composition according to the present invention was applied to the induction model of middle cerebral artery ligation (occlusion), and various behavioral tests, electrophysiology, and immunohisto-chemistry experiments were performed in a designated time course. was used for

An induction model of middle cerebral artery ligation (occlusion) without experience in the behavioral tests, etc., and normal rats of the same age were used as controls.

1-3. Experimental drug treatment

The present inventors applied i) Sildenafil citrate, ii) GSK429286A and iii) Sildenafil citrate and GSK429286A to experimental animals, respectively, to treat direct brain damage caused by mild ischemic stroke or various phenotypic sequelae of phosphodiesterase type 5 activity. The effect of type 5 inhibitor) and/or ROCK inhibitor (Rho-associated kinase inhibitor) was evaluated.

More specifically, the following experimental drugs were administered intraperitoneally 30 minutes before reperfusion after occlusion of the middle cerebral artery and 30 minutes after reperfusion after occlusion of the middle cerebral artery, respectively.

i) Sildenafil citrate (20mg/kg/saline, Hanmi Parm. Co., Republic of Korea)

ii) GSK429286A (10mg/kg/DMSO, Sigma, USA)

iii) Sildenafil citrate (20mg/kg/saline) and GSK429286A (10mg/kg/DMSO)

1-4. Barnes maze test

The Barnes maze consists of a circular platform (122 cm in diameter) with 20 holes around the same distance, raised 105 cm from the floor. Four different visual cues were placed on each quadrant wall surrounding the platform at a height convenient for observing the experimental animals, and one hole in the quadrant area (the escape hole) contained an escape chamber below the platform. In addition, bedding was added to the escape chamber for the safety of the experimental animals. To amplify the anxiety for motivation to find the escape chamber, a metronome and bright lights were used. More specifically, a metronome was used to continuously generate noise of 80 Hz, and the illuminance measured at the center of the platform was maintained at 300 lux.

During the acclimatization phase, the experimental animals were placed in a black cylinder at the center of the platform, and the acclimatization phase lasted for 4 days. After 10 seconds, when the cylinder was removed, the animal navigated the platform from the center and this activity was recorded by a video camera. In addition, a time of 180 seconds was given for the experimental animal to find the escape hole. When the experimental animal entered the escape chamber through the escape hole within 180 seconds, a cover was placed on the hole for 120 seconds to block the light and stop the 80Hz noise.

In addition, if the experimental animal could not find the escape hole, the experimental animal was carefully pulled and guided to the escape hole with the escape chamber to induce learning about the space. The learning was performed on each experimental animal for 3 times at 15-minute intervals as an adaptive step to improve spatial memory for finding a way out.

On day 5, the space acquisition phase (probe phase), the experimental animals were given 90 s to find a way out, but the escape chamber was removed. This step was performed only once.

Distance traveled and duration in the quadrant section with the escape chamber connected to the escape hole were analyzed with Ethovision® software and the waiting time to reach the escape chamber connected to the escape hole was analyzed manually.

1-5. fEPSP slope measurement

Field potentials (fEPSP) were recorded at slightly modified sites from CA1 of the hippocampus. After the behavioral test, the animals were intraperitoneally anesthetized using urethane (1.5 g/kg) and placed in a stereotaxic frame. A temperature controller (Harvard Instruments, USA) was used to maintain the rectal temperature at 37 ± 0.3 °C during the surgical procedure.

Next, the scalp was opened and separated, and a hole was drilled through the skull to introduce the electrodes.

The coordinates (in mm) with respect to the bregma (the junction of the coronary artery of the skull and the sagittal suture) are as follows.

i) recording electrode, to the Schaffer collateral: 4.0 posterior to bregma, 3.0 laterally to centerline, 2.5 deep

ii) stimulating electrode, to the stratum radiatum of CA1: 3.5 posterior to bregma, 2.0 lateral to midline, and 3.5 deep to hippocampus.

The electrode depth was finally determined by observing whether the evoked response was optimized. fEPSP was adjusted to ~60% of the maximal response magnitude for testing, and stimulation was generated by a BNC-2110 apparatus (National Instruments, USA) and a Digital Stimulus Isolation unit (Getting Instruments, CA, USA). The response of pyramidal neurons to the Schaffer collateral stimulation was P55 A.C. Recorded using a pre-amplifier (3 - 1000 Hz bandpass, Astro-Med Inc.), WinLTP ver. 2.01 software (WinLTP Ltd.) was used for analysis. In addition, responses were triggered by single-pulse stimulation and delivered at 20-second intervals. A stable baseline was recorded for 30 to 60 minutes.

Long-term potential (LTP) is a strong theta patterned stimulus (theta patterned stimulus, sTPS, four trains of 10 bursts of 5 pulses at 400 Hz with a 200-ms inter-burst interval, 15-s inter-train interval) was induced by This is because bursts of 400 Hz stimuli (sTPS) are NMDA-receptor dependent and potent LTPs in CA1 and DG regions are induced by sTPS in vivo.

To analyze the change in fEPSP, the slope of fEPSP was averaged at 60 sec intervals and expressed as a percentage of the mean fEPSP slope measured during a 30-minute reference time, which was expressed as 100%. The response of fEPSP to the age-matched control group was also measured using the same method.

Example 2. Confirmation of improvement in cognitive function (long-term memory, long-term memory) decline through Barnes maze test when sildenafil and a ROCK inhibitor are co-administered

Using MCAo30, an acute stage stroke (cerebral infarction) animal model, i) sildenafil or ROCK inhibitor alone, ii) sildenafil and ROCK inhibitor were administered in combination to determine the degree of cognitive decline, which is one of the sequelae of stroke. , the Barnes maze test was performed, and the cognitive function was based on the escape time of the normal control group. The experiment was performed based on the method described in 1-4.

As a result, as shown in FIG. 3 , it was confirmed that the escape time to find the escape hole of the stroke (cerebral infarction) animal model (MCAo30) was increased by about 3 times compared to the normal control group. The above results confirm that memory loss is one of the most serious sequelae following stroke.

In addition, the escape times of the sildenafil alone group and the ROCK inhibitor alone group were both measured at similar levels to those of the normal control group, confirming that cognitive decline was significantly improved when sildenafil or ROCK inhibitor alone was administered.

In addition, the escape time of the group administered with sildenafil and a ROCK inhibitor was measured at a level similar to that of the normal control group, confirming that cognitive decline was significantly improved. It was confirmed that it exhibited improved cognitive function (memory enhancement) than the cognitive function of the normal control group.

In addition, the escape time of the group administered with the drug after reperfusion was significantly shorter than that of the group administered with the drug before reperfusion after occlusion of the middle cerebral artery, and it was confirmed that the effect of improving cognitive function was excellent in the group administered with the drug after reperfusion after occlusion of the middle cerebral artery. .

Based on the above experimental results, it can be seen that co-administration of sildenafil and a ROCK inhibitor after reperfusion after occlusion of the middle cerebral artery can not only more effectively improve cognitive decline due to stroke, but also enhance cognitive function compared to the normal control group. have.

Example 3. Confirmation of improvement in neuroplasticity when sildenafil and a ROCK inhibitor were co-administered

Using MCAo30, an acute stage stroke (cerebral infarction) animal model, an experiment to determine whether neuroplasticity improved when i) sildenafil was administered alone before reperfusion after middle cerebral artery occlusion, and ii) sildenafil was administered alone after reperfusion after middle cerebral artery occlusion was performed, and the cognitive function was compared with that of the normal control group. The above experiment was performed based on the method described in 1-5.

As a result, it was confirmed that the fEPSP slope deteriorated to 84.11% in MCAo30, a stroke model, as shown in FIGS. 4 and 5 .

However, in the group administered with sildenafil alone, after middle cerebral artery occlusion and before reperfusion, the fEPSP slope was improved to 102.35%, almost the same as that of the normal control group. .

Comparing the experimental results with numerical values, the drug administration group after middle cerebral artery occlusion and reperfusion showed a 4.06 fold improvement in fEPSP slope compared to the drug administration group after middle cerebral artery occlusion and reperfusion before reperfusion. It was confirmed that the improvement effect was significantly improved, and the result is consistent with the result of Example 2.

In addition, when the above experimental results are combined, it can be seen that the improvement effect of neuroplasticity reduction due to stroke is maximized when sildenafil is administered alone after reperfusion after middle cerebral artery occlusion in an animal model of stroke (cerebral infarction).

The description of the present invention stated above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. There will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (5)

phosphodiesterase type 5 inhibitors; And ROCK inhibitor (Rho-associasted kinase inhibitor) comprising, as a pharmaceutical composition for the treatment of cognitive decline due to ischemic cerebrovascular disease,
The phosphodiesterase type 5 activity inhibitor is sildenafil, and the ROCK inhibitor is GSK429286A (N-(6-Fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[ 4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide), wherein the ischemic cerebrovascular disease is an ischemic stroke (cerebral infarction), a pharmaceutical composition.
delete delete delete According to claim 1,
The pharmaceutical composition is for administration before, concurrently with, or after reperfusion after occlusion of a blood vessel in the brain.

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