JP2006131511A - Ischemic encephalopathy inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an ischemic encephalopathy inhibitor useful for the prophylaxis or treatment of ischemic encephalopathy. <P>SOLUTION: This ischemic encephalopathy inhibitor contains an L-type channel calcium antagonist as an active ingredient. The ischemic encephalopathy inhibitor contains a hypotensive drug as the above L-type channel calcium antagonist. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an ischemic brain injury inhibitor containing, for example, an L-type channel agonist calcium antagonist as an active ingredient.

  Hypertension is involved in the progression of arteriosclerosis and is a risk factor for ischemic brain damage such as stroke. Management such as prevention or treatment of hypertension is an important prevention strategy for ischemic brain damage.

  In the development of modern medicine, antihypertensive therapy is used for the treatment or prevention of hypertension. In the antihypertensive therapy, an antihypertensive agent having an antihypertensive action is used. Antihypertensive therapy significantly reduces the frequency of severe hypertensive intracerebral hemorrhage. On the other hand, antihypertensive therapy increases the incidence of cerebral infarction, an obstructive disease. Thus, antihypertensive therapy has the effect of suppressing the development of arteriosclerosis, which is the cause of hypertensive intracerebral hemorrhage, in the long term. However, antihypertensive therapy may reduce organ blood flow, particularly local cerebral blood flow that is directly involved in the development of cerebral infarction. That is, long-term antihypertensive therapy is effective for the prevention or treatment of hypertension, the progression of arteriosclerosis, or the occurrence of cerebral hemorrhage. However, antihypertensive therapy can sometimes exacerbate pathological ischemic conditions in patients with ischemic brain disorders such as cerebral infarction or the risk of developing them. Therefore, antihypertensive therapy must always be used appropriately in consideration of the progress of stenotic vascular lesions possessed by individual patients.

  To date, antihypertensive agents with various mechanisms of action for use in antihypertensive therapy have been developed. However, many antihypertensive agents have the potential to exacerbate potential ischemic conditions in patients at risk of suffering from ischemic diseases such as ischemic brain damage.

  As described above, in the prevention or treatment method such as antihypertensive therapy, it is desired to develop a drug having a brain protective effect by reducing the risk of suffering ischemic disease such as ischemic brain injury. In particular, it is estimated that there are currently 33 million hypertensive patients in need of treatment in Japan. For many of these patients, antihypertensive agents having a brain protective effect under ischemic conditions are significant. However, to date, there has been no antihypertensive agent with proven brain protective effects.

  On the other hand, when the brain direct current (DC) potential is changed by applying a stimulus such as a pathological condition or physical damage in the brain, depolarization with respect to a normal state of intracellular / external potential polarization occurs. In the brain, it is known that the depolarization wave that slowly spreads around the local depolarization at a specific speed of 2 to 5 mm / min is repeatedly generated around the local depolarization. This phenomenon is a transient reversible cell depolarization phenomenon called spreading suppression (Non-patent Documents 1 and 2). The present inventors have previously found that, by subjecting the brain to spread suppression, the brain becomes resistant to ischemia after a certain period of time, that is, induces a strong ischemic tolerance termed cerebral infarction tolerance. (Non-Patent Document 3).

  In the nerve cell through which the wave of spreading suppression passes, a calcium channel such as voltage-dependent L-type is temporarily opened with depolarization of the cell membrane. It is considered that a large amount of calcium ion flows into the cell from the opened calcium channel, which causes various biological reactions including the production of stress proteins (Non-patent Document 4). In ischemic brain injury, a large amount of extracellular calcium ions flows into cells via various routes during ischemia. Due to the inflow of the calcium ions, it is thought that it eventually leads to neuronal cell damage or neuronal cell death (Non-patent Document 5). On the other hand, L-type calcium channels have been considered to be mainly involved in vasoconstriction. Inhibition of L-type calcium channels includes cardiomyocyte excitation suppression, circulatory improvement by vasodilation, and antihypertensive action. L-type channel agonist calcium antagonists are used as antiarrhythmic or antihypertensive agents. Yes.

  In addition, it has been reported that a vascular permeability enhancement inhibitor containing a dihydropyridine derivative having a calcium antagonistic action is useful for, for example, prevention or treatment of brain edema (Patent Document 1). However, Patent Document 1 does not describe that the dihydropyridine derivative having the calcium antagonistic action has an effect of inhibiting ischemic brain injury or a brain protecting effect.

JP 2000-103736 A Leao AAP, Spreading depression of activity in the cerebral cortex, `` Journal of Neurophysiology '', 1944, 7, 359-390 Bures J et al., “The Mechanism and Applications of Leao's Spreading Depression of Electroencephalographic Activity”, Academia publisher, Prague, 1974 Yanamoto H. et al., Infarct tolerance against temporary focal ischemia following spreading depression in rat brain, `` Brain Research '', 1998, 784, p. .239-249 Yanamoto H. et al., Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei, `` Brain Research '', 2000, Vol. 877, p.331 -344 Lee KS et al., Calcium-activated proteolysis as a therapeutic target in cerebrovascular disease, "Annals of the New York Academy of Sciences", 1997, 825, p. .95-103

  In view of the above-described circumstances, an object of the present invention is to provide an ischemic brain injury inhibitor and a brain protective agent that can be used reliably and safely and that suppress ischemic brain injury.

  As described above, various phenomena have been observed in the development of ischemic brain damage, but no knowledge has been obtained that can achieve suppression or protection of the ischemic brain damage.

  As a result of intensive studies to solve the above-mentioned problems, it was found that an L-type channel-acting calcium antagonist suppresses ischemic brain injury, and the present invention has been completed.

The present invention includes the following.
(1) An ischemic brain injury inhibitor containing an L-type channel agonist calcium antagonist as an active ingredient.

  (2) The ischemic brain injury inhibitor according to (1), wherein the L-type channel agonist calcium antagonist is an antihypertensive agent.

  (3) The ischemic brain injury inhibitor according to (2), wherein the antihypertensive agent is selected from the group consisting of azelnidipine, nifedipine, diltiazem, nicardipine, nimodipine, benidipine, cilnidipine and amlodipine.

(4) The ischemic brain injury inhibitor according to any one of (1) to (3), wherein the ischemic brain injury is cerebral infarction.
(5) A brain protective agent comprising the ischemic brain injury inhibitor according to any one of (1) to (4).

  According to the present invention, an ischemic brain injury inhibitor is provided. Since the ischemic brain injury inhibitor according to the present invention has an inhibitory effect on the progression of ischemic brain injury, it can be used for the prevention or treatment of ischemic brain injury. In addition, due to the inhibitory effect on the development of ischemic brain injury, the ischemic brain injury inhibitor according to the present invention can be used for brain protection.

Hereinafter, the present invention will be described in detail.
The ischemic brain injury inhibitor according to the present invention contains an L-type channel agonist calcium antagonist as an active ingredient. By administering the ischemic brain injury inhibitor according to the present invention to animals such as humans, the development of ischemic brain injury can be suppressed.

  The L-type channel agonist calcium antagonist is a general term for substances having an inhibitory action on the L-type calcium channel. The inhibitory effect on the L-type calcium channel can be measured by, for example, applying an L-type channel agonist calcium antagonist from outside and inside the cell and suppressing the L-type calcium channel current by the patch clamp method. In the presence or absence of an L-type channel agonist calcium antagonist, the L-type calcium channel current is activated, for example, with a 120-200 ms pulse from -90-40 mV to + 0-70 mV.

  The L-type channel agonist calcium antagonist used in the ischemic brain injury inhibitor according to the present invention is not particularly limited as long as it has an inhibitory action on the L-type calcium channel, for example, azelnidipine ( azelnidipine (pharmaceutical name: Calblock), nifedipine (Pharmaceutical name: Adalat), diltiazem (Pharmaceutical name: Herbesser), nicardipine (Pharmaceutical name: Perdipine), nimodipine, Benidipine ( benidipine) (pharmaceutical name: Conil), cilnidipine (pharmaceutical name: atelec) and amlodipine (medicine name: amrodin or norvasque) and other compounds used as antihypertensive agents, and verapamil (pharmaceutical name) : Wasoran), mibefradil, and flunarizine Nar), and the like. In particular, L-type channel agonist calcium antagonists used as antihypertensive agents are preferred.

  Currently, azelnidipine is used for the purpose of improving hypertension as an antihypertensive agent because it has a hypotensive action. Among the above-mentioned L-type channel agonist calcium antagonists, in addition to azelnidipine, for example, nifedipine, diltiazem, nicardipine, nimodipine, benidipine, cilnidipine and amlodipine have antihypertensive action and are used as antihypertensive agents. Yes. In the antihypertensive therapy for hypertension, by using the above-mentioned L-type channel-acting calcium antagonist having antihypertensive effect, it is possible to prevent or treat hypertension, reduce the risk of ischemic encephalopathy, and provide a brain protective effect. Can be granted.

  The calcium channel means an ion channel that selectively permeates calcium ions. Calcium channels are classified into L-type, N-type, P / Q-type, R-type, and T-type based on voltage dependence, activation / deactivation rate, tissue distribution, and pharmacological properties. Is done. L-type calcium channels are localized, for example, in the myocardium, smooth muscle, nerve cells, or skeletal muscle, kidney, and ovary. L-type calcium channels are characterized by (1) high threshold for membrane depolarization required for opening (activation), (2) relatively slow activation and deactivation, and (3) inflow through opening Calcium causes excitatory contraction of muscle and excitatory secretion of secretory cells and some neurons. In the present invention, L-type calcium channels are targeted.

  When the brain direct current (DC) potential is changed by applying a stimulus such as a physical condition or a physical injury to the brain, spread suppression (hereinafter referred to as “SD”) repeatedly occurs. FIG. 1 shows the mechanism of SD in the brain. As shown in FIG. 1, in a neuron cell through which an SD wave passes, it is considered that an L-type calcium channel is temporarily opened and a large amount of calcium ions flows into the cell.

  On the other hand, FIG. 2 illustrates SD induction in the rat brain, and high-concentration potassium chloride injection into the brain cortex induces local cell depolarization, which is the focal point, and potential waves are generated throughout the brain. This is an image of how SD is expanding. SD is known to spread not only in the brain cortex, but also in various parts of the deep brain.

  As shown in FIG. 2, after subjecting the brain to a stimulus that causes SD (eg, local infusion of high concentrations of potassium chloride), the brain has ischemic tolerance after a certain period of time. The ischemic tolerance in the brain confers resistance to cerebral infarction caused by ischemia (cerebral infarction tolerance). In contrast to the opening of the L-type calcium channel by SD, the living body suppresses the opening of the L-type calcium channel, and this suppression is thought to force the brain to be resistant to ischemia. In the present invention, an L-type channel agonist calcium antagonist having an inhibitory action on L-type calcium channels is used to cause ischemic or cerebral infarction resistance in the brain and to suppress ischemic brain damage as described above. .

  Here, ischemic encephalopathy means that cerebral nerve cells cannot receive sufficient oxygen supply due to a decrease in local cerebral blood flow, and as a result, those cells cause metabolic disorders, and eventually cerebral nerve cell function declines. Or, it means the state that led to cell death. In the present invention, the ischemic cerebral disorder to be prevented or treated is not limited, for example, cerebral infarction and transient cerebral ischemic disorder, and cardiac arrest, hypotension, anemia, blood removal And brain damage caused by various gas poisoning or suffocation, and brain damage caused by hypoxia. Particularly preferred is cerebral infarction.

  On the other hand, the ischemic cerebral injury inhibitor according to the present invention suppresses ischemic encephalopathy without depending on the circulation improving action, and thus can be said to have a brain protective effect. Here, the brain protective effect means that the brain that has fallen into a lethal ischemic state such as ischemic brain injury is protected from dysfunction or death. The ischemic brain injury inhibitor according to the present invention can be used as a brain protective agent.

  In order to suppress the development of ischemic brain injury or protect the brain, it may be necessary to administer the ischemic brain injury inhibitor according to the present invention to animals such as humans over a long period of time. In such a case, when using the ischemic brain injury inhibitor according to the present invention, it is necessary that long-term administration is safe for the living body of an animal such as a human. In this regard, L-type channel agonist calcium antagonists such as azelnidipine described above have already been used in clinical settings. Therefore, it has already been confirmed that the ischemic brain injury inhibitor according to the present invention containing an L-type channel agonist calcium antagonist such as azelnidipine as an active ingredient has high safety for the living body of animals such as humans. .

  The ischemic brain injury inhibitor according to the present invention can be formulated into one or more L-type channel agonist calcium antagonists described above alone or in combination with a pharmaceutical ingredient.

  The dosage form of the ischemic brain injury inhibitor according to the present invention is not particularly limited, and examples thereof include tablets, powders, emulsions, capsules, granules, fine granules, powders, liquids, syrups, Examples include oral preparations such as suspensions and elixirs, and parenteral preparations such as injections, drops, suppositories, inhalants, transdermal absorption agents, transmucosal absorption agents, patches, and ointments.

  Examples of the pharmaceutical ingredient that can be combined with the L-type channel agonist calcium antagonist include, for example, excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, corrigents, coloring agents. An agent and a fragrance | flavor are mentioned.

  Examples of the excipient include starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.

  Examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium, Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkylmeta The Rate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, include purified sucrose and macrogol.

  Examples of the disintegrant include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized starch. , Hydroxypropyl starch, sodium carboxymethyl starch and tragacanth.

  Examples of the surfactant include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, Examples include sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate and lauromacrogol.

  Examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, metasilica. Examples include magnesium aluminate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.

  Examples of the fluidity promoter include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate and magnesium silicate.

  Moreover, when the dosage form of the ischemic brain injury inhibitor according to the present invention is a solution, a syrup, a suspension, an emulsion or an elixir, it may contain a flavoring agent, a coloring agent and the like.

  Furthermore, the ischemic brain injury inhibitor according to the present invention may contain a further component. Examples of components that can be contained in the ischemic brain injury inhibitor according to the present invention include platelet function inhibitors, blood coagulation inhibitors, serine protease inhibitors, gastric mucosa protective agents, various vitamins and various minerals, and coenzymes. Examples of so-called supplements such as Q10 are mentioned.

  On the other hand, the content of the L-type channel agonist calcium antagonist in the ischemic brain injury inhibitor according to the present invention can be appropriately changed according to the administration purpose, administration route, dosage form and the like.

  The number of administrations, the dosage, and the administration period of the ischemic cerebral disorder inhibitor according to the present invention are not particularly limited. For example, the type of illness, the age, sex, weight, or symptom of the patient, or the administration method It can be appropriately determined according to the above. In addition, if you take it once a day or more several times a day, if you take it every day, the drug accumulation effect in the body occurs like a general drug, so compared with a single oral method, Sufficient effects may be obtained even at relatively low doses. In other words, the optimal effective drug dose per time varies depending on the metabolic rate (blood half-life) of the drug and the internal use. The frequency of administration is, for example, 1 to 6 times a day, preferably 1 to 3 times a day by oral administration. The dose of the L-type channel agonist calcium antagonist contained in the ischemic brain injury inhibitor according to the present invention is 0.01 to 10 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight per day. The administration period is 3 days to 10 years or more, preferably continuous administration.

  The administration route of the ischemic cerebral disorder inhibitor according to the present invention can be appropriately determined according to the dosage form and intended use. For example, oral administration and parenteral administration (intraperitoneal administration, intravenous administration, muscle Internal administration, subcutaneous administration, rectal administration, intranasal administration, sublingual administration, etc.).

  The pharmacological evaluation of the ischemic brain injury inhibitor according to the present invention can be performed using, for example, a model animal of cerebral infarction, which is one of the ischemic brain injury.

  Examples of the method for producing a cerebral infarction model animal include an intravascular embolus insertion method and a three-vessel occlusion opening technique (hereinafter referred to as “three-vessel occlusion method”).

  The intravascular embolus insertion method is a method in which a small hole is formed in one side of the carotid artery, and an embolus such as nylon thread is inserted toward the head side from there. The tip of the embolus reaches the cerebral blood vessel (middle cerebral artery) in the cranium, where the cerebral blood flow is blocked. However, in this method, foreign matters such as nylon thread inserted into the blood vessel stimulate the coagulation proteolytic enzyme group, and clots of various degrees are generated. Therefore, the ischemic region extends to various regions other than the middle cerebral artery where the embolus can reach. In addition, the clot generated by the embolus causes new cerebral ischemia, and the ischemic state due to the clot may continue even after the embolus is removed. In other words, in model animals prepared by the intravascular embolization method, platelet inhibitors or blood coagulation inhibitors that do not have a brain-protecting effect improve cerebral circulation, resulting in mild ischemia and false May improve blood brain damage.

  On the other hand, the three-vessel occlusion method is a technique in which a total of three blood vessels, i.e., intracranial blood vessels such as the carotid artery on one side and the middle cerebral artery on one side, are simultaneously occluded. Therefore, it is possible to introduce cerebral ischemia only by reducing blood flow. In a model animal produced by the three-vessel occlusion method, a blood clot basically does not occur. Therefore, a blood coagulation inhibitor or the like cannot improve an ischemic state or an ischemic brain injury.

  In assessing the inhibitory effect on ischemic brain injury, there is a strict distinction between the ischemic brain injury-inhibiting effect due to the local cerebral circulation improvement effect resulting from ischemic relief and the brain-protecting effect due to the ischemic brain injury-inhibiting effect. Is to be done. The cerebral infarction observed in the model animal prepared by the three-vessel occlusion method described above does not depend on new vascular occlusion due to the progress of intravascular blood coagulation, etc., so for example, the clot formed in the blood vessel is dissolved. Therefore, cerebral circulation improvement therapy such as so-called thrombolytic therapy that improves local cerebral blood flow is not effective. Cerebral infarction in a model animal prepared by 3 vessel occlusion method is not caused by coagulation / thrombosis in the blood vessel, but depends on temporary local blood flow decrease due to vessel occlusion alone and occlusion time (Yanamoto H. Et al., Exp. Neurol., 2003, 182, 261-274). As described above, by using a model animal prepared by the three-vessel occlusion method, the ischemic cerebral disorder inhibitor according to the present invention is not a local cerebral circulation improvement effect (for example, due to coagulation / thrombus suppression or thrombolysis effect). The true brain protective effect by the ischemic brain injury inhibitory effect can be determined.

  From the above, in the pharmacological evaluation of the ischemic cerebral disorder inhibitor according to the present invention, it is preferable to use a model animal produced by the three-vessel occlusion method as a cerebral infarction model animal.

  For example, the ischemic brain injury inhibitor according to the present invention is once orally administered to C57BL / 6J male mice in advance. After the administration of the ischemic cerebral disorder inhibitor according to the present invention, the mouse is subjected to the three-vessel occlusion method at intervals (for example, 1 hour). The mouse is used as a cerebral infarction model mouse, that is, a model mouse prepared by the three-vessel occlusion method. In addition, the ischemic brain injury inhibitor according to the present invention may be administered to treat ischemic brain injury after being subjected to the three-vessel occlusion method. Next, the volume of cerebral infarction in a model mouse prepared by the three-vessel occlusion method is measured. In addition, a model mouse prepared by a three-vessel occlusion method in which a placebo (for example, a solvent) is administered instead of the ischemic brain injury inhibitor according to the present invention is used as a control.

  Compared with the model mice prepared by the control 3-vessel occlusion method, the cerebral infarct volume was statistically significantly different in the model mice prepared by the 3-vessel occlusion method administered with the ischemic brain injury inhibitor according to the present invention. If it decreases, it can be determined that the development of ischemic brain injury could be suppressed (shows a brain protective effect).

  The L-type channel agonist calcium antagonist contained as an active ingredient in the ischemic cerebral disorder inhibitor according to the present invention suppresses the progression of ischemic cerebral disorder. Administration to animals such as can suppress the development of ischemic brain damage in vivo. For example, the ischemic brain injury inhibitor according to the present invention can be used in a new acute treatment method for ischemic stroke such as cerebral infarction. Moreover, the ischemic brain injury inhibitor according to the present invention can also be used for the purpose of reducing the onset risk of patients having a risk factor related to the ischemic brain injury.

  In the brain, when a nutrient blood vessel is occluded or when a stenosis occurs, sufficient blood flow and supply of oxygen cannot be obtained, and when this condition persists, metabolic disorders occur. As a result, organ damage such as the appearance of permanent dysfunction and cell death (partial organ necrosis) is caused. Therefore, in order to prevent or treat organ damage such as partial organ necrosis due to ischemic metabolic disorder, without relying on the effect of improving local cerebral circulation due to ischemic alleviation, the imaginary according to the present invention. Hematological encephalopathy inhibitor can be used.

  Furthermore, since the ischemic brain injury inhibitor according to the present invention has a brain protective effect, it can be applied to the brain protection of all animals. On the other hand, cell metabolic damage or cell death due to persistent oxygen supply is not limited to cranial nerves. Various organs, muscles, bones, and skin are blocked by various blood vessel obstructions or stenosis. It can also occur in extremities consisting of etc. In these organs, various functional disorders and cell death occur as in the brain. Therefore, the ischemic brain injury inhibitor according to the present invention can be applied to organ protection of all animals. In particular, the ischemic cerebral disorder inhibitor according to the present invention can be suitably applied to brain protection or organ protection of mammals (eg, humans, monkeys, cows, sheep, horses, etc.).

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example, the technical scope of this invention is not limited to these Examples. Prior to the examples, experimental examples to be referred to in describing the present invention will be described.

[Experimental example 1] Changes in cerebral infarction volume with respect to ischemia time (vascular occlusion time) in cerebral infarction model animals prepared by intravascular embolus insertion method or three-vessel occlusion method Using male rats, halothane inhalation general anesthesia The following operations were performed below.

  First, the common transarterial artery on both sides was exposed by skin incision in the midline of the front neck, and the blood flow to the cranial side was blocked by applying a surgical miniclip to this. Next, the skin was transversely incised at the left temporal region, the zygomatic arch was partially excised, the inside of the temporomandibular joint was released, the left mandible was squeezed downward, and the left temporal bone was exposed. A burr hole with a diameter of about 2 mm was made just above the left middle cerebral artery, and only the dura mater was incised so as not to damage the brain.

  The left middle cerebral artery was occluded by electrocoagulation at the lateral side of the olfactory nerve. At this point, 3 vessels (bilateral common carotid artery, left middle cerebral artery) occlusion are achieved. During ischemic load, systemic arterial blood pressure, body temperature, arterial blood oxygen / carbon dioxide partial pressure, and Ph were kept strictly within the physiological range, and transient focal cerebral ischemia was loaded for various times. The determination of cerebral infarction was performed for 2 days after ischemic load, after being kept in a normal cage, the whole brain was taken out under general anesthesia, a 2 mm thick coronal brain slice was prepared, and 2,3,4-triphenyltetrazolium chloride ( The survival part in the brain tissue was colored red by TTC) staining. The cerebral infarct volume can be calculated from the stained section using an image analyzer. The local cerebral blood flow during ischemia can be measured using a laser Doppler blood flow meter and a hydrogen clearance method. In addition, this method confirmed that blood flow beyond the middle cerebral artery coagulation was maintained 2 days after surgery, that is, there was no intravascular blood coagulation (due to new vascular occlusion) spreading from the vascular occlusion site. (Yanamoto H. et al., Exp. Neurol., 2003, 182, 261-274).

  As described above, cerebral infarction model rats prepared by the three-vessel occlusion method (hereinafter referred to as “three-vessel occlusion model rats”), as well as published literature (hereinafter referred to as “reference documents”), intravascular Changes in cerebral infarction volume with respect to ischemia time (blood vessel occlusion time) in cerebral infarction model rats (hereinafter referred to as “intravascular embolus insertion model rats”) and 3-vascular occlusion model rats prepared by embolization method Comparison was made (Yanamoto H. et al., Exp. Neurol., 2003, 182, 261-274). The results are shown in FIG.

In FIG. 3, each plot shows the following ischemic time.
Downward solid triangle plot: 1 hour ischemia (model rat described in reference).
Black triangle triangle pointing upward: 1.5 hours ischemia (model rat described in reference).
Black circle plot: 2 hours ischemia (model rat described in reference).
Black square plot: 3 hours ischemia (model rat described in reference).
Black diamond plot: permanent ischemia (model rat described in reference).
Downward white triangle plot: 1 hour ischemia (3-vessel occlusion model rat prepared above).
Open white triangle plot: 1.5 hours ischemia (3-vessel occlusion model rat prepared above).
Open circle plot: 2-hour ischemia (3-vessel occlusion model rat prepared above).
In FIG. 3, the horizontal axis is a document number indicating the following reference.

References
1: Wang L., Kittaka M., Sun N., Schreiber SS, Zlokovic BV, Chronic nicotine treatment enhances focal ischemic brain injury and depletes free pool of brain microvascular tissue plasminogen activator in rats. J. Cereb. Blood Flow Metab. 1997 ; 17: 136-146.
2: Kawamura S., Li Y., Shirasawa M., Yasui N., Fukasawa H., Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg. Neurol. 1994; 41: 368-373.
3: Relton JK, Beckey VE, Hanson WL, Whalley ET, CP-0597, a selective bradykinin B ₂ receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion. Stroke 1997; 28: 1430-1436.
4: Zhang Y., Pardridge WM, Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke 2001; 32: 1378-1384.
5: Onal MZ, Li F., Tatlisumak T., Locke KW, Sandage BW, Jr., Fisher M., Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke 1997; 28: 1060-1065 .
6: Matsushima K., Hakim AM, Transient forebrain ischemia protects against subsequent focal cerebral ischemia without changing cerebral perfusion. Stroke 1995; 26: 1047-1052.
7: Liu Y., Belayev L., Zhao W., Busto R., Ginsberg MD, MRZ 2/579, a novel uncompetitive N-methyl-D-aspartate antagonist, reduces infarct volume and brain swelling and improves neurological deficit after focal cerebral ischemia in rats.Brain Res. 2000; 862: 111-119.
8: Zhang ZG, Chopp M., Chen H., Duration dependent post-ischemic hypothermia alleviates cortical damage after transient middle cerebral artery occlusion in the rat. J. Neurol. Sci. 1993; 117: 240-244.
9: Kawamura S., Li Y., Shirasawa M., Yasui N., Fukasawa H .. Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg. Neurol. 1994; 41: 368-373.
10: Harukuni I., Bhardwaj A., Shaivitz AB, DeVries AC, London ED, Hurn PD, Traystman RJ, Kirsch JR, Faraci FM, σ ₁ -receptor ligand 4-phenyl-1- (4-phenylbutyl) -piperidine affords neuroprotection from focal ischemia with prolonged reperfusion.Stroke 2000; 31: 976-982.
11: Karibe H., Chen J., Zarow GJ, Graham SH, Weinstein PR, Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats. J. Neurosurg. 1994; 80: 112-119.
12: Belayev L., Busto R., Zhao W., Clemens JA, Ginsberg MD, Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J. Neurosurg. 1997; 87: 595- 601.
13: Bhardwaj A., Castro AFIII., Alkayed NJ, Hurn PD, Kirsch JR, Anesthetic choice of halothane versus propofol: impact on experimental perioperative stroke. Stroke 2001; 32: 1920-1925.
14: Arii T., Kamiya T., Arii K., Ueda M., Nito C., Katsura KI, Katayama Y., Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia Neurol. Res. 2001; 23: 755-760.
15: Kawaguchi K., Graham SH, Neuroprotective effects of the glutamate release inhibitor 619C89 in temporary middle cerebral artery occlusion. Brain Res. 1997; 749: 131-134.
16: Phillips JB, Williams AJ, Adams J., Elliott PJ, Tortella FC, Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia. Stroke 2000; 31: 1686-1693.
17: Kawamura S., Li Y., Shirasawa M., Yasui N., Fukasawa H., Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg. Neurol. 1994; 41: 368-373.
18: Schabitz WR, Schwab S., Spranger M., Hacke W., Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 1997; 17: 500-506.
19: Kawamura S., Li Y., Shirasawa M., Yasui N., Fukasawa H., Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg. Neurol. 1994; 41: 368-373.
20: Yanamoto H. et al., Exp. Neurol., 2003, 182, 261-274 (describes the three-vessel occlusion model rat prepared above).
21: Liu TH, Beckman JS, Freeman BA, Hogan EL, Hsu CY, Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am. J. Physiol. 1989; 256: H589-H593.
22: Toyoda T., Kassell NF, Lee KS, Induction of ischemic tolerance and antioxidant activity by brief focal ischemia. Neuroreport 1997; 8: 847-851.
23: Yanamoto H. et al., Exp. Neurol., 2003, 182, 261-274 (describes the three-vessel occlusion model rat prepared above).
24: Yip PK, He Y.-Y., Hsu CY, Garg N., Marangos P., Hogan EL, Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology 1991; 41: 899-905.
25: Liu TH, Beckman JS, Freeman BA, Hogan EL, Hsu CY, Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am. J. Physiol. 1989; 256: H589-H593.
26: Yip PK, He Y.-Y., Hsu CY, Garg N., Marangos P., Hogan EL, Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology 1991; 41: 899-905.
27: Yanamoto H., Nagata I., Hashimoto N., Kikuchi H., Three-vessel occlusion using a micro-clip for the proximal left middle cerebral artery produces a reliable neocortical infarct in rats. Brain Res. Brain Res. Protoc. 1998; 3: 209-220.
28: Yanamoto H., Hashimoto N., Nagata I., Kikuchi H., Infarct tolerance against temporary focal ischemia following spreading depression in rat brain. Brain Res. 1998; 784: 239-249.
29: Yanamoto H. et al., Exp. Neurol., 2003, 182, 261-274 (describes the 3 vascular occlusion model rat prepared above).
30: Liu TH, Beckman JS, Freeman BA, Hogan EL, Hsu CY, Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am. J. Physiol. 1989; 256: H589-H593.
31: Sakata M., Yanamoto H., Hashimoto N., Iihara K., Tsukahara T., Taniguchi T., Kikuchi H., Induction of infarct tolerance by platelet-derived growth factor against temporary focal ischemia. Brain Res. 1998; 784: 250-255.
32: Hong S.-C., Goto Y., Lanzino G., Soleau S., Kassell NF, Lee KS, Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 1994; 25: 663-669.
33: Toyoda T., Kassell NF, Lee KS, Attenuation of ischemia-reperfusion injury in the rat neocortex by the hydroxyl radical scavenger nicaraven. Neurosurgery 1997; 40: 372-378.
34: Buchan AM, Xue D., Slivka A., A new model of temporary focal neocortical ischemia in the rat. Stroke 1992; 23: 273-279.
35: Xue D., Huang ZG, Smith KE, Buchan AM, Immediate or delayed mild hypothermia prevents focal cerebral infarction. Brain Res. 1992; 587: 66-72.
36: Goto Y., Kassell NF, Hiramatsu K., Soleau SW, Lee KS, Effects of intraischemic hypothermia on cerebral damage in a model of reversible focal ischemia. Neurosurgery 1993; 32: 980-985.
37: Buchan AM, Xue D., Slivka A., A new model of temporary focal neocortical ischemia in the rat. Stroke 1992; 23: 273-279.
38: Yanamoto H., Nagata I., Niitsu Y., Zhang Z., Xue J.-H., Sakai N., Kikuchi H., Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke 2001; 32: 232-239.

  As shown in FIG. 3, in the intravascular embolus insertion model rat, the cerebral infarct volume is independent of the vascular occlusion time (1 hour, 1.5 hours, 2 hours, 3 hours or permanent) and does not increase. That is, the ischemia time and the onset of cerebral infarction due thereto in the intravascular embolus insertion model rat may depend not only on the embolization time but also on other factors such as intravascular thrombus formation. On the other hand, in the three-vessel occlusion model rat, the cerebral infarction volume increases in proportion to the occlusion time of the blood vessel. The onset of cerebral infarction in the three-vessel occlusion model rat is not influenced by thrombus or embolism, but can be said to be caused only by a decrease in local blood flow due to vascular occlusion.

[Experiment 2] Ischemic tolerance induction by SD stimulation
(1) Preparation of 3-vessel occlusion model rat and SD stimulation for 3-vessel occlusion model rat In advance, 8 to 13-week-old Sprague-Dawley rat was continuously treated with 4 M potassium chloride at a rate of 1 μl per hour. By injecting into the brain cortex for a day, continuous spreading suppression was produced. On the other hand, as a control group, physiological saline was similarly injected into the rats for 2 days. It was confirmed that infusion of physiological saline did not cause continuous spreading suppression as observed during potassium chloride infusion. Each group had 8 animals.

  Transient regional cerebral ischemia was loaded by transient bilateral carotid artery occlusion and unilateral middle cerebral artery occlusion (3-vessel occlusion) 12 or 15 days after the infusion of potassium chloride or saline. By this method, a cerebral infarction having a certain volume limited to the brain cortex appears.

(2) Examination of the effect of SD stimulation on cerebral infarction By controlling the cerebral infarction volume of the 3-vessel occlusion model rats that were given or not given in advance as described in (1) above, the spread suppression was Of cerebral infarction on cerebral infarction.

  Two days after transient regional cerebral ischemia was loaded by the three-vessel occlusion method, the volume of cerebral infarction was measured by the following method for the spread control group and the control group. First, the rat brain was removed under deep general anesthesia, and the brain was made into 2 mm thick coronal brain slices, and 2% 2,3,4-triphenyltetrazolium chloride (TTC) was used to survive them at the time of brain extraction. The brain tissue site was stained red. Use a computer image analyzer to capture images of each brain section after staining, and measure the area of the surviving brain in these brain sections and the area of the infarcted brain infarction. Volume was calculated.

(3) Analysis Results of SD Stimulation Effect on Cerebral Infarction FIG. 4 shows SD waves observed by local injection of high-concentration potassium chloride in a 3-vessel occlusion model rat. In FIG. 4, panel (a) is a typical transient depolarizing potential change observed on a DC potential monitor in the cerebral cortex, ie, one spreading suppression wave. This single spreading suppression continues to occur continuously during the injection of high concentrations of potassium chloride. For example, panel (b) is an example in which a relatively long interval is observed after one SD, and panel (c) is an example in which a relatively short interval is observed after one SD.

  In this way, one SD wave passes through the needle electrode placed in the brain over approximately 1 minute (panel (a)), and by continuous local injection of high-concentration potassium chloride, the surrounding brain is continuously It was shown that SD waves were generated (panels (b) and (c)).

  On the other hand, FIG. 5 shows a photograph of a brain cross-sectional view of a three-vessel occlusion model rat subjected to SD pretreatment. In FIG. 5, the part of the arrow shows the part of cerebral infarction. As shown in FIG. 5, in the three-vessel occlusion model rat subjected to SD pretreatment, a clear reduction in cerebral infarction was observed as compared to the control three-vessel occlusion model rat. Therefore, it was proved that pretreatment of SD induces an intrinsic brain protective mechanism called ischemic tolerance or cerebral infarction resistance after a certain period of time.

[Example 1] Inhibitory activity of L-type channel agonist calcium antagonist on ischemic brain injury
(1) Preparation of 3-vessel occlusion model mouse and administration of L-type channel agonist calcium antagonist In advance (before ischemia), C57BL / 6J male mice aged 8-9 weeks were treated with medicinal calblock as azelnidipine. These were administered orally as a solution dissolved in 0.2 ml of physiological saline at a dose of 0.3 mg, 1 mg or 3 mg (hereinafter referred to as “0.3 mg / kg, 1 mg / kg or 3 mg / kg”) per 1 kg of body weight. On the other hand, as a control group, only 0.2 ml of physiological saline was similarly orally administered to the mice. During ischemia and reperfusion, L-type calcium channels are inhibited in the brains of mice administered calblock. Each group had 8 animals.

  One hour after calblock or saline administration, transient regional cerebral ischemia was loaded by transient bilateral carotid artery occlusion and unilateral middle cerebral artery occlusion (3-vessel occlusion). By this method, a cerebral infarction having a certain volume limited to the brain cortex appears. A mouse loaded with transient local cerebral ischemia by the above-described three-vessel occlusion method was used as a three-vessel occlusion model mouse.

(2) Examination of the effect of L-type channel-operated calcium antagonists on cerebral infarction The effect on cerebral infarction was examined.

  One day after transient local cerebral ischemia was loaded by the three-vessel occlusion method, the volume of cerebral infarction was measured and calculated for the calblock administration group and the control group by the same method as in Experimental Example 2. First, the mouse brain was removed under deep anesthesia, and the brain was cut into 1 mm thick sections by coronal amputation. By using 2% TTC, the brain tissue that had survived at the time of brain removal was stained red. did. Take a stained image of each brain section using a computer analyzer, measure the area of the surviving brain in these brain sections, and the area of the infarcted cerebral infarction, and calculate the cerebral infarct volume per individual from those values did.

(3) Results of analysis of effect of L-type channel agonist calcium antagonist on cerebral infarction FIG. 6 shows a photograph of a cross-sectional view of a brain of a 3-vessel occlusion model mouse to which calblock and 1 mg / kg were previously administered. In FIG. 6, panels (a) to (j) are photographs of brain cross sections of the following three-vessel occlusion model mice.
Panels (a) to (e): Cross-sectional views of the brain one day after ischemia in a 3-vessel occlusion model mouse administered with calblock 1 mg / kg. Each of the cross-sectional views of panels (a) to (e) is a cross-sectional view using brain sections of different brain positions prepared from the brains of the same three-vessel occlusion model mouse. The cross-sectional views of panels (a) to (e) are cross-sectional views of the brain that gradually and gradually moved from the most rostral side (panel (a)) to the most caudal side (panel (e)).
Panels (f) to (j): Cross-sectional views of the brain one day after ischemia of a control group three-vessel occlusion model mouse administered with physiological saline. Each of the cross-sectional views of panels (f) to (j) is a cross-sectional view using brain slices of different brain positions prepared from the brains of the same three-vessel occlusion model mouse. The cross-sectional views of panels (f) to (j) are cross-sectional views of the brain that gradually and gradually moved from the most rostral side (panel (f)) to the most caudal side (panel (j)).
Moreover, in each panel of FIG. 6, a white location is a cerebral infarction site.

  As can be seen from FIG. 6, in the 3-vessel occlusion model mouse that received a single dose of calblock at a dose of 1 mg / kg compared to the control group, after transient regional cerebral ischemia was loaded by the 3-vessel occlusion method. The resulting cerebral infarct volume was reduced.

Furthermore, the measurement result of the cerebral infarction volume in the group of 3 blood-vessel occlusion model mice which administered calblock once before ischemia is shown in FIG. FIG. 7 shows the mean volume (mm ³ ) of cerebral infarction for each group (control group and group administered with calblock at a dose of 0.3 mg / kg, 1 mg / kg or 3 mg / kg). In FIG. 7, * indicates that there is a significant difference compared to the control group.

  As can be seen from FIG. 7, it is clear that the volume of cerebral infarction is significantly reduced in the three-vessel occlusion model mouse group administered with a single calblock at a medium dose (1 mg / kg) compared to the control group. It became.

  From the above, it was revealed that L-type channel agonist calcium antagonists such as azelnidipine suppress ischemic brain damage such as cerebral infarction and have a brain protective effect.

[Example 2] Measurement of regional cerebral blood flow before, during and after ischemia Confirmed that the reduction of cerebral infarct volume by azelnidipine shown in Example 1 is not an effect of improving local cerebral blood flow Therefore, local cerebral blood flow was measured in a 3-vessel occlusion model mouse.

  The regional cerebral blood flow in the brains of the three-vessel occlusion model mice of the control group and the group administered with a single calblock at a dose of 1 mg / kg prepared in Example 1, were measured from the time of physiological saline and calblock administration, respectively. Measured up to minutes. Local cerebral blood flow was measured with a laser Doppler cerebral blood flow meter.

  The measurement results are shown in FIG. The percentage of local cerebral blood flow over time is shown. In addition, the ratio of local cerebral blood flow is a ratio when the value measured before calblock or physiological saline administration is 100%.

  As can be seen from FIG. 8, when comparing the control group and the group of 3-vascular occlusion model mice to which calblock was administered once at 1 mg / kg, there was no difference in local cerebral blood flow during ischemia. Therefore, it was revealed that calblock does not improve cerebral blood flow (cerebral circulation) in the ischemic region. Thus, it was shown that the reduction of the cerebral infarct volume in the group of model mice administered with calblock was not due to the local cerebral blood flow (cerebral circulation) improving action. L-type channel-operated calcium antagonists such as azelnidipine protect the brain from ischemic brain injury caused by ischemia without relying on local cerebral blood flow (cerebral circulation) improving action, that is, brain protection in a strict sense Proven to have an effect.

[Example 3] Therapeutic activity of L-type channel agonist calcium antagonist on ischemic encephalopathy
(1) Effects of post-ischemic administration of L-type channel agonist calcium antagonist in 3-vessel occlusion model mice
C57BL / 6J male mice aged 8-9 weeks were subjected to transient focal cerebral ischemia by transient bilateral carotid artery occlusion and unilateral middle cerebral artery occlusion (3-vessel occlusion method). By this method, a cerebral infarction having a certain volume limited to the brain cortex appears. Immediately after the ischemic load, the drug calblock as azelnidipine was orally administered once as a solution dissolved in 0.2 ml of physiological saline at a dose of 1 mg / kg body weight (hereinafter referred to as “1 mg / kg”). On the other hand, as a control group, only 0.2 ml of physiological saline was similarly orally administered to the mice. During ischemia and reperfusion, L-type calcium channels are inhibited in the brains of mice administered calblock. Each group had 8 animals.

(2) Examination of the effect of L-type channel-acting calcium antagonists on cerebral infarction In the acute phase of cerebral infarction of calblock by measuring the volume of cerebral infarction in a 3-vessel occlusion model mouse administered calblock for the first time after ischemia The therapeutic effect was examined.

  One day after transient local cerebral ischemia was loaded by the 3-vessel occlusion method, the volume of cerebral infarction was measured and calculated for the calblock single administration group and the control group in the same manner as in Example 1 above.

(3) Results of analysis of the effect of a single administration of L-type channel agonist calcium antagonist on cerebral infarction after ischemia after a ischemia Photograph of a brain cross-section of a 3-vessel occlusion model mouse administered at 1 mg / kg after ischemia Is shown in FIG. In FIG. 9, panels (a) to (d) are photographs of brain cross sections of the following three-vessel occlusion model mice.
Panels (a) and (b): Cross-sectional views of the brain one day after ischemia in a 3-vessel occlusion model mouse in a control group administered with physiological saline. Each cross-sectional view of panels (a) and (b) is a cross-sectional view using brain sections at different brain positions prepared from the brains of the same three-vessel occlusion model mouse.
Panels (c) and (d): Cross-sectional views of the brain one day after ischemia in a 3-vessel occlusion model mouse administered with calblock 1 mg / kg after ischemia. Each of the cross-sectional views of panels (c) and (d) is a cross-sectional view using brain slices prepared from the same three-vessel occlusion model mouse brain at different brain positions.
Moreover, in each panel of FIG. 9, the white part (part of the arrow) is a cerebral infarction part.

  As can be seen from FIG. 9, in the 3-vessel occlusion model mouse in which calblock was administered once after ischemia at a dose of 1 mg / kg as compared with the control group, transient local cerebral ischemia was observed by the 3-vessel occlusion method. The cerebral infarct volume that occurred after loading was reduced.

Furthermore, the measurement result of the cerebral infarction volume in the group of 3 blood-vessel occlusion model mice administered with calblock after ischemia is shown in FIG. FIG. 10 shows the mean volume (mm ³ ) of cerebral infarction for the control group and the group to which calblock was administered once. In FIG. 10, * indicates that there is a significant difference compared to the control group.

  As can be seen from FIG. 10, it is clear that the volume of cerebral infarction is significantly reduced in the 3-vessel occlusion model mouse group in which calblock was administered once after ischemia at 1 mg / kg as compared to the control group. became.

  Based on the above, L-type channel agonist calcium antagonists such as azelnidipine suppress the progression of cerebral infarction when used in the acute phase of ischemic encephalopathy such as cerebral infarction, that is, have a therapeutic effect on ischemic encephalopathy. It became clear.

FIG. 1 shows the mechanism of spread suppression in the brain. FIG. 2 shows an image of a spreadable suppression wave generated by the local brain brain potassium injection method. FIG. 3 shows changes in cerebral infarct volume with respect to ischemia time (blood vessel occlusion time) in cerebral infarction model rats. FIG. 4 shows a spreading suppression wave observed by local injection of high-concentration potassium chloride in a three-vessel occlusion model rat. FIG. 5 shows a photograph of a cross-sectional view of a brain in a three-vessel occlusion model rat subjected to pretreatment for suppression of spreadability. FIG. 6 shows a photograph of a cross-sectional view of the brain of a 3-vessel occlusion model mouse in which 1 mg / kg of the control group and calblock were administered before the onset of ischemia. FIG. 7 shows the measurement results of cerebral infarction volume in a control group and a group of 3 blood vessel occlusion model mice administered with calblock before the onset of ischemia. FIG. 8 shows the measurement results of local cerebral blood flow in the brains of the control group and the group of 3 blood vessel occlusion model mice administered with calblock at the dose of 1 mg / kg before the start of ischemia. FIG. 9 shows a photograph of a cross-sectional view of a brain of a three-vessel occlusion model mouse to which a control group and calblock (azelnidipine) were administered after initiation of ischemia. FIG. 10 shows the measurement results of cerebral infarction volume in a control group and a group of three-vessel occlusion model mice administered with calblock after the onset of ischemia.

Claims (5)

  An ischemic brain injury inhibitor comprising an L-type channel agonist calcium antagonist as an active ingredient.   The ischemic brain injury inhibitor according to claim 1, wherein the L-type channel agonist calcium antagonist is an antihypertensive agent.   The agent for suppressing ischemic brain damage according to claim 2, wherein the antihypertensive agent is selected from the group consisting of azelnidipine, nifedipine, diltiazem, nicardipine, nimodipine, benidipine, cilnidipine and amlodipine.   The ischemic brain injury inhibitor according to any one of claims 1 to 3, wherein the ischemic brain injury is cerebral infarction.   The brain protective agent containing the ischemic brain damage inhibitor of any one of Claims 1-4.

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