Brain cell- or nerve cell-protecting agents comprising medicinal ginseng

Abstract

The present invention provides medicinal or pharmaceutical compositions and preparations for administration, which are useful as cytoprotective agents and a remedy for neurotrauma, comprising ginseng, its extract, ginseng components, metabolites thereof or salts thereof (for example, red ginseng powder or components thereof). More particularly, the present invention provides medicinal or pharmaceutical compositions for inhibiting apoptosis or apoptosis-like cell death, medicinal or pharmaceutical compositions for promoting the expression of a cell death-suppressing gene product BCl-xL, or preparations for oral or intravenous administration, comprising ginseng, its extracts, ginseng components, metabolites thereof or salts thereof preferably at low concentrations. These medicinal or pharmaceutical compositions and / or preparations for administration are characterized by containing, as the active ingredient(s), ginseng, its extracts, ginseng components, metabolites thereof or salts thereof at low concentrations. These drugs are useful for therapy, prevention or treatment of brain and nervous diseases, heart diseases, etc.

Description

RELATED APPLICATIONS [0001] This application is a divisional application of U.S. Ser. No. 10 / 070,209, filed on Jul. 12, 2002, which in turn claims priority to PCT / JP00 / 04102 filed on Jun. 22, 2000, published as WO / 2001 / 015717 on Aug. 3, 2001, which also in turn claims priority to Japanese Application No. 11 / 243378, filed on Aug. 30, 1999.TECHNICAL FIELD [0002] The present invention relates to medicinal ginseng, extracts thereof, ginseng components or metabolites thereof useful as cell-protecting agents. More particularly, the present invention relates to medicinal or pharmaceutical compositions for suppressing apoptosis or apoptosis-like cell death or for promoting the expression of a cell death-suppressing gene product Bcl-xL comprising ginseng, its extracts, ginseng components, metabolites thereof or salts thereof. [0003] Further, the present invention relates to a medicinal or pharmaceutical composition(s) for protecting cells comprising ginsenoside Rb1, metabolites thereof or sa...

AI Technical Summary

Benefits of technology

[0031] An object of the present invention is to provide medicament exhibiting an excellent brain cell- or nerve cell-protecting effect and protecting cells by promoting expression of a cell death-suppressing gene product Bcl-xL protein. A further object of the present invention is to provide: a preparation which can be used at low dosages by intravenous administration for the prevention, therapy and / or treatment of cerebral edema, brain edema, brain and nervous tissue edema or spinal cord tissue edema; a preparation which can be used at low doses by intravenous administration for the prevention, therapy and / or treatment of bedsores (decubitus) which accompany spinal cord injuries; a preparation for intravenous administration to promote the expression of a cell death-suppressing gene product Bcl-xL in the nervous tissues; a medicinal or pharmaceutical composition to promote expression of the cell death-suppressing gene Bcl-xL in oligodendrocytes; a protective agent for oligodendrocytes; a medicinal or pharmaceutical composition to promote expression of the cell death-suppressing gene Bcl-xL in myocardial cells; and a medicinal or pharmaceutical composition to suppress apoptosis or apoptosis-like cell death in myocardial cells. A further object of the present invention is to provide a preparation for intravenous administration which can be used for the prevention, treatment or therapy of diseases caused by injury or trauma to the nervous tissues or spinal cord tissue, and to provide a medicinal or pharmaceutical composition for suppressing demyelination, apoptosis or apoptosis-like cell death of oligodendrocytes, or secondary degeneration of the nervous tissues, which are caused by injury or trauma to the nervous tissues or spinal cord tissue.

Problems solved by technology

Once such functional disorders occur, the improvement, therapy and treatment of the diseases are very difficult and the QOL (quality of life) of patients is damaged for a long term.

Consequently, although excellent preparations for oral administration which could prevent damage to these nerve cells are highly desirable for use prior to brain cell death or nerve cell death, such medicinal or pharmaceutical compositions have not been invented up to the present time.

However, if the red ginseng powder is administered orally to patients with cerebrovascular disorder at chronic stage (e.g. cerebral apoplexy patients at chronic stage), no improvement in cerebral apoplectic lesion itself is found.

Further, it is not known whether the red ginseng powder is used for the prevention, therapy and / or treatment of cerebrovascular disorders at acute stage (e.g. acute cerebral apoplexy) in common clinical practice.

Further, there is no known experimental medical basis for the use of red ginseng powder to treat other neurodegenerative diseases accompanied by nerve cell death, head injury or spinal cord injury in clinical medicine.

However, when red ginseng powder was administered orally at the same dose for one week after the 5-minute forebrain ischemia, the nerve cell death in the hippocampal CA1 area of gerbils was not suppressed; and the neuroprotective effect of oral administration of red ginseng powder was not so strong.

Consequently, application of red ginseng powder to patients with more severe brain infarction than transient ischemic attack, e.g. to patients with permanent cerebrovascular occlusion), was thought to be unreasonable.

Furthermore, the mechanism by which the oral administration of red ginseng powder suppresses the delayed neuronal death in the hippocampal CA1 area has not been elucidated.

However, cerebral apoplexy is a serious disease resulting in a permanent disorder in higher functional activities, and threatening the survival of patients if no treatment is performed to protect the nerve cells or neurons at the lesion site at the earliest possible opportunity.

Even the period of time required for the CT inspection of the brain is, to put it strongly, a factor in reducing the possibility of recovery for patients with cerebral apoplexy.

Quite unfortunately, at present, whatever is the disease type of cerebral apoplexy (cerebral infarction, cerebral hemorrhage, cerebral embolism, subarachnoidal hemorrhage or transient ischemic attack), the actual situation is that very few drugs are known which show a potent effect, even if they are administered immediately after the onset of cerebral apoplexy.

However, since it can not be said that the main cause of Alzheimer's disease is a functional disturbance of the acetylcholine-containing nerve cells, this hypothesis has many remaining problems to be solved.

Further, the above U.S. patent did not disclose problems whether ginsenoside Rb1 could extend the survival of acetylcholine-containing nerve cells, particularly whether it prevents the death of acetylcholine-containing cells or not.

Even though ginsenoside Rb1 is effective in direct intracerebroventricular infusion, it appears impossible, however, to apply ginsenoside Rb1 to human transient cerebral ischemic attack (TIA) and cerebral infarction due to problems in the route of administration.

However, it is important to note that the cerebral ischemia / reperfusion model using gerbils or rats does not always reflect, as explained later, the pathologic condition involved in human cerebral infarction.

However, this effect can not always be said to be superior to the candidate substances of drugs (for example, glutamate antagonists and free radical scavengers) so far developed for treatment of cerebral ischemia / reperfusion, rather it may be inferior (Slusher, B. S. et al., Nature Med., 5, 1396-1402, 1999).

Furthermore, the intravenous administration of ginsenoside Rb1 at the dose of 40 mg / kg, which produced a comparatively good effect and high efficacy for the prevention and treatment of cerebral ischemia / reperfusion injuries, as reported earlier by Zhang, Y. G. and Liu, T. P., can be said to be too high in dose.

For a single intravenous administration, such a high dose of ginsenoside Rb1 is critical, and intravenous administration on consecutive days (or continuous intravenous administration) may be difficult.

Furthermore, when the high dose (40 mg / kg) of ginsenoside Rb1 is administered to rats with permanent occlusion of the middle cerebral artery before cerebral infarction occurs, it produces a very weak effect.

However, if the same drug candidate is not administered on consecutive days thereafter, the cerebral infarct lesion will surely expand, and eventually in one month after the permanent cerebrovascular occlusion (namely, when the cerebral infarct lesion enters the almost stable stage), almost no effect is observed.

However, based on the previous report of Zhang, Y. G. and Liu, T. P., it was thought to be practically impossible to apply intraveous administration of the high doses of ginsenoside Rb1 in a repeated or continuous manner for treating, preventing or curing cerebral infarction or cerebral apoplexy.

As a result, the pressure on the brain is significantly increased and this frequently threatens the survival of patients.

However, problems from the rebound effect and other side effects following termination of the drug administration have not been solved.

Consequently, a safe drug for the therapy or treatment of brain edema, which can be administered over a long time, may certainly be required in the future, but no such drugs are available.

However, no report to prove this hypothesis has been published.

It is very difficult to reproduce or maintain such high concentrations of ginsenoside Rb1 in the in vivo lesioned tissues or in the extracellular fluid of the nervous tissues.

Furthermore, considering the cost and the possibility of side (ill)effects appearing, the present inventors (Sakanaka and Tanaka) speculate that the administration of large amounts of ginsenoside Rb1 in vivo is not feasible.

Although ginsenoside Rb1 is a kind of purified saponin which is contained in medicinal ginseng, it can not be detected in the blood following a single oral administration.

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