JPH0393728A - Remedy and preventive for senile dementia - Google Patents

Abstract

PURPOSE:To obtain a remedy and preventive for senile dementia containing interleukin 3(IL-3) as an active ingredient. CONSTITUTION:The objective remedy and preventive containing interleukin 3(IL-3) being a glucoprotein (having about 25000 molecular weight) having 152 amino acids (in case of human) or 166 amino acids 8 in case of mouse), being one of lymphokine which helper T cell produces by antigen stimulation and acting in differentiation and proliferation of bone marrow cell as an active ingredient. IL-3 has nutrition activation action and cholinacetyltransferase activation action against central cholinergic neuron and is effective against treatment, preventive, remission, improvement, etc., of cerebrovascular disease accompanied by Alzhimer's disease, Alzheimer type senile dementia, Parkinson disease, cerebral hemorrhage, cerebral arteriosclerosis, cranial injury, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a medicament containing interleukin-3 as an active ingredient. More specifically, the present invention relates to a therapeutic/preventive agent for senile dementia containing interleukin-3 as an active ingredient.

[Background leading to the invention and prior art]

With the aging population rapidly increasing, there is a strong desire to establish a treatment for senile dementia such as Alzheimer's type senile dementia.

However, although various attempts have been made to treat senile dementia with drugs, there are currently no drugs that are fundamentally effective against these diseases.

The development of therapeutic drugs for these diseases is being researched from various directions, but a promising direction is the use of acetylcholine precursors and acetylcholinesterase inhibitors, since Alzheimer's type senile dementia is accompanied by a decline in brain cholinergic function. It has been proposed and actually attempted to develop from this direction. Typical anticholinesterase inhibitors include physostigmine and tetrahydroaminoacridine, but these drugs have drawbacks such as insufficient efficacy and undesirable side effects, so they are not definitive therapeutic agents. The current situation is that there is no such thing.

Furthermore, recently choline acetyltransferase (ChA
T) It has been noticed that the activation effect is also effective in treating these diseases.

Therefore, the present inventors have conducted extensive research over many years on compounds that have this choline acetyltransferase-activating effect.

C Structure and Effects of the Invention] As a result, it was surprisingly found that inleukin-3 has an effect of increasing choline acetyltransferase activity.

Therefore, the present invention relates to a therapeutic/preventive agent for diseases, which contains interleukin-3 (hereinafter simply referred to as IL-3) as an active ingredient and is effective in activating choline acetyltransferase. In particular, the present invention relates to therapeutic and preventive agents for senile dementia such as Alzheimer's disease and Alzheimer's type senile dementia, which contain IL-3 as an active ingredient.

IL-3 has 152 (human) to 166 amino acids (
It is a glycoprotein (molecular weight approximately 25,000) that has a molecular weight of about 25,000 (molecular weight), and is one of the lymphokines produced by helper T cells upon antigen stimulation. It has been found that it acts on the differentiation and proliferation of bone marrow cells.

In the present invention, IL-3 may be obtained by any production method. That is, it may be produced by genetic engineering or extracted from nature, and its origin does not matter.

That is, its origin may be human or mouse, for example.

Next, an experimental example will be shown to explain the effects of the present invention in detail.

i) Experimental method Nerve cells in the septal area of the mouse brain on day 15 of embryonic development were injected into a complete serum-free medium (a 1:1 mixture of Eagle medium and }Ian+F12 medium) with 2.25 g of glucose and 15II.
IM Hepes buffer (p}17.4), 30 nM sodium selenate, 20 IllM penicillin-streptomycin, 100 μg/IIll transferrin, 2
5 μg 7 ml insulin, 20 nM progesterone,
20 nM hydrocortisone-21-phosphate, 10 μl carnitine, 30 nM 3.3'. 5-Iodination-
L-thyronine, 'Ing/ml! Tocopherol, 7
ng/m 1 retinol, 1 μn thioctic acid and 1
(containing μil/tll mineral mixture) (5% CO, 37°C), to which IL-3 was added at 10 to 100 units/ta1, and after 0, 20, 40, and 50 hours, the cells were cultured. The number of neurons with neurites was counted under a phase-contrast microscope, and control 1 (no addition) and control 2 (neuropathic factor) were counted.
β-NGF) 100 ng/mj2).

Similarly, 7 ml of 50 units of IL-3 was added, and the choline acetyltransferase activity before and 5 days after addition was measured according to the method of Fonnu1. compared with. The IL-3 used in this experimental example was human recombinant IL-3 (hIL-3) and mouse high-purity IL-3.
3 (mlL-3), and the former is manufactured by Dienzyme (Ge
zyme, Inc. (Boston, MA), the latter from ICN Biochem.
Che+sical (Creepland, Ohio) was used.

1) F. Fonun+: J. Neurochem
．． ．． 24, 407-409 (1975) ii) Experimental Results Table 1 shows the neurite outgrowth effect of IL-3. The numerical values indicate the percentage of the number of neurite-bearing neurons 0.20 and 40.50 hours after addition of each factor.

The effect of anti-IL-3 monoclonal antibody (α-IL-3
hIL-3 in the table means IL-3 of human origin, and mlL-3 means IL-3 of mouse origin.

Table 2 shows the effect of IL-3 on increasing choline acetyltransferase activity. In Table 2, α-IL-3 means anti-IL-3 antibody.

A detailed explanation of the results in Tables 1 and 2 is as follows. The percentage of neurons possessing processes is the same as that of the unadded control and β
-NGF added control was 20 to 24%, whereas the IL-3 added group of the present invention (10μ/tag.
0U/tar! It increased to 26-35% after 20 hours, 30-47% after 40 hours, and 37-51% after 50 hours (
Table 1).

Next, as is clear from Table 2 below, regarding ChAT activity, IL-3 (50 U/10) has a specific activity of 1.83 to 2.20 times and a specific activity of 2.37 to 3.
This resulted in a 57-fold increase in Chat activity. This effect was stronger than β-NGF (100 ng/mj!). In addition, IL-3 From the above pharmacological experiments, IL-3
It has been revealed that the drug has a trophic effect on central cholinergic neurons, and also has a strong choline acetyltransferase activating effect.

In senile dementia, particularly Alzheimer's dementia, there is a loss of cholinergic neurons, which has been linked to some of the symptoms of dementia. Therefore, a search is underway for factors that nourish and activate cholinergic neurons, and neurotrophic factor (NGF), which was used in the above experiment, is attracting attention as one of them.

Therefore, the compound of the present invention, IL-3, is effective against various dementias based on its trophic effect on central cholinergic neurons and its choline acetyltransferase activating effect.

The compound of the present invention, IL-3, has been tried to be administered to terminal cancer patients whose bone marrow has been irradiated with X-rays and to AIDS patients, but no particular side effects have been found.

The compounds of the present invention are effective for all diseases for which choline acetyltransferase activation is effective. Typical diseases include various senile dementias; particularly Alzheimer's disease, Alzheimer's type senile dementia, Birkinson's disease, stroke (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, cerebrovascular disorders associated with head trauma, etc. It is effective in the treatment, prevention, remission, and improvement of encephalitis sequelae, cerebral palsy, decreased attention, language disorders, decreased motivation, emotional disorders, memory disorders, hallucinations and delusions, behavioral abnormalities, etc.

It has recently been shown that IL-3, the compound of the present invention, may be produced by astroglia, and IL-3 mRNA
It has been shown that A is present in neurons and dahlia. Considering these facts and the experimental effects of the compounds of the present invention described above, it is highly likely that IL-3 acts as a trophic factor for neurons, particularly cholinergic neurons.

Furthermore, the effectiveness of the choline acetyltransferase-activating effect of the compounds of the present invention on these diseases is thought to be due to the fact that the amount of acetylcholine in the brain is increased by the above-mentioned effect.

When the compound of the present invention is used as a pharmaceutical for these diseases, it is formulated so that IL-3 is effective for the treatment and prevention of this disease by oral or parenteral administration, and the active ingredient IL-3 is administered. The dosage of IL-3 varies depending on the severity of symptoms; age, sex, weight, and sensitivity differences of the patient; administration method: timing and interval of administration; nature, preparation, and type of pharmaceutical preparation; type of active ingredient, etc. Although not particularly limited, it is usually about 0.0% per day. 1 to 300 cm, preferably about o. i to 100 μ, which is usually administered in 1 to 4 divided doses a day (1 μ for human recombinant IL-3 is 1Os). In order to formulate the compound of the present invention, it is formulated into a dosage form such as an injection, suppository, sublingual tablet, tablet, or capsule by a conventional method in the field of pharmaceutical preparation. When preparing injections, add PN adjusters, buffers, suspending agents, solubilizing agents, stabilizers, isotonic agents, preservatives, etc. to the herbal medicine as necessary, and administer intravenously, using a conventional method. It is administered as a subcutaneous or intramuscular injection. If necessary, it can also be freeze-dried using conventional methods. Examples of suspending agents include methyl cellulose, polysorbate 80, hydroxyethyl cellulose,
Examples include gum arabic, powdered tragacanth, sodium carboxymethyl cellulose, and polyoxyethylene sorbitan monolaurate.

Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid ξ-do, polyoxyethylene sorbitan monolaurate, magrogol, and castor oil fatty acid ethyl ester. Examples of stabilizers include sodium sulfite, sodium metasulfite, and ether, and examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. .

Claims (4)

[Claims] (1) A therapeutic/preventive agent for senile dementia containing interleukin-3 as an active ingredient. (2) Treatment of diseases for which the choline acetyltransferase activation effect of interleukin-3 as an active ingredient is effective.
Preventive agent. (3) A choline acetyltransferase activator containing interleukin-3 as an active ingredient. (4) The agent for treating and preventing senile dementia according to claim 1, wherein the senile dementia is Alzheimer's disease or Alzheimer's type senile dementia.