Preventing neuronal degeneration in Alzheimer's disease

• US 6,391,871 B1
• Filed: 09/27/1999
• Issued: 05/21/2002
• Est. Priority Date: 09/20/1996
• Status: Expired due to Fees

• Current Assignee: John W. Olney, Nuri B. Farber
• Original Assignee: John W. Olney, Nuri B. Farber
• Inventors: Olney, John W., Farber, Nuri B.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): JAGOE, DONNA A
• Application Number:
  US09/406,315
• Time in Patent Office: 967 Days
• Field of Search: 514/217, 514/214.01, 514/220, 514/249, 514/285, 514/317.18, 514/315, 514/428, 514/646
• US Class Current: 514/214.01
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam

Abstract

A method of treating Alzheimer'"'"'s disease is disclosed, not just with palliatives, but in a manner that prevents the progressive degeneration caused by Alzheimer'"'"'s disease. Certain types of “safener” drugs, which can reduce the neurotoxic damage caused by a potent NMDA antagonist drug such as dizocilpine maleate (also known as MK-801) can also retard the type of corticolimbic damage which, in the brain of a patient who suffers from Alzheimer'"'"'s disease, results from over-excitation of corticolimbic neurons. This over-excitation is caused or aggravated by NMDA receptor dysfunction in neuronal circuits which normally limit and control excitatory neurotransmitter release within those corticolimbic regions. Safener drugs include various known drugs that can suppress activity at muscarinic acetylcholine receptors, sigma receptors, kainic acid receptors, or AMPA receptors. They also include various drugs which can stimulate activity at alpha-2 adrenergic or 5HT-2A serotonin receptors.

Claims

1. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and suppresses activation of muscarinic acetylcholine receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

2. The method of claim 1, wherein the drug suppresses activation of muscarinic acetylcholine receptors without also substantially suppressing activity at N-methyl-D-aspartate receptors.

3. The method of claim 1, wherein the drug is selected from the group consisting of scopolamine, atropine, benztropine, benactyzine, and biperiden, and salts, isomers, and analogs thereof which suppress activation of muscarinic acetylcholine receptors and which are effective in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons.

4. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and suppresses activation of sigma receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

5. The method of claim 4, wherein the drug suppresses activation of sigma receptors without also substantially suppressing activity at N-methyl-D-aspartate receptors.

6. The method of claim 4, wherein the drug is selected from the group consisting of di(2-tolyl)guanidine, rimcazole, haloperidol, and thioridazine, and salts, isomers, and analogs thereof which suppress activity at sigma receptors and which are effective in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons.

7. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and suppresses activation of kainic acid-type glutamate receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

8. The method of claim 7, wherein the drug suppresses activation of kainic acid-type glutamate receptors without also substantially suppressing activity at N-methyl-D-aspartate receptors.

9. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and suppresses activation of AMPA-type glutamate receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

10. The method of claim 9, wherein the drug suppresses activation of AMPA-type glutamate receptors without also substantially suppressing activity at N-methyl-D-aspartate receptors.

11. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and stimulates activity at alpha-2-adrenergic receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

12. The method of claim 11, wherein the drug stimulates activity at alpha-2-adrenergic receptors without also substantially suppressing activity at N-methyl-D-aspartate receptors.

13. The method of claim 11, wherein the drug is selected from the group consisting of clonidine, xylazine, p-iodoclonidine, guanabenz, guanfacine, and lofexidine, and salts, isomers, and analogs thereof which stimulate activity at alpha-2-adrenergic receptors and which are effective in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons.

14. A method for treating Alzheimer'"'"'s disease, comprising the step of administering, to a human patient suffering from Alzheimer'"'"'s disease, a drug which penetrates mammalian blood brain barriers and stimulates activity at 5HT-2A serotonin receptors without also stimulating activity at 5HT-2C serotonin receptors, wherein:

(a) the drug is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons; and

,

(b) the drug is administered to the patient chronically, in a dosage which is therapeutically effective in retarding progressive neuronal degeneration due to Alzheimer'"'"'s disease in the patient'"'"'s brain.

15. The method of claim 14, wherein the drug stimulates activity at 5HT-2A serotonin receptors without substantially suppressing activity at N-methyl-D-aspartate receptors.

16. The method of claim 14, wherein the drug is selected from the group consisting of lisuride, and salts, isomers, and analogs thereof which stimulate activity at 5HT-2A serotonin receptors without also stimulating activity at 5HT-2C serotonin receptors, and which are effective in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons.

17. A method for treating a patient suffering from Alzheimer'"'"'s disease, comprising the step of chronically administering to the patient a neuroprotective drug which:

(a) penetrates mammalian blood brain barriers;

(b) is therapeutically effective in retarding progressive damage to corticolimbic neurons caused by over-excitation of such neurons, due to NMDA receptor hypofunction in neuronal circuits which normally inhibit excitatory neurotransmitter release within corticolimbic regions; and

,

(c) is effective, in in vivo mammalian animal tests, in preventing a neurotoxic dose of dizocilpine maleate from causing vacuole formation in posterior cingulate-retrosplenial neurons.