Neuronal circuit-dependent neuroprotection by interaction between nicotinic receptors

Abstract

A method of inhibiting excitotoxicity by indirectly activating α4β2 nicotinic acetylcholine receptors (nAChRs) which indirectly activate synaptic AMPA and NMDA receptors is disclosed. Inhibitors of α7 nACHRs, such as macrocyclic diterpenoids, more specifically cembranoids or methyllycaconitine (MLA), indirectly activate α4β2 nAChRs and can be used to treat neurodegenerative diseases, including, but not limited to, Alzheimer's Disease, Parkinson Disease, AIDS related dementia and the delayed effects of stroke. They can also be used to treat diseases associated with neuronal impairment, including, but not limited to glaucoma caused by optical nerve damage, delayed effects of epilepsy; and multiple sclerosis.

1 . A method of treating or preventing neuronal damage in a subject comprising: administering to the subject at least one macrocyclic diterpenoid, or a biologically active fragment, analog, or derivative thereof. 
     
     
         2 . The method of  claim 1  wherein at least one macrocyclic diterpenoid is administered in an amount sufficient to achieve a concentration between about 200 nM to about 20 μM. 
     
     
         3 . The method of  claim 1  wherein the subject has suffered, suffers from, or is at risk for at least one neurodegenerative disease selected from the group consisting of:
 (a) Alzheimer's Disease; 
 (b) Parkinson's Disease; 
 (c) Frontotemporal Dementia; 
 (d) Amyotrophic Lateral Sclerosis (ALS); 
 (e) Motor Neuron Disease; 
 (f) delayed effects of stroke; 
 (g) delayed effects of traumatic brain injury; and 
 (h) AIDS-related dementia. 
 
     
     
         4 . The method of  claim 1  wherein the subject has suffered, suffers from, or is at risk for developing a disease associated with neuronal impairment selected from the group consisting of:
 (a) glaucoma caused by optical nerve damage; 
 (b) delayed effects of epilepsy; and 
 (c) multiple sclerosis. 
 
     
     
         5 . The method of  claim 1  wherein the macrocyclic diterpenoid is administered during prenatal or postnatal treatment. 
     
     
         6 . The method of  claim 1  wherein the macrocyclic diterpenoid is selected from the group consisting of:
 4S,6R-Cembratriene 4,6 diol; Methyl pseudoplexaurate; Pseudoplexaurol; 4-Hydroxy, 15-cyclopropane, methyl-pseudoplexaurate; 4-Hydroxy, 15-pyrazoline-methyl pseudoplexaurate; 3,4-Epoxy, 15-pyrazoline, methyl-pseudoplexaurate; 15,17-Dihydro-methyl pseudoplexaurate; 14R-Sarcophytol A; Marasol; 4-Acetyl-eunicin; 12,13-Bis epi eupalmerin acetate; Eupalmerin acetate; Eunilide chlorohydrin; 3I-Methylpseudo plexaurate; 15-Hydrazone-methyl pseudoplexaurate; 14-Deoxy crassin; 12R-Eupalmerone; Eupalmerin; Euniolide; Crassin acetate; 12,13-bis epi Eupalmerin; 12S-Eupalmerone; Methyl-uproeuniolate; 3,4-Epoxy, 15-pyrazoline-methyl-pseudoplexaurate; 3,4 Epoxy, 15-pyrazoline-methyl pseudoplexaurate; Methyl pseudoplexaurate hydrazolactone; Methyl pseudoplexaurate hydrazone; 4-Hydroxy, methyl pseudoplexaurate; 3,4 Epoxy, 15-cyclopropane, methyl pseudoplexaurate; 14S-Sarcophytol A; Eunicin; Dimethyl (1R*,3S*,4S*,8R*,11Z)-3,15 Epoxycembr-11-ene-18,19-dioate; (1S*,4S*,8R*,11Z)-Cembr-11-ene-15,18,19-triol; Dimethyl (1R,3S,4S,7E,11Z)-3,15-Epoxycembra-7,11-diene-18,19-dioate; Mono (1R,3S,4R,7E,11Z)-3,15-Epoxy-19-oxocembra-7,11-dien-18-yl) malonate; Thumbergol (Isocembrol); 4-Epiisocembrol (Epithumbergol); (1S,2E,4E,6S,7E,11E)-Cembra-2,4,7,11-tetraen-6-ol; (3E,7E,11E)-Cembra-3,7,11,15-tetraen-6-ol; (1S,2E,4S,6E,11E)-Cembra-2,6,8(19),11-tetraen-4-ol; (1S,2E,4S,7E,11E)-4-Hydroxycembra-2,7,11-trien-6-one; Isoovatodiolide; Ovatodiolide; (1S,2E,4R,6R,7E,11E)-4-Methoxycembra-2,7,11-trien-6-ol; 2E,4R,6R,7E,11E)-Cembra-2,7,11-triene-4,6-dimethoxide; (1S,2E,4R,6E,8S,11E)-Cembra-2,6,11-triene-4,8-diol; (1S,2E,4S,6E,8S,11E)-Cembra-2,6,11-triene-4,8-diol; 2E,4R,6E,8S,11E)-Cembra-2,6,11-triene-4,8-dimethoxide; (1S,2E,4S,7E,11S,12S)-11,12-Epoxy-4-hydroxy-cembra-2,7-dien-6-one; (1S,2E,4S,6R,7S,8S,11E)-7,8-Epoxycembra-2,11-diene-4,6-diol; (1S,2E,4S,6R,7R,8R,11E)-7,8-Epoxycembra-2,11-diene-4,6-diol; 2E,4S,6R,7E,10R,11R)-10,11-Epoxycembra-2,7,12(20)-triene-4,6-diol; 2E,4S,6R,7E,10S,11S)-10,11-Epoxycembra-2,7,12(20)-triene-4,6-diol; 2E,4R,6R,7E,11S,12S)-11,12-Epoxycembra-2,7-diene-4,6-diol; (1S,2E,4S,6R,7E,11S,12S)-11,12-Epoxycembra-2,7-diene-4,6-diol; (1S,2E,4R,6R,7E,11R,12R)-11,12-Epoxycembra-2,7-diene-4,6-diol; Mukulol; Cembrol; (1R,2E,4Z,7E)-Cembra-2,4,7-trien-12-ol ; Cembrenol (Serratol); Incensole; Incensole oxide; Isoincensole oxide; Polianeic acid; (1R*,3E,7Z,12R*)-20-Hydroxycembra-3,7,15-trien-19-oic acid; Cleomaldeic acid; (3E,7Z,11Z)-17,20-Dihydroxycembra-3,7,11,15-tetraen-19-oic acid; (1R,3Z,7E,11Z)-15-Hydroxycembra-3,7,11-trien-19-oic acid; (1R,3Z,11Z)-15-Hydroxycembra-3,11-dien-19-oic acid; (1R,3R,4R,7Z,11Z)-3,15-Epoxycembra-7,11-dien-4-ol; (1R,3S,4S,7Z,11Z)-3,15-Epoxycembra-7,11-dien-18-oic acid; (1R,3S,4S,7E,11Z)-3,15-Epoxy-19-oxocembra-7,11-dien-18-oic acid; (1R*,3S*,4S*,8R*,11Z)-3,15-Epoxycembr-11-ene-18,19-dioic acid; Anisomelic acid 
 
     
     
         7 . The method of  claim 6  wherein one of said group is administered in an amount sufficient to achieve a concentration between about 200 nM to about 20 μM. 
     
     
         8 . The method of  claim 6  wherein the subject has suffered, suffers from, or is at risk for at least one neurodegenerative disease selected from the group consisting of:
 (a) Alzheimer's Disease; 
 (b) Parkinson's Disease; 
 (c) Frontotemporal Dementia; 
 (d) Amyotrophic Lateral Sclerosis (ALS); 
 (e) Motor Neuron Disease; 
 (f) delayed effects of stroke; 
 (g) delayed effects of traumatic brain injury; and 
 (h) AIDS-related dementia. 
 
     
     
         9 . The method of  claim 6  wherein the subject has suffered, suffers from, or is at risk for developing a disease associated with neuronal impairment selected from the group consisting of:
 (a) glaucoma caused by optical nerve damage; 
 (b) delayed effects of epilepsy; and 
 (c) multiple sclerosis. 
 
     
     
         10 . The method of  claim 6  wherein one of said group is administered during prenatal or postnatal treatment. 
     
     
         11 . The method of  claim 1  wherein said macrocyclic diterpenoid is 4R,6R-Cembratriene 4,6 diol. 
     
     
         12 . The method of  claim 11  wherein said macrocyclic diterpenoid is administered in an amount sufficient to achieve a concentration between about 200 nM to about 20 μM. 
     
     
         13 . The method of  claim 11  wherein the subject has suffered, suffers from, or is at risk for at least one neurodegenerative disease selected from the group consisting of:
 (a) Alzheimer's Disease; 
 (b) Parkinson's Disease; 
 (c) Frontotemporal Dementia; 
 (d) Amyotrophic Lateral Sclerosis (ALS); 
 (e) Motor Neuron Disease; 
 (f) delayed effects of traumatic brain injury; and 
 (g) AIDS-related dementia. 
 
     
     
         14 . The method of  claim 11  wherein the subject has suffered, suffers from, or is at risk for developing a disease associated with neuronal impairment selected from the group consisting of:
 (a) glaucoma caused by optical nerve damage; 
 (b) delayed effects of epilepsy; and 
 (c) multiple sclerosis. 
 
     
     
         15 . The method of  claim 11  wherein the said macrocyclic diterpenoid is administered during prenatal or postnatal treatment.