Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease.
OBJECTIVE
The therapeutic potential of cannabinoids in Huntington's disease (HD) has been investigated by several groups with complex and sometimes contrasting results. We sought to examine key points of intersection between cannabinoid receptor 1 (CB(1)) signalling, survival and the formation of mutant huntingtin aggregates in HD.


METHODS
Using a simplified pheochromocytoma (PC12) cell model of HD expressing exon 1 of wild-type or mutant huntingtin, we assayed cell death and aggregate formation using high-throughput cytotoxicity and image-based assays respectively.


RESULTS
CB(1) activation by HU210 conferred a small but significant level of protection against mutant huntingtin-induced cell death. Pertussis toxin uncoupled HU210 from the inhibition of cAMP, preventing rescue of cell death. Phosphorylation of extracellular signal-regulated kinase (ERK) was also critical to CB(1)-mediated rescue. Conversely, treatments that elevated cAMP exacerbated mutant huntingtin-induced cell death. Despite opposing effects on HD cell survival, both HU210 and compounds that elevated cAMP increased the formation of mutant huntingtin aggregates. The increase in aggregation by HU210 was insensitive to Pertussis toxin and UO126, suggesting a G-protein alpha subtype s (G(s))-linked mechanism.


CONCLUSIONS
We suggest that the CB(1) receptor, through G-protein alpha subtype i/o (G(i/o))-linked, ERK-dependent signal transduction, is a therapeutic target in HD. However the protective potential of CB(1) may be limited by promiscuous coupling to G(s), the stimulation of cAMP formation and increased aggregate formation. This may underpin the poor therapeutic efficacy of cannabinoids in more complex model systems and suggest that therapies that are selective for the G(i/o), ERK pathway may be of most benefit in HD.
Scotter
E L
EL
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Grafton, Auckland, New Zealand.
Goodfellow
C E
CE
Graham
E S
ES
Dragunow
M
M
Glass
M
M
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000517:prevention & control*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D037342:Pertussis Toxin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D000077285:Rimonabant
D002070:Butadienes; D044385:GTP-Binding Protein alpha Subunits; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009570:Nitriles; D009687:Nuclear Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011954:Receptors, Dopamine; C113580:U 0126; D013759:Dronabinol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D048052:Mitogen-Activated Protein Kinase 3; C062018:HU 211; D000077285:Rimonabant