Cannabinoid CB(1) receptor activation stimulates neurite outgrowth and inhibits capsaicin-induced Ca(2+) influx in an in vitro model of diabetic neuropathy.
Cannabinoid CB(1) receptors mediate, in part, the neuroprotectant properties of endocannabinoids, and altered signalling via the CB(1) receptor may contribute to the pathogenesis of diabetic neuropathy. We investigated CB(1) receptor function in PC12 cells differentiated into a neuronal phenotype with nerve growth factor (NGF, 50 ng/ml) in 5.5 and 50 mM concentrations of glucose. High glucose was associated with impaired NGF-induced neurite outgrowth (P < 0.01; n = 185-218) and reduced expression of CB(1) receptor mRNA (P < 0.01; n = 6) on day 6 of culture. Whilst treatment of hyperglycemic cells with HU210 (0.03-3 microM) increased neurite length in a concentration-dependent manner (P < 0.01; n = 136-218), CB(1) receptor expression was not significantly altered by chronic agonist stimulation (P = 0.32; n = 6 per group). Application of the CB(1) agonist HU210 (1 microM) inhibited capsaicin-induced calcium transients to a similar degree in cells cultured in high glucose (40%) versus normal (43%) (P < 0.05; n = 33-50). HU210-mediated rescue of neurite outgrowth and inhibition of calcium influx was blocked by the selective CB(1) antagonist AM251 (1 microM), but not by the selective CB(2) antagonist AM630 (1 microM), confirming the role of CB(1) receptors. High glucose treatment did not significantly elevate endocannabinoid levels. These results suggest that high glucose concentrations are associated with decreased expression, but preserved function of CB(1) receptors in nerve cells.
Zhang
Fan
F
School of Life Sciences, Edinburgh Napier University, Scotland, UK.
Challapalli
Sarat C
SC
Smith
Paula J W
PJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D018689:Sensory System Agents / Q000494:pharmacology*
D007211:Indoles; D018696:Neuroprotective Agents; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D018689:Sensory System Agents; C103505:AM 251; D013759:Dronabinol; D020932:Nerve Growth Factor; D005947:Glucose; C062018:HU 211; D002211:Capsaicin; D002118:Calcium; C094023:iodopravadoline