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NEUROPHARMACOLOGY

Expression of Cannabinoid CB₁ Receptors in Models of Diabetic Neuropathy

School of Life Sciences, Napier University, Edinburgh, Scotland (F.Z., V.S., P.J.W.S.); and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (S.H.)

A clearer understanding of the mechanisms underlying the development and progression of diabetic neuropathy is likely to indicate new directions for the treatment of this complication of diabetes. In the present study we investigated the expression of cannabinoid CB₁ receptors in models of diabetic neuropathy. PC12 cells were differentiated into a neuronal phenotype with nerve growth factor (NGF) (50 ng/ml) in varying concentrations of glucose (5.5–50 mM). CB₁ receptor expression was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level via immunohistochemical and Western blot analysis. CB₁ expression was also compared in dorsal root ganglia (DRG) removed from streptozotocin-induced diabetic rats versus control animals. Total neurite length induced by NGF was reduced in cells cultured in 20 to 50 mM glucose at day 6 (P < 0.01 versus 5.5 mM; n = 6). Cell viability assays conducted in parallel on day 6 confirmed that the total cell numbers were not significantly different among the various glucose concentrations (P = 0.86; n = 12). RT-PCR, immunohistochemical, and Western blot analysis all revealed down-regulation of the CB₁ receptor in cells treated with high glucose (P < 0.05; n = 4–5 for each), and in DRG removed from diabetic rats compared with controls (P < 0.01; n = 5 for immunohistochemistry, and n = 3 for Western blot). These results suggest that high glucose concentrations are associated with decreased expression of CB₁ receptors in nerve cells. Given the neuroprotective effect of cannabinoids, a decline in CB₁ receptor expression may contribute to the neurodegenerative process observed in diabetes.

Address correspondence to: Dr. Paula J. W. Smith, School of Life Sciences, Napier University, 10 Colinton Rd., Edinburgh, Scotland, UK EH10 5DT. E-mail: pjw.smith{at}napier.ac.uk

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