AbstractNeuregulins (NRGs) are growth factors which bind to Erb receptor tyrosine kinases that localize to Schwann cells (SCs). Although NRGs can promote cell survival, mitogenesis, and myelination in undifferentiated SCs, they also induce demyelination of myelinated co‐cultures of SCs and dorsal root ganglion (DRG) neurons. We have shown previously that Erb B2 activity increased in premyelinating SCs in response to hyperglycemia, and that this correlated with the downregulation of the protein caveolin‐1 (Cav‐1). As myelinated SCs undergo substantial degeneration in diabetic neuropathy, we used myelinated SC/DRG neuron co‐cultures to determine if hyperglycemia and changes in Cav‐1 expression could enhance NRG‐induced demyelination. In basal glucose, NRG1 caused a 2.4‐fold increase in the number of damaged myelin segments. This damage reached 3.8‐fold under hyperglycemic conditions, and was also associated with a robust decrease in the expression of Cav‐1 and compact myelin proteins. The loss of Cav‐1 and compact myelin proteins following hyperglycemia and NRG treatment was not due to neuronal loss, since the axons remained intact and there was no loss of PGP 9.5, an axonal marker protein. To examine if changes in Cav‐1 were sufficient to alter the extent of NRG‐induced demyelination, SC/DRG neurons co‐cultures were infected with antisense or dominant‐negative Cav‐1(P132L) adenoviruses. Either antisense‐mediated downregulation or mis‐localization of endogenous Cav‐1 by Cav‐1(P132L) resulted in a 1.5‐ to 2.4‐fold increase in NRG‐induced degeneration compared to that present in control cultures. These data support that hyperglycemia and changes in Cav‐1 are sufficient to sensitize myelinated SC/DRG co‐cultures to NRG‐induced demyelination. © 2008 Wiley‐Liss, Inc.