Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats

Abstract

Aims/hypothesis The aim of this study was to evaluate the nature and extent of neuronal loss in dorsal root ganglia (DRG) in diabetic polyneuropathy. Materials and methods We examined 10-month diabetic BioBreeding/Worcester (BB/Wor) rats with respect to DRG ultrastructure and morphometry, sural nerve morphometry, pro-and anti-apoptotic proteins, the expression of neurotrophic factors and their receptors, and sensory nerve functions. Results In diabetic rats, DRG neurons decreased to 73% of normal, owing to loss of substance P and calcitonin generelated peptide-positive neurons. Levels of pro-apoptotic active caspase-3, Bax and low-affinity nerve growth factor (NGF) were increased in DRG. The concentration of anti-apoptotic heat shock protein (HSP) 70 in DRG was decreased, whereas concentrations of Bcl-xl and HSP27 were unaltered. Levels of poly(ADP-ribose) polymerase (PARP) and cleaved PARP were unaltered. Levels of NGF in sciatic nerve and concentrations of the high-affinity NGF receptor, insulin receptor and IGF-I receptor in DRG were significantly decreased. Sensory nerve conduction velocity decreased to 78% of normal. Hyperalgesia increased up to 6 months. Myelinated and unmyelinated fibre numbers of the sural nerve were significantly decreased in diabetic rats. DRG examinations revealed no evidence of apoptosis, mitochondrial changes or abnormalities of the endoplasmic reticulum. Instead, neurons demonstrated progressive vacuolar degenerative changes of the Golgi apparatus, with fragmentation and formation of large cytoplasmic vacuoles. These data show that sustained apoptotic stress is present in DRG of chronically diabetic BB/Wor rats, but fails to proceed to apoptotic cell death. Conclusions/interpretation Progressive DRG neuronal loss, particularly of small neurons, occurs in the type 1 diabetic BB/Wor rat. This is associated with neurotrophic withdrawal and progressive degeneration of the Golgi apparatus.

Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the db − /db − mouse, a type 2 diabetes model

“…A reduced perikaryal volume of primary sensory neurons was noted early (53) and confirmed by Shimosige et al (54), but when unbiased stereological methods (55) were used, no significant change in DRG neuron numbers was observed in 12-mo-old STZ rats (17,27). However, a 27% loss of smallsized DRG neurons has been reported in type 1 diabetic BB/ Wor rats by Kamiya et al (56). Apoptotic changes in DRGs have been reported in other experimental diabetic animal models (SI Text).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…For example, 10 months of hyperglycemia markedly reduced Hsp70 levels in DRG from spontaneously diabetic Biobreeding/Worcester rats, a model of type 1 diabetes. This correlated with an advanced neuropathy characterized by loss of neurotrophic components and a decrease in both myelinated/unmyelinated fibers (Kamiya et al, 2006). On the other hand, after only 4 months of diabetes in the Bio-breeding/Worcester rat model, Hsp27 and Hsp70 were increased in DRG (Kamiya et al, 2005).…”

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

“…Upregulation of PGC-1α is protective against oxidative stress in hippocampal neurons (17) and prevents mutant Parkin-related degeneration in dopaminergic neurons (18). In the context of diabetes, the bioenergetic phenotype of mitochondria in dorsal root ganglia-derived (DRG-derived) sensory neurons is characterized by inner membrane depolarization, reduced expression of respiratory chain components, and suboptimal spare respiratory capacity (4,11) without remarkable ultrastructural alterations (19). Activation of AMPK by resveratrol protected mitochondrial function and peripheral nerve structure and function in rodent models of both type 1 and type 2 diabetes (11).…”