Does diabetes target ganglion neurones?: Progressive sensory neurone involvement in long-term experimental diabetes

Abstract

Targeting of dorsal root ganglia by diabetes could account for the selective sensory abnormalities that patients with early diabetic polyneuropathy develop. In this work, we addressed survival, phenotype and gene expression in sensory neurones in lumbar dorsal root ganglia in a long-term model of experimental streptozotocin-induced diabetes in rats, designed to reflect human disease. Motor and sensory conduction slowing developed early, by the 2-month time point. At 2 months, sensory neurones had no detectable alterations in their calibre or gene expression, assessed using quantitative in situ hybridization studies for mRNA markers that included alpha CGRP, beta CGRP, NFM, t alpha 1-tubulin, SP, VIP, B50 (GAP43), galanin, somatostatin, PACAP, HSP27, c-jun, SNAP 25, p75, TrkA, TrkB and TrkC. By 12 months, however, diabetics had developed neurone perikaryal and distal axon atrophy, accompanied by generalized downregulation of mRNA expression, particularly of CGRP transcripts, PACAP, SP, NFM, p75, trkA and trkC. With the exception of HSP-27, no elevation in mRNAs that increase after injury, such as VIP, galanin, CCK, PACAP, B50 and t alpha 1-tubulin, was observed and constitutive levels, when detectable, trended towards lower rather than increased levels. There was relative preservation of neurone numbers at 12 months; only a non-significant trend towards fewer diabetic neurones was detected using a rigorous and systematic physical dissector counting approach through the entire L5 ganglia. There was no change in the relative populations of CGRP- and SP-immunoreactive neurones. Our findings indicate that even long-term experimental diabetes is associated with relative preservation of sensory neurone populations, but the neurones are atrophic and their gene expression is altered. This pattern of change differs from that following axotomy, implies a degenerative rather than an injury phenotype and has important implications for how such neurones might be rescued.

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

“…Others detect some loss of DRG (Russell et al, 1999;Zochodne et al, 2001;Kishi et al, 2002) and in particular there is a statistically significant loss of large DRG neurons (Kishi et al, 2002). Using rigorous counting techniques, Zochodne et al, concluded that there was no significant loss of neurons in the DRG of diabetic animals (Zochodne et al, 2001); although this study did detect a 14.5% decrease in the mean number of neurons (determined by nuclei). There is clear evidence that not all neurons are affected equally and, as with human patients, not all rodents develop the same degree of neuropathy or the same degree of neuronal injury.…”

“…Multiple studies report activation of caspases in DRG neurons both in vitro and in vivo (Russell et al, 1999;Srinivasan et al, 2000;Kishi et al, 2002;Russell et al, 2002;Cheng and Zochodne, 2003;Schmeichel et al, 2003;. Others detect some loss of DRG (Russell et al, 1999;Zochodne et al, 2001;Kishi et al, 2002) and in particular there is a statistically significant loss of large DRG neurons (Kishi et al, 2002). Using rigorous counting techniques, Zochodne et al, concluded that there was no significant loss of neurons in the DRG of diabetic animals (Zochodne et al, 2001); although this study did detect a 14.5% decrease in the mean number of neurons (determined by nuclei).…”

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

“…The neuronal cell bodies in the DRG possibly are more capable of responding to metabolic insult through constant synthesizing and refolding of proteins than the axonal compartment, which would explain why we did not observe abundant alterations in the DRG proteome/ metabolome. Perikaryal preservation is a key feature of DN because no neuronal loss was detected in the DRG after 12 months of hyperglycemia in STZ-diabetes (31,32). The DRG plays a crucial role in axonal support, as evidenced by findings in STZ-diabetes when direct support of DRG neurons through intrathecal administration of insulin (which did not reduce hyperglycemia) improved SN conduction velocity and protected against distal axonal atrophy and intraepidermal nerve fiber loss (33,34).…”

Uncoupling Proteins Prevent Glucose-Induced Neuronal Oxidative Stress and Programmed Cell Death

“…Most studies indicate some loss of DRG neurons (1,36), and in particular there is a statistically significant loss of large DRG neurons (36). In one study (37), using rigorous counting techniques of DRG nuclei in 6 -12 pairs of sections from the whole DRG, it was concluded that there was no loss of neurons in the DRG from diabetic animals. In fact, this study showed a 14.5% decrease in the mean number of neurons (determined by nuclei) per ganglion in 12-month diabetic animals (31,629 Ϯ 2,427 neurons) compared with that of control animals (36,986 Ϯ 3,035).…”