Abstract
Peripheral sensory diabetic neuropathy is characterized by morphological, electrophysiological and neurochemical changes to a subpopulation of primary afferent neurons. Here, we utilized a transgenic mouse model of diabetes (OVE26) and age-matched controls to histologically examine the effect of chronic hyperglycemia on the activity or abundance of the enzymes acid phosphatase, cytochrome oxidase and NADPH-diaphorase in primary sensory neuron perikarya and the dorsal horn of the spinal cord. Quantitative densitometric characterization of enzyme reaction product revealed significant differences between diabetic, compared to control, animals for all three enzymes. Levels of acid phosphatase reaction product were found to be significantly reduced in both small diameter primary sensory somata and the dorsal horn. Cytochrome oxidase activity was found to be significantly lower in small primary sensory somata while NADPH-diaphorase labeling was found to be significantly higher in small primary sensory somata and significantly lower in the dorsal horn. In addition to these observed biochemical changes, ratiometric analysis of the number of small versus large diameter primary sensory perikarya in diabetic and control animals demonstrated a quantifiable decrease in the number of small diameter cells in the spinal ganglia of diabetic mice. These results suggest that the OVE26 model of diabetes mellitus produces an identifiable disturbance in specific metabolic pathways of select cells in the sensory nervous system and that this dysfunction may reflect the progression of a demonstrated cell loss.
Highlights
Diabetic sensory neuropathies are a common, clinically observed sequelae of hyperglycemia and are characterized by a progressive degradation of primary afferent function [1,2]
Functional and structural evidence suggest an early and frequent involvement of small diameter primary sensory neurons leading to nociceptive abnormalities [2,3,4]
Enzyme histochemical techniques demonstrated to be sensitive to neuronal perturbation [7] were used to examine the impact of long-standing hyperglycemia and hypoinsulinemia on the distribution and activity of lysosomal acid β-glycerophosphatase (AP), cytochrome oxidase (CO), and NADPH-diaphorase (NADPH-d; a correlate of nitric oxide synthase in aldehyde fixed tissue [8]) in both sensory ganglia and the spinal cord
Summary
Diabetic sensory neuropathies are a common, clinically observed sequelae of hyperglycemia and are characterized by a progressive degradation of primary afferent function [1,2]. Quantitative densitometric analysis supported the qualitative observations and revealed significantly reduced levels of AP (P = 0.026; 27 sections quantified) and NADPH-d (P < 0.001; 27 sections quantified) reaction product in lamina I and II of the dorsal horn of control and diabetic mice (Table 1). No significant differences were observed in qualitative staining appearance or intensity of CO reaction product labeling in the dorsal horn of diabetic, compared to non-diabetic animals (31 sections quantified). Diabetic animals most likely represents a loss of unmyelinated or small myelinated primary sensory neurons a relative increase in the number of large myelinated neurons, unlikely, cannot be discounted The former interpretation is supported by the observed decrease in AP labeling in the dorsal horn of the spinal cord. Our results suggest that the OVE26 model of chronic hyperglycemia does alter the overall neurochemical profile of the sensory nervous system through cell loss and/or altered enzyme activity and that this pathology seems to impact unmyelinated and/or small myelinated primary sensory neurons
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