Denervation and hyperinnervation in the nervous system of diabetic animals. II. Monoaminergic and peptidergic alterations in the diabetic encephalopathy

Abstract

The monoaminergic innervation of the central nervous system (CNS) is characterized by long and short projecting neurons. The neurological correlates of diabetes are usually referred to as processes of degenerative atrophy affecting motor and sensory peripheral nerves. We have found that the long serotoninergic axons innervating the spinal cord and the cerebral cortex are unaffected in diabetic animals and that the noradrenergic innervation of the cortex is normal as well. The serotonin content is doubled in the hypothalamus with no apparent alteration of 5-HIAA levels, suggesting a supernumerary innervation that is accompanied by a reduced release. In pons medulla oblongata, serotonin and dopamine with the relative metabolites 5-HIAA and DOPAC are significantly reduced, whereas noradrenaline is markedly increased. In the hippocampus, there is a reduction of serotonin content. The serotoninergic alterations are peculiar as suggested by the sparing of the most distal projections that is accompanied by hyperinnervation of the hypothalamus and the loss of shorter collaterals in the pons medulla oblongata. In the hypothalamus and in the striatum of diabetic rats, there are significant higher levels of substance P and met-enkephalin, respectively. The abundance of proenkephalin A mRNA is also increased in the striatum. Conversely, in the lumbar cord of diabetic animals, the levels of substance P and met-enkephalin are significantly reduced. Such alterations likely reflect retrograde degeneration of the peripheral sensory input. The CNS changes are unlikely due to vascular abnormalities in the brain of diabetic rats; rather, we suggest that the persistent lack of insulin is the major factor involved as a trigger of the monoaminergic changes in the diabetic brain.

Sympathetic axonopathies and hyperinnervation in the small intestine smooth muscle of aged Fischer 344 rats

“…In examining this present series of whole mounts, we evaluated the hypothesis that the extrinsic sympathetic inputs to the aged gut might evidence profiles of hyperinnervation similar to those described for other organs (e.g., brain: Di Giulio et al, 1989b; heart: Hassankhani et al, 1995; diabetic intestines: Di Giulio et al, 1989a; lung: Hoyle et al, 1998; adipose tissue: Straub et al, 2011; blood vessels: Luff et al, 2005). In keeping with such observations on non-GI tissues, we observed that sites of hyperinnervation in the gut also occurred in punctate, spatially random patterns.…”

“…Indeed, Belai et al (1995) noted an increased density in noradrenergic fibers in the sphincters of the aged rat GI tract consistent with a hyperinnervation hypothesis. And, additionally, in diabetes, which often involves neuropathies similar to those associated with aging, Di Giulio and colleagues (1989a) observed that sympathetic axons hyperinnervate the duodenum (though apparently not jejunum).…”

Effect of Insulin and Clonidine on the Evoked Release of Norepinephrine and Serotonin from the Nucleus tractus solitarius of the Diabetic Rat

“…This was espe cially perplexing, and we are presently pursu ing this finding. It may be that medullary 5-HT levels are significantly depressed by as much as 71% in diabetic rats [15,19,22,[42][43][44][45], therefore, less 5-HT is available for re lease in our slices. These 5-HT neurons clearly possess functional ci2-adrenergic receptors be cause clonidine depresses S2 release in both normal and diabetic slices.…”

Perinatal supplementation of low doses of ethanol enhances 5-HT restoration in the central nervous system

“…Animals were kept under standard conditioned and killed at the appropriate time. Brain and spinal cord were quickly dissected out, frozen in liquid nitrogen and kept at -80°C until assay (Di Giulio et al, 1987, 1989aGorio et al, 1993Gorio et al, , 1996. An approximate equal number of female and male animals were studied in each group.…”