Abstract
Apart from its pivotal role in the regulation of carbohydrate metabolism, insulin exerts important neurotrophic and neuromodulator effects on dorsal root ganglion (DRG) neurons. The neurite outgrowth-promoting effect is one of the salient features of insulin’s action on cultured DRG neurons. Although it has been established that a significant population of DRG neurons express the insulin receptor (InsR), the significance of InsR expression and the chemical phenotype of DRG neurons in relation to the neurite outgrowth-promoting effect of insulin has not been studied. Therefore, in this study by using immunohistochemical and quantitative stereological methods we evaluated the effect of insulin on neurite outgrowth of DRG neurons of different chemical phenotypes which express or lack the InsR. Insulin, at a concentration of 10 nM, significantly increased total neurite length, the length of the longest neurite and the number of branch points of cultured DRG neurons as compared to neurons cultured in control medium or in the presence of 1 μM insulin. In both the control and the insulin exposed cultures, ∼43% of neurons displayed InsR-immunoreactivity. The proportions of transient receptor potential vanilloid type 1 receptor (TRPV1)-immunoreactive (IR), calcitonin gene-related peptide (CGRP)-IR and Bandeiraea simplicifolia isolectin B4 (IB4)-binding neurons amounted to ∼61%, ∼57%, and ∼31% of DRG neurons IR for the InsR. Of the IB4-positive population only neurons expressing the InsR were responsive to insulin. In contrast, TRPV1-IR nociceptive and CGRP-IR peptidergic neurons showed increased tendency for neurite outgrowth which was further enhanced by insulin. However, the responsiveness of DRG neurons expressing the InsR was superior to populations of DRG neurons which lack this receptor. The findings also revealed that besides the expression of the InsR, inherent properties of peptidergic, but not non-peptidergic nociceptive neurons may also significantly contribute to the mechanisms of neurite outgrowth of DRG neurons. These observations suggest distinct regenerative propensity for differing populations of DRG neurons which is significantly affected through insulin receptor signaling.
Highlights
Insulin, besides being essential in the regulation of glucose homeostasis, is involved in several neuronal processes such as neural survival and neurite outgrowth in both the central and the peripheral nervous system (Fernyhough et al, 1993; Wan et al, 1997; Barber et al, 2001; Stella et al, 2001; Gerozissis, 2003; Singh et al, 2012)
The morphology of cultured dorsal root ganglion (DRG) neurons was studied in specimens stained with the mouse anti-β3-tubulin antibody
Our data revealed that insulin significantly increased the total neurite length from 513.21 ± 25.86 μm to 853.95 ± 52.65 μm, FIGURE 3 | Size-frequency distribution histogram of the total and the insulin receptor (InsR)-immunopositive and -negative populations of adult rat cultured dorsal root ganglion (DRG) neurons
Summary
Besides being essential in the regulation of glucose homeostasis, is involved in several neuronal processes such as neural survival and neurite outgrowth in both the central and the peripheral nervous system (Fernyhough et al, 1993; Wan et al, 1997; Barber et al, 2001; Stella et al, 2001; Gerozissis, 2003; Singh et al, 2012). Previous studies demonstrated that a unique population of C-fiber DRG neurons is sensitive to capsaicin and express the transient receptor potential vanilloid type 1 receptor (TRPV1) (Jancsó et al, 1977; Buck and Burks, 1986; Holzer, 1991; Caterina et al, 1997; Guo et al, 2001) These neurons are involved in pain sensation and, in a variety of organs, local regulatory functions, including neurogenic inflammation brought about by the release of sensory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) (Jancsó, 1960; Jancso et al, 1968, Jancsó et al, 1977, 2009; Maggi and Meli, 1988; Holzer, 1991; Nagy et al, 2004). It has been shown that peptidergic and non-peptidergic sensory neurons have distinct sensitivities to neurotrophic factors such as nerve growth factor (NGF) and glial cell derived neurotrophic factor (GDNF) (Molliver et al, 1997)
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