Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restorati... more Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restoration, and anti-inflammatory effects. This study aims to investigate the efficacy of oral cilostazol for preventing the development of diabetic peripheral neuropathy (DPN).Materials and Methods: Ninety adult male Sprague-Dawley rats were divided into five groups: 1) naïve (control); 2) diabetic (DM); 3) DM receiving 10 mg/kg cilostazol (cilo-10); 4) DM receiving 30 mg/kg cilostazol (cilo-30); and 5) DM receiving 100 mg/kg cilostazol (cilo-100). Hindpaw responses to thermal and mechanical stimuli were measured. Activation of microglia and astrocytes in the spinal dorsal horn (SDH) and expression of NaVs in the dorsal root ganglia (DRG) were examined with Western blots and immunofluorescence.Results: DM rats displayed decreased withdrawal thresholds to mechanical stimuli (mechanical allodynia) and blunted responses to thermal stimuli. In addition, the expression of microglia increased, but as...
Background and Objective: Our previous study demonstrated that consistent treatment of oral cilos... more Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hi...
Gremlin1 (grem1) has been previously identified as being significantly up-regulated during regene... more Gremlin1 (grem1) has been previously identified as being significantly up-regulated during regeneration of Xenopus laevis limbs. Grem1 is an antagonist of bone morphogenetic proteins (BMPs) with a known role in limb development in amniotes. It forms part of a self regulating feedback loop linking epithelial (FGF) and mesenchymal (shh) signalling centres, thereby controlling outgrowth, anterior posterior and proximal distal patterning. Spatiotemporal regulation of the same genes in developing and regenerating Xenopus limb buds supports conservation of this mechanism. Using a heat shock inducible grem1 (G) transgene to created temperature regulated stable lines, we have shown that despite being upregulated in regeneration, grem1 overexpression does not enhance regeneration of tadpole hindlimbs. However, both the regenerating and contralateral, developing limb of G transgenics developed skeletal defects, suggesting that overexpressing grem1 negatively affects limb patterning. When grem...
The eukaryotic Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signal... more The eukaryotic Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling pathways, which in turn provide readout for morphogens such as fibroblast growth factors (Fgfs) that are essential for many developmental processes, including limb development. In a transcriptome analysis of early proximo-distal patterning of the Xenopus laevis limb bud, spry1a, 2 and 4 were predicted to be expressed predominantly in the distal third. Expression of all three in the distal limb initially corresponded to the progress zone mesenchyme, adjacent to the fgf8b-positive cryptic apical ectodermal ridge (AER). Spry2 transcripts were also expressed ectodermally, and later localized to the AER. During formation of the autopod, spry1a and spry4 became restricted to the anterior distal mesenchyme. All three spry genes were re-expressed in the mesenchyme cells of the blastema during hindlimb regeneration, with spry2 also overlapping with the region of fgf8b re-expression. However, the anterior bias seen in developing limbs was not recapitulated. We conclude that Spry1a, 2 and 4 have partially overlapping expression in developing and regenerating Xenopus limbs, which correspond with known areas of Fgf signaling. Sprys may therefore be involved in refining of Fgf signal transduction from the AER during development and regeneration.
Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restorati... more Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restoration, and anti-inflammatory effects. This study aims to investigate the efficacy of oral cilostazol for preventing the development of diabetic peripheral neuropathy (DPN).Materials and Methods: Ninety adult male Sprague-Dawley rats were divided into five groups: 1) naïve (control); 2) diabetic (DM); 3) DM receiving 10 mg/kg cilostazol (cilo-10); 4) DM receiving 30 mg/kg cilostazol (cilo-30); and 5) DM receiving 100 mg/kg cilostazol (cilo-100). Hindpaw responses to thermal and mechanical stimuli were measured. Activation of microglia and astrocytes in the spinal dorsal horn (SDH) and expression of NaVs in the dorsal root ganglia (DRG) were examined with Western blots and immunofluorescence.Results: DM rats displayed decreased withdrawal thresholds to mechanical stimuli (mechanical allodynia) and blunted responses to thermal stimuli. In addition, the expression of microglia increased, but as...
Background and Objective: Our previous study demonstrated that consistent treatment of oral cilos... more Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hi...
Gremlin1 (grem1) has been previously identified as being significantly up-regulated during regene... more Gremlin1 (grem1) has been previously identified as being significantly up-regulated during regeneration of Xenopus laevis limbs. Grem1 is an antagonist of bone morphogenetic proteins (BMPs) with a known role in limb development in amniotes. It forms part of a self regulating feedback loop linking epithelial (FGF) and mesenchymal (shh) signalling centres, thereby controlling outgrowth, anterior posterior and proximal distal patterning. Spatiotemporal regulation of the same genes in developing and regenerating Xenopus limb buds supports conservation of this mechanism. Using a heat shock inducible grem1 (G) transgene to created temperature regulated stable lines, we have shown that despite being upregulated in regeneration, grem1 overexpression does not enhance regeneration of tadpole hindlimbs. However, both the regenerating and contralateral, developing limb of G transgenics developed skeletal defects, suggesting that overexpressing grem1 negatively affects limb patterning. When grem...
The eukaryotic Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signal... more The eukaryotic Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling pathways, which in turn provide readout for morphogens such as fibroblast growth factors (Fgfs) that are essential for many developmental processes, including limb development. In a transcriptome analysis of early proximo-distal patterning of the Xenopus laevis limb bud, spry1a, 2 and 4 were predicted to be expressed predominantly in the distal third. Expression of all three in the distal limb initially corresponded to the progress zone mesenchyme, adjacent to the fgf8b-positive cryptic apical ectodermal ridge (AER). Spry2 transcripts were also expressed ectodermally, and later localized to the AER. During formation of the autopod, spry1a and spry4 became restricted to the anterior distal mesenchyme. All three spry genes were re-expressed in the mesenchyme cells of the blastema during hindlimb regeneration, with spry2 also overlapping with the region of fgf8b re-expression. However, the anterior bias seen in developing limbs was not recapitulated. We conclude that Spry1a, 2 and 4 have partially overlapping expression in developing and regenerating Xenopus limbs, which correspond with known areas of Fgf signaling. Sprys may therefore be involved in refining of Fgf signal transduction from the AER during development and regeneration.
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