Abstract
Dogs share many chronic morbidities with humans and thus represent a powerful model for translational research. In comparison to rodents, the canine ganglioside metabolism more closely resembles the human one. Gangliosides are components of the cell plasma membrane playing a role in neuronal development, intercellular communication and cellular differentiation. The present in vitro study aimed to characterize structural and functional changes induced by GM1 ganglioside (GM1) in canine dorsal root ganglia (DRG) neurons and interactions of GM1 with nerve growth factor (NGF) and fibroblast growth factor (FGF2) using immunofluorescence for several cellular proteins including neurofilaments, synaptophysin, and cleaved caspase 3, transmission electron microscopy, and electrophysiology. GM1 supplementation resulted in increased neurite outgrowth and neuronal survival. This was also observed in DRG neurons challenged with hypoxia mimicking neurodegenerative conditions due to disruptions of energy homeostasis. Immunofluorescence indicated an impact of GM1 on neurofilament phosphorylation, axonal transport, and synaptogenesis. An increased number of multivesicular bodies in GM1 treated neurons suggested metabolic changes. Electrophysiological changes induced by GM1 indicated an increased neuronal excitability. Summarized, GM1 has neurotrophic and neuroprotective effects on canine DRG neurons and induces functional changes. However, further studies are needed to clarify the therapeutic value of gangliosides in neurodegenerative diseases.
Highlights
Dogs share many chronic morbidities with humans and represent a powerful model for translational research
Supplementation of neurons with GM1 ganglioside lead to a significant increase in the mean number of processes in cultures both with and without nerve growth factor (NGF) supplementation (5.5 and 3.9 processes per neuron, respectively). Neurons supplemented with both NGF and GM1 possessed significantly more processes than neurons cultured with FGF2 alone (3.1) or a combination of FGF2 and GM1 (2.9) In contrast, GM2 and GM3 supplementation did not affect neurite outgrowth and the glucosylceramide synthase inhibitor D-PDMP blocked neurite outgrowth
The observed effects of GM1 ganglioside, NGF, and FGF2 on dorsal root ganglia (DRG) neurons instigated the analysis of their impact on additional components of the neuronal cytoskeleton focusing on microtubular proteins and NFs
Summary
Dogs share many chronic morbidities with humans and represent a powerful model for translational research. Cellular gangliosides concentrate in lipid microdomains termed lipid rafts, which are signaling platforms rich in cholesterol and glycosphingolipids and contain amongst others high affinity tropomyosin-related kinase (Trk) and low affinity neurotrophin receptors (p75NTR)[30,31,32] These receptors are activated by nerve growth factor (NGF) and other neurotrophic factors and have a strong impact on neuronal development, maintenance, and survival as well as memory formation and storage[33,34]. GM1 and NGF protect primary cultured rat embryonic dorsal root ganglia (DRG) and spinal cord neurons from glutamate-induced excitotoxicity[37,38] Both molecules may function by modulating Ca2+ homeostasis, maintaining normal mitochondrial membrane potential or by promoting the mRNA expression of neuronal proteins such as growth associated protein 43 and neurofilaments (NFs)[38,39]. The recent development of semisynthetic and potent GM1 compounds as well as solid lipid nanoparticles as drug delivery systems motivates the therapeutic use of GM151,52
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