Neurotrophic effects of GM1 ganglioside, NGF, and FGF2 on canine dorsal root ganglia neurons in vitro

Abstract

certain growth factors 23. Gangliosides are sialic acid-containing glycosphingolipids that can be found in different cellular membranes. In the CNS gangliosides account for up to 10% of the total lipid content in neurons 24. They are involved in intercellular communication, cellular differentiation, neuronal development, and regeneration 25-28 due to their capacity to modulate Ca 2+ influx and their influence on the function of receptors for muscarinic acetylcholine, serotonin, glutamine, neurotransmitters, and neurotrophic factors 29. 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 (p75 NTR) 30-32. 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. Anti-G M1 antibodies modulate the membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity thereby inhibiting NGF action on rat pheochromocytoma (PC12) cells 35,36. G M1 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 Ca 2+ 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. G M1 also protects rats against high altitude cerebral edema by suppressing oxidative stress and production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α 40. Nevertheless, another study using an ischemia/reperfusion model in rats demonstrated that G M1 neuroprotection seems to be dependent on p75 NTR 41. Exogenous gangliosides also directly interact with growth factors such as basic fibroblast growth factor (FGF2) and inhibit FGF receptor binding 42,43. Moreover, G M1 can inhibit FGF2-mediated effects by acting on the same intracellular signaling molecules. For instance, FGF2 stimulates the activity of glycogen synthase kinase 3 (GSK3) in proliferating adult rat hippocampal progenitor cells, whereas G M1 prevents GSK3 activation in organotypic hippocampal slice cultures 44,45. In contrast, cell-associated G M1 has been described to act as a functional co-receptor for FGF2 43. Despite its name, FGF2 plays an essential role in neurogenesis, differentiation, axonal branching, and neuron survival in various types of brain and peripheral nerve lesions 46,47. FGF2 also stimulates the proliferation of neuronal precursor cells isolated from postnatal murine DRGs 48. The ability of adult rat ganglion cells to regrow axons in vitro can be influenced by FGF2 and G M1 49. Neurotrophic effects of FGF2 seem to be also mediated by soluble mediators released from glial cells 50. Summarized, NGF, FGF2 and gangliosides such as G M1 ...

Neural Function Recovery and Safety of Mild Hypothermia Therapy Combined with Monosialotetrahexosylganglioside on Neonatal Asphyxia Complicated by Hypoxic Ischemic Encephalopathy

“…Based on the above research, this study further proved that GM1 combined with mild hypothermia treatment has a better protective efficacy on the neural function of neonates with HIE. The possible mechanism may be that the metabolic rate of brain tissues and cell energy are slowed down under mild hypothermia, which reduces neuron necrosis and apoptosis [ 23 ]. While low temperature environment alone cannot restore the damaged nerve cells, GM1, as an essential substance for the regeneration and development of brain nerves, can promote nerve regeneration [ 24 ], which makes up for the shortcomings of mild hypothermia therapy.…”

Ganglioside-monosialic acid (GM1) for prevention of chemotherapy-induced peripheral neuropathy: a meta-analysis with trial sequential analysis

“…Ganglioside-monosialic acid (GM1) is a monosialoglycosphingolipid mainly found in neurons and belongs to the family of gangliosides which are unique acidic glycolipids consisting of sphingosine, fatty acid, and sialic acid [8]. GM1 has been associated with essential functions in the processes of signal transduction, cell recognition, neurogenesis, and nerve development and differentiation [9][10][11]. In the 1980s, ganglioside treatment was found to be useful in the mitigation of vincristine-associated neuropathy, both in rabbit models and cancer patients [12,13].…”

Monosialotetrahexosylganglioside in the treatment of chronic oxaliplatin-induced peripheral neurotoxicity: TJMUCH-GI-001, a randomised controlled trial

“…Furthermore, GM1 elevates superoxide dismutase and glutathione levels to decrease anti-oxidant stress [42,43]. Animal studies showed that GM1 enhanced the activity of nerve growth factor, a protective factor of DRG [44]. To our knowledge, 3 studies (1 retrospective study and 2 randomised placebo-controlled trials) have evaluated the effectiveness of GM1 on chronic OIPN prevention [45À47].…”