GM1 Oligosaccharide Efficacy in Parkinson’s Disease: Protection against MPTP

Abstract

Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson’s disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood–brain barrier is denied. Recently, we demonstrated that the GM1 oligosaccharide head group (GM1-OS) is the GM1 bioactive portion that, interacting with the TrkA-NGF complex at the membrane surface, promotes the activation of a multivariate network of intracellular events regulating neuronal differentiation, protection, and reparation. Here, we evaluated the GM1-OS neuroprotective potential against the Parkinson’s disease-linked neurotoxin MPTP, which destroys dopaminergic neurons by affecting mitochondrial bioenergetics and causing ROS overproduction. In dopaminergic and glutamatergic primary cultures, GM1-OS administration significantly increased neuronal survival, preserved neurite network, and reduced mitochondrial ROS production enhancing the mTOR/Akt/GSK3β pathway. These data highlight the neuroprotective efficacy of GM1-OS in parkinsonian models through the implementation of mitochondrial function and reduction in oxidative stress.

GM1 ganglioside exerts protective effects against glutamate‐excitotoxicity via its oligosaccharide in wild‐type and amyotrophic lateral sclerosis motor neurons

“…Next, we evaluated mitochondrial using the specific MitoSOX Red dye [36,41,57] 4 h after glutamate administration (Fig. 4C).…”

“…GM1, via GM1‐OS, has been demonstrated to counteract the toxicity of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrocholoride (MPTP), a neurotoxin able to induce neurodegeneration by inhibiting mitochondrial complex I [18,36,41]. Additionally, we specifically found that GM1‐OS stimulated mitochondria biogenesis, boosted mitochondria function and reduced mitochondria ROS levels in neuronal cells [31,41]. Importantly, GM1‐OS potentiated mitochondria function by boosting mitochondrial complex I and II activities in a N2a model of mitochondrial dysfunction [31].…”

“…Interestingly, the capability of GM1 and GM1‐OS to preserve mitochondria and avoid ROS accumulation is in line with data reported in literature. GM1, via GM1‐OS, has been demonstrated to counteract the toxicity of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrocholoride (MPTP), a neurotoxin able to induce neurodegeneration by inhibiting mitochondrial complex I [18,36,41]. Additionally, we specifically found that GM1‐OS stimulated mitochondria biogenesis, boosted mitochondria function and reduced mitochondria ROS levels in neuronal cells [31,41].…”

“…An array of molecular processes was shown to be induced by GM1‐OS in a TrkA‐dependent manner, including antioxidant mechanisms, mitochondrial bioenergetics [31], and an anti‐inflammatory response [36]. Accordingly, GM1‐OS was found to be able to counteract neurodegeneration in vitro and in vivo in Parkinson's disease models [36,41,67,68].…”

“…For each experimental condition, 30 pictures (representative of all the well's area) per well were automatically taken using ImageXpress® (Molecular Devices, San Jose, CA, US) with 20× magnification, using the same acquisition parameters. From images, analyses were directly and automatically performed by MetaXpress® (Molecular Devices) [41–43].…”