Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease

Schneider, Jay S.; Seyfried, Thomas N.; Choi, Hyo-S.; Kidd, Sarah K.

doi:10.1371/journal.pone.0143351

Cited by 32 publications

(28 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, to obtain a relevant result in Parkinson's patients, the quantity of injected GM1 was remarkable, and even for Alzheimer's patients, GM1 had to resort to intracranial injections [105], an administration route not compatible with human life. As reported below, many unsuccessful efforts have been made by researchers to find soluble analogues of GM1 [106][107][108] or to increase the amount of GM1 enzymatically [109]. However, new light comes from our recent recognition that the soluble oligosaccharide of GM1 represents the bioactive portion of the entire ganglioside [96,[110][111][112][113].…”

Section: The Fate Of Gm1 Administered In Vivo Within the Brainmentioning

confidence: 99%

“…In 2015, Scheneider noted that the plasma membrane GM1 increase by intraventricular injection of Vibrio Cholerae sialidase exerted a neuroprotective effect on the damaged nigrostriatal dopaminergic system of MPTP mice [109]. This enzyme removes sialic acid residues from brain polysialogangliosides (i.e., GD1a), thus increasing plasma membrane GM1, further evidence that the oligosaccharide may act as the mediator of GM1 function [109].…”

Section: The Oligosaccharide Chain Is the Functional Portion Of Gm1mentioning

confidence: 99%

See 1 more Smart Citation

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Chiricozzi

Lunghi

Biase

et al. 2020

IJMS

102

140

View full text Add to dashboard Cite

Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico-chemical properties have been studied in detail since 1963. Scientists were immediately attracted to the GM1 molecule and have carried on an ever-increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component.

show abstract

Section: The Fate Of Gm1 Administered In Vivo Within the Brainmentioning

confidence: 99%

Section: The Oligosaccharide Chain Is the Functional Portion Of Gm1mentioning

confidence: 99%

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Chiricozzi

Lunghi

Biase

et al. 2020

IJMS

102

140

View full text Add to dashboard Cite

show abstract

“…1), protects against kainate-induced destruction of pyramidal neurons in the CA3 hippocampal subfield (Dhanushkodi & McDonald, 2011). VCS has also been shown to protect against neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Schneider et al , 2015). …”

Section: Introductionmentioning

confidence: 99%

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

Akkhawattanangkul

Maiti

Xue

et al. 2017

Genes Brain and Behavior

View full text Add to dashboard Cite

Parkinson’s disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside—such as inhibition of GD3 synthase (GD3S) or administration of sialidase—are neuroprotective in vitro and in a number of preclinical models. In the present study we investigated the effects of GD3S deletion on parkinsonism induced by 1-Methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S−/− mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day x 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures—such as the force-plate actimeter and treadmill gait parameters—detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S−/− mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results demonstrate that inhibition of GD3S has neuroprotective properties in the MPTP model may warrant further investigation as a therapeutic target.

show abstract

“…For example, the soluble alternative of GM1, known as LIGA 20, has been proposed. This molecule is modified in the ceramide structure with a dichloroacetyl group instead of the acyl chain, which although rendering the molecule more permeable, has made it toxic in the long term [14][15][16][17][18][19][20].Another strategy attempted in rodents employed the intraventricular injection of the Vibrio cholerae sialidase, which removes residues of sialic acid from the polysialylated gangliosides (i.e., GD1a), thus increasing the endogenous GM1 levels in the membrane [21]. Unfortunately, even this strategy cannot be performed in the clinic, and peripheral injection of the enzyme would result in it being blocked by the BBB if not properly conveyed to the brain.…”

mentioning

confidence: 99%

“…Another strategy attempted in rodents employed the intraventricular injection of the Vibrio cholerae sialidase, which removes residues of sialic acid from the polysialylated gangliosides (i.e., GD1a), thus increasing the endogenous GM1 levels in the membrane [21]. Unfortunately, even this strategy cannot be performed in the clinic, and peripheral injection of the enzyme would result in it being blocked by the BBB if not properly conveyed to the brain.…”

mentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

View full text Add to dashboard Cite

Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

show abstract

Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease

Cited by 32 publications

References 33 publications

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Targeted deletion of GD3 synthase protects against MPTP‐induced neurodegeneration

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Contact Info

Product

Resources

About