GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding

Schneider, Jay S.; Cambi, Franca; Gollomp, Stephen; Kuwabara, Hiroto; Brašić, James Robert; Leiby, Benjamin E.; Sendek, Stephanie; Wong, Dean F.

doi:10.1016/j.jns.2015.06.028

Cited by 44 publications

(37 citation statements)

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“…Administration of GM1 has been found to be beneficial for Parkinson patients ( 9 ), and the high fraction of GM1 in neurons has been correlated with their plasticity and axonal growth (see Ref. ( 4 ) and references therein).…”

Section: Resultsmentioning

confidence: 99%

“…GM1 plays a crucial role in connection with receptor proteins for cell-cell communication and can be found at high concentrations in the central nervous system of mammals. It strongly influences neural plasticity ( 4 ), was recently recognized as a factor in slowing down the progression of Parkinson disease ( 9 ), and is involved in a large number of essential functions in the plasma membrane and intracellular loci (for a recent review, see Ref. ( 10 )).…”

Section: Introductionmentioning

confidence: 99%

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GM1 Softens POPC Membranes and Induces the Formation of Micron-Sized Domains

Fricke

Dimova

2016

Biophysical Journal

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The influence of the glycolipid GM1 on the physical properties of POPC membranes was studied systematically by using different methods applied to giant and large unilamellar vesicles. The charge per GM1 molecule in the membrane was estimated from electrophoretic mobility measurements. Optical microscopy and differential scanning calorimetry were employed to construct a partial phase diagram of the GM1/POPC system. At room temperature, phase separation in the membrane was detected for GM1 fractions at and above ∼5 mol %, whereby GM1-rich gel-like domains were observed by fluorescent microscopy. Fluctuation analysis, vesicle electrodeformation, and micropipette aspiration were used to assess the bending rigidity of the membrane as a function of GM1 content. In the fluid phase, GM1 was shown to strongly soften the bilayer. In the region of coexistence of fluid and gel-like domains, the micropipette aspiration technique allowed measurements of the bending rigidity of the fluid phase only, whereas electrodeformation and fluctuation analysis were affected by the presence of the gel-phase domains. The observation that GM1 decreased the bilayer bending rigidity is important for understanding the role of this ganglioside in the flexibility of neuronal membranes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GM1 Softens POPC Membranes and Induces the Formation of Micron-Sized Domains

Fricke

Dimova

2016

Biophysical Journal

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“…Past clinical trials for the treatment of other conditions have shown that GM1 administration in patients is relatively safe (Alter, ; Chinnock & Roberts, ; Schneider et al , , ). In spite of poor permeability of the blood–brain barrier to GM1 (Ghidoni et al , ; Saulino & Schengrund, ), sustained benefits of GM1 were observed in a small randomized double‐blind placebo‐controlled trial in Parkinson's disease patients even when this ganglioside was administered by subcutaneous injections (Schneider et al , , , ). Potential drug delivery challenges in HD patients could be circumvented through intrathecal (or intraventricular) drug administration, as in recent clinical trials with antisense oligonucleotides, or with strategies and formulations to improve drug delivery to the brain.…”

Section: Discussionmentioning

confidence: 99%

Disease‐modifying effects of ganglioside GM1 in Huntington's disease models

et al. 2017

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Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD. In this study, we provide evidence that intraventricular administration of GM1 has profound disease‐modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L‐Ser and D‐Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric‐like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease‐modifying potential in HD.

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“…Probably the reason is that these clinical trials included peripheral administration of the ganglioside, which inefficiently permeates through the BBB. Although the BBB has been reported to be dysfunctional [12,13,[72][73][74][75][76], it remains a huge obstacle to adequate drug delivery to the brain.…”

Section: Discussionmentioning

confidence: 99%

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

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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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...

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GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding

Cited by 44 publications

References 45 publications

GM1 Softens POPC Membranes and Induces the Formation of Micron-Sized Domains

GM1 Softens POPC Membranes and Induces the Formation of Micron-Sized Domains

Disease‐modifying effects of ganglioside GM1 in Huntington's disease models

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

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