GM1 ganglioside in Parkinson's disease: Results of a five year open study
ABSTRACT Previous work demonstrated that short-term (i.e., 16 weeks) use of GM1 ganglioside resulted in significant symptom reduction in Parkinson's disease (PD) patients. As GM1 use may have long-term benefit for PD patients, the present study was conducted to evaluate the long-term safety and efficacy of GM1 in PD patients. Twenty-six patients who concluded a previous randomized double blind placebo controlled trial of GM1 volunteered for this open-extension study. At the end of 5 years of GM1 use, patients generally had lower Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (assessed during a practically defined "off" period) than at baseline prior to randomization into the original study. A similar result was found for UPDRS Activities of Daily Living scores. Performance of timed motor tests also remained mostly stable over the 5 year observation period. No consistent clinically significant changes in blood chemistry, hematologic indices or urine chemistry were noted over the course of this study. These results suggest that long-term GM1 use by PD patients is safe and may provide some clinical benefit for PD patients. Additional study is required to more completely assess the degree to which GM1 treatment may be a symptomatic and/or disease-modifying agent for treatment of PD.
- SourceAvailable from: John Forsayeth
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- "A recent report indicated that chronic GM1 application enhanced RET activity and phosphorylation in the striatum of MPTP-treated mice while promoting recovery of DA and DOPAC deficits (Newburn et al., 2014), consistent with the suggestion that applied GM1 may function as a GDNF mimetic. The experimental paradigm employing exogenous GM1, which may underlie the symptomatic improvements reported in PD clinical trials (Schneider et al., 2010, 2013), does not, in our opinion, reveal the functional role of GM1 in regard to normal GDNF signaling. "
ABSTRACT: The new mouse model of PD based on deficiency of GM1 manifests deficient GDNF neuroprotective signaling.•Similar deficiency in GDNF signaling is described in brains of PD subjects, which were also deficient in GM1.•GM1 is necessary for the formation of the GDNF receptor complex; we show that GM1 is an integral part of this complex.•LIGA20, a membrane permeable analog of GM1, rectified the impaired GDNF signaling both in vivo and in vitro.•GM1 in the occipital cortex of PD subjects was significantly below controls (p = 0.002, n = 13/13); systemic effect.Experimental Neurology 01/2015; 263. DOI:10.1016/j.expneurol.2014.10.010 · 4.70 Impact Factor
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- "An extensive body of literature can be found on the potential involvement of GM1 gangliosides in the pathogenesis of PD , through either accelerated αS aggregation in mice having decreased GM1 levels ,  or a decrease in PD-type symptoms upon administration of GM1 , . There is also evidence for a connection between Parkinson’s disease and disorders with defective glucocerebroside metabolism like Gaucher’s disease that indirectly affect GM1 levels . "
ABSTRACT: A switch in the conformational properties of α-synuclein (αS) is hypothesized to be a key step in the pathogenic mechanism of Parkinson's disease (PD). Whereas the beta-sheet-rich state of αS has long been associated with its pathological aggregation in PD, a partially alpha-helical state was found to be related to physiological lipid binding; this suggests a potential role of the alpha-helical state in controlling synaptic vesicle cycling and resistance to β-sheet rich aggregation. N-terminal acetylation is the predominant post-translational modification of mammalian αS. Using circular dichroism, isothermal titration calorimetry, and fluorescence spectroscopy, we have analyzed the effects of N-terminal acetylation on the propensity of recombinant human αS to form the two conformational states in interaction with lipid membranes. Small unilamellar vesicles of negatively charged lipids served as model membranes. Consistent with previous NMR studies using phosphatidylserine, we found that membrane-induced α-helical folding was enhanced by N-terminal acetylation and that greater exothermic heat could be measured upon vesicle binding of the modified protein. Interestingly, the folding and lipid binding enhancements with phosphatidylserine in vitro were weak when compared to that of αS with GM1, a lipid enriched in presynaptic membranes. The resultant increase in helical folding propensity of N-acetylated αS enhanced its resistance to aggregation. Our findings demonstrate the significance of the extreme N-terminus for folding nucleation, for relative GM1 specificity of αS-membrane interaction, and for a protective function of N-terminal-acetylation against αS aggregation mediated by GM1.PLoS ONE 07/2014; 9(7):e103727. DOI:10.1371/journal.pone.0103727 · 3.23 Impact Factor
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- "GM1 is located on the outer layer of the plasma membrane, and plays a vital role in neurogenesis, nerve development, differentiation and repair after injury . Currently, preclinical research has demonstrated the potential neuroprotective effects of GM1 in central nervous system diseases and Parkinson’s disease [14-16]. Notably, GM1 is also used in the treatment of peripheral neuropathy such as diabetic peripheral neuropathy in preclinical animal models, owing to its superior neuroprotective effects and function of nerve repair . "
ABSTRACT: Background Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. Methods In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. Results The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann–Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). Conclusion The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors.World Journal of Surgical Oncology 01/2013; 11(1):19. DOI:10.1186/1477-7819-11-19 · 1.41 Impact Factor