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GM-1 ganglioside Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for participation in the Neuroprotection Clinical Trial.

GM-1 ganglioside

The rationale for the use of GM1 in PD is that it has been shown to have neuroprotective and neurorestorative properties in some situations, and it can modulate neurotransmitter activity. These properties may be important in a chronic degenerative disease where the precise mode of cell death is uncertain. The modes of action of GM1 in PD might include protection, rescue, and improving the function of remaining neurons.

Only mild side effects (e.g. injection site events) were reported In a study assessing the long term use of GM-1 (200 mg daily by subcutaneous injection for 2 years) in patients with PD with no laboratory abnormalities. PD patients treated with a higher dose (2000 mg, 3 times per week by intravenous injection) for 8 weeks had increased serum cholesterol, triglycerides and apolipoprotein B.

In a study of 48 PD patients, GM-1 treatment improved Universal Parkinson's Disease Rating Scale (UPDRS) scores, activities of daily living (ADL) and cognitive function. In patients that continued with this treatment, there appeared to be a slower progression of symptoms. A subset of 15 PD patients have received GM-1 treatment for 4 years, and this group has been found to have improved performances on UDPRS and ADL, as well as other motor tests, without experiencing any serious side effects.

Scientific Rationale

  • Potentiates the action of neurotrophic molecules; BDNF1 and NGF2.
  • Reduces excitotoxin- induced neural injury in culture3
  • May reduce the sensitivity of DA neurons to toxins1
  • GM1 is a receptor modulator: modulates trophic factor-stimulated receptor dimerization, tyrosine phosphorylation and signal transduction events of several tyrosine kinase receptors 4
  • GM1 may enhance transmitter release4a by enhancing influx of Ca ions into terminals upon membrane depolarization5
  • GM1 has direct anti-apoptotic actions6

The rationale for the use of GM1 in PD is that it has been shown to be neuroprotective under some circumstances, neurorestorative under other circumstances, and can modulate neurotransmitter synthesis and release. These properties may be important in a chronic degenerative disease where the precise mode of cell death is uncertain. The modes of action of GM1 in PD might include protection, rescue, and stimulation of terminal sprouting and enhanced function of residual neurons.

1. Fadda, Neurosci Lett 1993; 159:147-150
2. Fusco, Ann NY Acad Sci 1993;695: 314-317
3. Sleeper, JPET 1992; 263: 1440-1446
4. Yates and Rampersaud, Ann. NY Acad Sci, 1998: 57-71
4a. Maysinger, Neuropharmacol., 1990, 29: 151-159.
5. Jope, J. Neurochem., 1986: 46: 1567-1572.
6. Ferrari, J. Neurosci., 1993, 13:1879-1887.

Animal Model Data

RODENT: Mice were administered MPTP 30 mg/kg IP x 7 days, followed by GM1 ganglioside 30 mg/kg days 8-23, with sacrifice at day 23. Admin of GM1 resulted in recovery of DA content to 83% control and GM1 caused an increase in cell size.1

Young mice were administered MPTP 30 mg/kg twice daily x 5 days. GM1 30 mg/kg admin with every MPTP injection did NOT prevent the decrease in mean striatal DA levels when the animals were sacrificed 3 days after the end of the injections. However when GM1 was administered for 4 wks after the end of the MPTP injections, DA levels were restored, even when GM1 didn't start until 3 days after the end of the MPTP. The recovery persisted even when GM1 had been decreased for 2 weeks.2

In order for GM1 to have an effect, cells need to be damaged. GM1 has no effect on the intact DA system. Also, if GM1 treatment is started long after the cell death process has been initiated or after lesion has occurred3a, GM1 is ineffective. Its potential benefit in PD is related to the ongoing neurodegenerative process. While GM1 has not been able to prevent the cell damage in this model (i.e., interfere with the processes initiating cell death), it has been repeatedly able to rescue cells that are in the process of dying. GM1, however has been shown to prevent cell death in other model systems3b.

Mice administered MPTP 20 mg/kg twice daily x 5 days with GM1 30 mg/kg administered daily 24 h after the last MPTP x 3 weeks. GM1 treated animals had increased density of DA uptake sites in all striatal areas tested. This was thought to indicate new "sprouting" mechanism. Also, K+ stimulated DA release was recovered in the dorsal striatum compared to the MPTP + saline control. This may indicate an increased production mechanism3.

Mice administered MPTP 20mg/kg twice daily x 5 days. GM1 ganglioside 30 mg/kg daily for 21 days, starting 24 h after last MPTP dose was successful in increasing striatal DA content and stimulating synthesis of levodopa in remaining neurons. GM1 did not work when the DA loss was severe (75-95%). This supports other data that GM1 is most effective in partial lesion conditions.

Mice treated as in reference 4 (above) were given GM1 with l-deprenyl, in varied doses. While high dose l-deprenyl (10 mg/kg) was synergistic with GM1; low dose l-deprenyl (0.01 mg/kg) appeared to antagonize the effects of GM1 on striatal DA.

In two studies in mice, semisynthetic GM1 derivatives were MORE effective than GM1 in increasing DA content. The derivatives also have the benefit of being orally bioactive. In vitro studies, semisynthetic derivatives are several fold more potent than GM1 in rescuing DAergic neurons from MPP+-induced damage.

Aged and young rats were admin GM1 30 mg/kg daily for 30 days after which they were sacrificed. Brains were compared to saline treated animals. Treatment with the ganglioside increased TH activity and improved morphology of DA neurons in the SNc and VTA, increased DA levels in the striatum and improved age-related behavioral deficits8.

PRIMATE: Monkeys (total n=9)administered 0.75 mg/kg MPTP IV once weekly x 2 weeks were given GM1 20 mg/kg IM started 4 days BEFORE the first MPTP dose and continued for 4 days after the second dose. GM1 increased DA content by 36% but no evidence of neuroprotection could be seen. Since other studies in MPTP mice have not shown much of neuroprotective effect with pre- or co-administration of GM1 with MPTP, these data are not surprising. The duration of GM1 administration was also quite short and perhaps not long enough to fully rescue damaged neurons. GM1 treatment did increase the TH staining of residual neurons suggesting a possible enhanced functional capacity of these neurons. Only 3 animals were used per treatment group9.

Monkeys (n=13) were given MPTP 0.5 mg/kg weekly for various durations. Three animals received GM1 20 mg/kg daily for 4 days before and until 4 days after the second and final dose of MPTP. There were saline treated and levodopa- treated controls. There was no difference in the level of neuronal death in the GM1 animals, however DA content was significantly higher in the remaining striatal neurons.

These data and data in Herrero, Neurosci, 1993, 56: 965-972 are somewhat confusing. There were small numbers of animals in treatment groups and in the paper mentioned above, MPTP alone caused only a minor DA cell loss (<30%). It is surprising that such a small lesion resulted in a 78% loss of DA in the caudate. GM1 treatment caused these levels to be doubled, but because of small Ns (3 per group) this was not statistically significant.

Fifteen squirrel monkeys and 4 cynomolgus macaques were treated with MPTP until symptoms developed and were observed over a 48-60 hr. observation period. Seven squirrel monkeys then received GM1 (30 mg/kg) daily for 6 weeks; 8 received daily saline; 2 cynos received daily GM1 (15 mg/kg) for 8 weeks; 2 received saline. GM1 significantly increased DA and metabolite levels in caudate and putamen and increased the number of TH-positive fibers in the striatum. GM1-treated animals also had significant reductions in parkinsonian behavioral deficits11.

Fourteen squirrel monkeys received MPTP until symptomatic and then 7 animals received daily GM1 for 6 weeks starting approximately 3 days after the last MPTP injection. Autoradiographic studies showed significant increases in striatal mazindol binding, decreases in D1 receptor binding and no change in D2 receptor binding in GM1-treated animals compared to MPTP-saline controls. Data showed partial restoration of DAergic terminals and partial correction of postsynaptic receptor changes associated with parkinsonism11a.

Five macaques were chronically treated with low dose MPTP for 26 weeks until stable cognitive deficits and minimal motor deficits were observed. Three animals then received daily GM1 (30 mg/kg) for 90 weeks, 2 received saline: all continued to receive low dose MPTP. In weeks 1-31, GM1 ameliorated early appearing cognitive deficits and protected against further cognitive decline. During weeks 32-52 when MPTP doses were increased, GM1-treated animals had a delayed onset of motor deficits. During weeks 53-90 when MPTP doses were lowered again, GM1-treated animals showed significant recovery of function while saline-treated animals continued to have severe impairments11b.

OTHER: Cats (n=17) were given MPTP 5 mg/kg subcutaneous once daily for either 7-10 days (severe) or 3-5 days (moderate). Two days after the last MPTP injection, 4 cats were randomly assigned to receive either saline or GM1 30 mg/kg daily for 3 weeks (severe) or 6 weeks (moderate). They were sacrificed after the last dose of GM1 or saline. GM1 resulted in a significant attenuation in the loss of DA in both the severe and the moderate groups but the effect was much larger in the moderate group.

Cats (n=16) were administered MPTP 7.5 mg/kg IM. Seven animals received GM1 30 mg/kg IM x 6 wks, starting 48 h after MPTP. Nine animals received saline. GM1 animals had enhanced sensorimotor behavioral recovery compared to "spontaneously recovered" cats. Improved behavioral function was associated with an increase in the number of DAergic terminals in the striatum. There was some spontaneous recovery in the saline treated animals but that was not associated with increased DAergic innervation of the striatum. Seventeen cats were administered MPTP 7.5 mg/kg IM. 6 cats received GM1 (30 mg/kg) daily for 6 weeks; 11 cats spontaneously recovered over the same period. Striatal DA clearance rates were faster in GM1-treated cats and KCl-induced transmitter release was significantly increased compared to saline-treated cats. Results show enhanced release and reuptake of DA in GM1-treated animals and an increase in functional DA terminals.12a

1. Hadjiconstantinou, Brain Res 1989;484:297-303
2. Schneider, Exp Neurol 1989;105: 177-183
3. Rothblat, Ann NY Acad Sci 1998;845:274-277
3a. Emborg, Mol and Chem Neurpoathol., 1994, 21: 75-82.
3b. Lombardi, Eur. J. Pharmacol., 1989, 174:123-125.
4. Schneider, J Neurosci Res 1995;42:117-123
5. Rothblat, Brain Res 1998;779:226-230
6. Schneider, Neuroreport 1993; 5:103-104
7. Schneider, Neurology 1994; 44:748-750
8. Goettl, Neuroscience 1999; 92:991-1000
9. Herrero, Neurology 1993; 43: 2132-2134
10. Kastner, Ann Neurol 1994; 36:206-214
11. Schneider, Science 1992; 256: 843-846
11a. Pope-Coleman, Synapse, 2000, 36: 120-128.
11b. Pope-Coleman, Restorative Neurol. And Neurosci., 1998, 12: 255-266.
12. Schneider, J Neurosci Res 1992; 31:112-119
12a. Schneider, Restorative Neurol. And Neurosci., 2000, 16: 97-104.
13. Schneider, Brain Res 1998; 813:82-87

Pharmacokinetics(including BBB penetration)

Administered parenterally in humans, has a half-life of 70-80 hours after subcutaneous (sc) or intramuscular (IM) routes. Alzheimer's patients (n=16) were given 100 mg radiolabelled GM1 either by sc or IM routes. Sc route resulted in a 50% higher peak concentrations in the blood. Half-lives were 70-80 h. In 5 healthy male volunteers administered 100 mg GM1 either by a 30 min IV infusion or by IM injection. Steady state was reached in 6 days due to alpha compartment. Concentrations were higher with IV admin. Terminal half-lives were 70-120 hours and were longer after IM injection. It is 80% metabolized. Tissue distribution studies in rodents showed GM1 detectable in brain after IV or IM injection (2.5 - 50 mg/kg).3a Exogenous GM1 incorporates into plasma membranes in brain.3b

1. Parnetti, Clin Pharmacokinet 1995; 29:110-129
2. Svennerholm, Acta Neurol Scand 1990;81:48-53
3. Rost, Clin Pharmacol Ther 1991; 50:141-149
3a. Toffano, 1988 (internal Fidia report).
3b. Tettamenti, Gangliosides in Neurological and Neuromuscular Function, 1981; pp. 225-240.

Safety/Tolerability in Humans

Long term use (200 mg sc daily) for up to 2 years in 48 PD patients has been assoc with only injection-type mild side effects and no laboratory abnormalities. There may have been increased incidence of insomnia in the GM1 group but this is debatable. In a group of PD patients administered 2000 mg IV 3 x per week x 8 week, all had increased serum cholesterol (2-3 x upper limit of normal), triglycerides and apolipoprotein

1. Schneider, Ann NY Acad Sci 1998; 845:363-373
2. Schneider, Neurology 1995; 1149-1154
3. Schneider Neurology 1998; 50:1630-1636
4. Roberts, Lancet 1993; 342: 115

Drug Interaction Potential

Possible interaction with low doses of deprenyl. Deprenyl may antagonize the effects of GM1. This has not been replicated.

1. Rothblat, Brain Res 1998;779:226-230

Clinical Trial/Epidemiological Evidence in Human PD

In a 48 patient PD study, improved UPDRS scores, ADLs and cognitive functioning have been accompanied by a suggestion of slowed symptom progression when continuing on an OPEN-label fashion for up to 2 years. Fifteen patients have been followed over 4 years of continuous open label GM1 use. 11 of 15 patients had UPDRS scores lower (by average 30%) at 4 years than at start of study. Improved performance was also seen on timed motor tests and ADL scores. No serious adverse events were noted.4

1. Schneider, Ann NY Acad Sci 1998; 845:363-373
2. Schneider, Neurology 1995; 1149-1154
3. Schneider Neurology 1998; 50:1630-1636
4. Schneider, Neurol., 2000, 54 (Suppl.3).

Last updated February 09, 2005