g(m1)-ganglioside and Parkinson-Disease--Secondary

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson's disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; Autophagy; Autophagy-Related Protein-1 Homolog; Autophagy-Related Proteins; Cell Line, Tumor; G(M1) Ganglioside; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice, Inbred C57BL; Neuroprotection; Parkinson Disease, Secondary; Rats

Cryopreservation may allow long-term storage of embryonic ventral mesencephalon (VM) for neural transplantation. We investigated whether the ganglioside GM1 or the lazaroid tirilazad mesylate (U-74006F) could improve survival of grafts derived from cryopreserved VM in a rat model of Parkinson's disease. VM was dissected from rat embryos (E14-E15), frozen and stored in liquid nitrogen under controlled conditions, thawed, dissociated, and then grafted into the 6-hydroxydopamine-lesioned rat striatum. In Experiment I, VM fragments were exposed in vitro either to GM1 (100 microM) or to lazaroid (0.3 microM) during all preparative steps. In Experiment II, rats receiving GM1-pretreated VM were, in addition, treated systematically with GM1 (30 mg/kg) daily for 3.5 weeks. Rats grafted with untreated cryopreserved or fresh VM were used as controls, respectively. Rats receiving fresh VM control grafts showed complete recovery from lesion-induced rotations after 6 weeks whereas rats grafted with cryopreserved VM (untreated or pretreated) did not recover. Cryografts contained significantly less (18%, control; 23%, GM1; and 12%, lazaroid) tyrosine hydroxylase-positive cells compared to fresh grafts (1415 +/- 153; mean +/- SEM). Graft volume was also significantly smaller after cryopreservation. In contrast, with additional systemic GM1 treatment cryografts contained almost the same number of tyrosine hydroxylase-positive cells (376 +/- 85) as fresh grafts (404 +/- 56), which was significantly more than that of untreated cryografts (147 +/- 20), showed a significantly larger volume (0.15 mm(3)) compared to that of untreated grafts (0.08 mm(3)) (fresh controls, 0.19 mm(3)), and induced significant and complete functional recovery in the rotation test. In conclusion, systemic treatment of rats with GM1 improved the low survival and functional inefficacy of grafts derived from cryopreserved VM whereas tissue pretreatment alone with either GM1 or lazaroid was not effective.

Topics: Animals; Brain Tissue Transplantation; Cell Count; Cell Survival; Corpus Striatum; Cryopreservation; Disease Models, Animal; Female; Fetal Tissue Transplantation; G(M1) Ganglioside; Graft Survival; Mesencephalon; Motor Activity; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Pregnatrienes; Rats; Rats, Sprague-Dawley; Recovery of Function; Tyrosine 3-Monooxygenase

GM1 ganglioside has been shown to stimulate repair of the nigrostriatal dopamine system after injury. This has been particularly evident in the mouse MPTP model of Parkinsonism. Systemic administration of GM1 has been shown to increase striatal dopamine levels and lead to increased density of substantia nigra pars compacta neurons after MPTP administration versus mice treated with MPTP and saline. The purpose of the present study was to assess regional changes in dopaminergic innervation of the striatum of mice treated with MPTP then GM1. Studies consisted of [3H] mazindol binding of dopamine uptake sites, postmortem striatal tissue dopamine levels, and peak dopamine release in response to KCl stimulation measured in vivo. Results showed that measures of dopamine innervation were significantly increased in most striatal areas in MPTP+GM1-treated mice compared to MPTP+saline-treated controls. The results indicate that GM1 treatment increases measures of dopaminergic innervation after an MPTP lesion, possibly through sprouting of new terminals or increased dopamine production and release from remaining terminals.

Topics: Animals; Corpus Striatum; Dopamine; G(M1) Ganglioside; Mazindol; Mice; Mice, Inbred C57BL; MPTP Poisoning; Parkinson Disease, Secondary; Potassium

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Dopamine; G(M1) Ganglioside; Levodopa; Macaca fascicularis; Neurons; Parkinson Disease, Secondary; Tyrosine 3-Monooxygenase

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to young C57/B16J black mice caused a striatal dopamine depletion that could be at least partially reversed by chronic intraperitoneal administration of GM1 ganglioside. The present study shows that the semisynthetic sphingolipids LIGA 4 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-acetamide-4-t rans-octadacene) and LIGA 20 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-chloro-acetam ide-4- trans-octadacene) are also effective in at least partially reversing MPTP-induced striatal dopamine depletions in mice after oral administration. These results suggest that semisynthetic ganglioside derivatives may be superior to the parent GM1 ganglioside for human clinical use.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Administration, Oral; Animals; Corpus Striatum; Dopamine; G(M1) Ganglioside; Homovanillic Acid; Male; Mice; Mice, Inbred C57BL; Osmolar Concentration; Parkinson Disease, Secondary; Sphingolipids; Sphingosine

GM1 has been reported to promote sprouting of dopaminergic mesencephalic neurons when administered at the time of MPTP treatment. Owing to its potential clinical significance, we evaluated behavioral effects of GM1 treatment in three Cebus apella monkeys with a persistent hemiparkinsonian syndrome after 20-22 mo of an intracarotid infusion of MPTP. MPTP monkeys compared with normal ones presented difficulty in solving motor cognitive tests and reversal of circling activity after apomorphine treatment. Monkeys were treated during 3 wk with daily saline, followed by 4 wk with GM1 (20 mg/kg, im). Neither during saline nor GM1 treatment, nor 30 d afterwards, did the animals improve their performances nor did the apomorphine tests reveal significant changes in circling behavior. These results are discussed in terms of their possible implications for Parkinson disease treatment.

Topics: Animals; Cebus; Conditioning, Operant; Drug Resistance; G(M1) Ganglioside; Motor Activity; MPTP Poisoning; Parkinson Disease, Secondary; Psychomotor Performance; Reward

Administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to aged (12 months) C57 black mice results in a striatal dopamine depletion that can be partially reversed only by long-term (i.e. 8 weeks) intraperitoneal administration of GM1 ganglioside. The present study shows that the semi-synthetic sphingolipid LIGA 20 (II3Neu5AcGgOse4-2-d-erythro-1,3-dihydroxy-2-dichloro-acetrylam ide-4- transoctadene) can partially reverse MPTP-induced striatal dopamine depletions in aged mice after being administered orally for only 4 weeks. GM1 ganglioside administered for 4 weeks had no effect on striatal dopamine levels. These results suggest that LIGA 20 is more potent than the parent GM1 ganglioside and may exert effects on the damaged nervous system under conditions in which GM1 is ineffective.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antiparkinson Agents; Corpus Striatum; Dopamine; Drug Resistance; G(M1) Ganglioside; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Parkinson Disease, Secondary; Sphingosine

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.

Topics: Animals; Cell Death; G(M1) Ganglioside; Macaca fascicularis; Mesencephalon; Motor Activity; MPTP Poisoning; Nerve Fibers; Parkinson Disease, Secondary

A parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; G(M1) Ganglioside; Homovanillic Acid; Immunohistochemistry; Macaca fascicularis; Motor Activity; Parkinson Disease, Secondary; Putamen; Reference Values; Saimiri; Tyrosine 3-Monooxygenase

The effects of GM1 ganglioside administration on functional recovery and recovery of caudate nucleus dopamine levels have been assessed in cats made parkinsonian by administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cats made severely parkinsonian by MPTP administration began to show spontaneous functional recovery by the third week after MPTP, as had been observed in previous studies with this model. In contrast, cats with similar initial impairment but which received 3 weeks of GM1 ganglioside treatment (30 mg/kg, i.p. daily) showed an accelerated behavioral recovery, showing significant functional improvement after the first week of GM1 treatment and almost normal function by the end of the third week of treatment. The GM1-treated cats had caudate nucleus dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and HVA levels significantly increased above levels measured in saline-treated MPTP control cats. A second group of cats received MPTP only until the first signs of parkinsonism were observed and thus overall had a less severe initial syndrome than the cats described previously. Again, while all cats showed functional recovery over time, the recovery process was accelerated in GM1-treated cats. GM1 treatment also caused a significant increase in caudate dopamine levels in these cats. These results suggest that GM1 ganglioside administration can result in increased dopamine levels even in the heavily denervated striatum and accelerate functional recovery after an MPTP-induced lesion of the nigrostriatal dopamine system in the cat. This suggests that GM1 or other trophic factor therapies may be fruitful treatment strategies for a disorder of nigrostriatal function such as Parkinson's disease.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Behavior, Animal; Cats; Caudate Nucleus; Dopamine; Female; G(M1) Ganglioside; Homovanillic Acid; Male; Motor Activity; MPTP Poisoning; Parkinson Disease, Secondary

The effects of systemic injection of GM 1 ganglioside on dopaminergic (DA) nigrostriatal and mesolimbic system following 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) have been studied in C 57 BL/6 mice. MPTP treatment (4 x 20 mg/kg i.p. given 12 hr apart) resulted in significant depletion of DA concentration in the major terminal fields of the nigrostriatal and mesolimbic DA systems, i.e. dorsal striatum, ventral striatum, nucleus accumbens and olfactory tubercle 5 weeks after treatment in young (2 month old) mice. In aging (12 month old) mice treated with MPTP, significant depletion of DA concentration was observed in the cell body regions, i.e. substantia nigra and ventral tegmental area in addition to the major terminal fields, suggesting that the effect of MPTP is more widespread in aging mice. Although GM 1 ganglioside treatment (30 mg/kg, i.p. daily for 5 weeks) partially restored DA concentration in every major terminal field in young mice, such an apparent recovery was not seen in aging mice. GM 1 ganglioside treatment also reduced the increased 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio following MPTP injection in the striatum of young mice, but such an effect was not observed in aging mice. We conclude that DA nigrostriatal and mesolimbic system in aging mice demonstrates reduced regenerative capacity following MPTP depletion compared with young mice, and the beneficial effect of GM 1 ganglioside for the recovery of DA nigrostriatal and mesolimbic system neurons declines with age.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adrenergic Fibers; Age Factors; Animals; Corpus Striatum; Disease Models, Animal; Dopamine; G(M1) Ganglioside; Limbic System; Mice; Mice, Inbred C57BL; Parkinson Disease, Secondary; Substantia Nigra

We investigated the effect of GM1 gangliosides on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson disease. Five groups of mice (saline, GM1 (30 mg/kg), MPTP, MPTP + GM1 (15 mg/kg), MPTP + GM1 (30 mg/kg] were compared. GM1 was given daily via intraperitoneal injection before and during 13 daily doses of MPTP (30 mg/kg). Mice were tested for locomotion (1) within 2 h of an MPTP dose (to measure reduced motor activity), and (2) within 24 h of an MPTP dose (after animals had recovered and exhibited hyperactivity). We found that mice given GM1 gangliosides exhibited significantly less MPTP-induced behavior. This effect was most evident with the 15 mg/kg GM1 dose. GM1 also appeared to attenuate MPTP-induced neurochemical changes. GM1 effects indicating enhancement of DA turnover and preservation of DA, DOPAC and HVA concentrations in the striatum were found after the 8th MPTP dose. These latter neurochemical changes, however, were transient and not present after the 13th MPTP dose. Our data would suggest that gangliosides may reduce acute MPTP-induced neurotoxicity in mice either through an increase in DA neuron survival and/or the augmentation of striatal DA activity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Behavior, Animal; Corpus Striatum; Dopamine; G(M1) Ganglioside; Homovanillic Acid; Male; Mice; Mice, Inbred Strains; Movement; Parkinson Disease; Parkinson Disease, Secondary

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice results in the loss of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the mouse striatum and a loss of cells containing tyrosine hydroxylase (TH)-immunoreactivity from the substantia nigra. The cells that remained in the nigra after MPTP treatment were smaller in diameter than normal cells. Treatment with GM1 ganglioside beginning 24 h after establishing the MPTP lesion resulted in partial restoration of DA and DOPAC content in the striatum and an increase in the diameter of the TH-immunoreactive nigra cells. It appears, therefore, that treatment of MPTP-intoxicated mice with GM1 ganglioside results in the partial restoration of both the biochemistry and morphology of dopaminergic neurons.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; G(M1) Ganglioside; Immunohistochemistry; Male; Mice; Parkinson Disease, Secondary; Pyridines; Substantia Nigra; Tyrosine 3-Monooxygenase

GM1 ganglioside (GM1) has in the past been reported to promote regenerative sprouting and functional recovery in both central and peripheral nervous systems. The present experiments were performed in order to investigate whether GM1 might have any therapeutic effect on young mice who had been exposed to the Parkinson-producing neurotoxin MPTP. GM1 caused moderate to dramatic increases in striatal dopamine levels, depending upon duration of exposure to GM1, in animals previously exposed to MPTP. Furthermore, the effects of GM1 on enhancing striatal dopamine levels were apparent when GM1 administration was delayed until 3 days after the last MPTP injection was given and these effects were not reversed when GM1 was withdrawn. Tyrosine hydroxylase (TH) immunohistochemistry of the striatum demonstrated increased numbers of TH-positive fibers and TH-positive terminal fields in GM1-treated animals as compared to animals that received only MPTP. TH immunohistochemistry of the substantia nigra revealed little or no loss of parts compacta neurons in the MPTP-treated mice. On the basis of these observations, GM1 appears to increase the dopamine content of the striatum by promoting or stimulating regenerative sprouting of dopaminergic terminals and perhaps collateral sprouting from remaining intact fibers in the MPTP model of Parkinsonism in the young mouse. We suggest that GM1 ganglioside may hold some promise as a potential adjunct in the treatment of Parkinson's Disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dopamine; G(M1) Ganglioside; Male; Mice; Mice, Inbred Strains; Osmolar Concentration; Parkinson Disease, Secondary; Pyridines; Reference Values; Tyrosine 3-Monooxygenase