G_M1 ganglioside rescues substantia nigra pars compacta neurons and increases dopamine synthesis in residual nigrostriatal dopaminergic neurons in MPTP‐treated mice

Abstract

GM1 ganglioside has been shown to stimulate recovery of the damaged dopamine system under a number of different circumstances. In addition to rescue of damaged dopamine neurons, the present study assessed the ability of GM1 to enhance the synthesis of dopamine in remaining nigrostriatal neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. There was a significantly greater accumulation of L-dopa 30 min after aromatic amino acid decarboxylase inhibition with NSD-1015 (100 mg/kg) and an increase in the ratio of L-dopa to dopamine in MPTP+GM1-treated mice than in mice that received only MPTP. This effect of GM1 on dopamine synthesis was dependent upon the degree of initial damage to the nigrostriatal dopamine system. That is, the GM1 effect on dopamine synthesis could not be demonstrated in mice with greater than 95% striatal dopamine loss and 75% substantia nigra dopamine neuron loss. These results suggest that in addition to previously reported effects of GM1 on rescue and repair of dopaminergic neurons, GM1 may also have the ability to enhance dopamine synthesis in residual dopaminergic neurons. Direct effects on dopamine neurochemistry may contribute to functional improvement seen after GM1 treatment in various models of parkinsonism.

The multi-tasked life of GM1 ganglioside, a true factotum of nature

“….are second to no other class of biomolecules in the capacity of information coding using Box 1. Major functions of GM1 ganglioside Modulation of ion transport Na + /K + -ATPase antiporter [25] Ca 2+ influx via T type channel [28] Ca 2+ influx via TRPC5 channel [42] Ca 2+ efflux via plasma membrane Ca 2+ -ATPase (PMCA) [128,129] Na + /Ca 2+ exchange in nuclear membrane [130] Ca 2+ transfer from nucleoplasm to ER lumen [52] Neuronal differentiation Induction of ectopic neurites in gangliosidoses [61,62] Promotion of axonogenesis via sialidase and enhanced Ca 2+ influx [35,69,73] GM1 crosslinking activates TRPC5 Ca 2+ channels and neuritogenesis [42] Exogenous GM1 activates neuritogenesis nonspecifically [66][67][68] Neurotrophin modulation and neuroprotection Endogenous GM1 promotion of NGF activity via association with TrkA [86,131] Endogenous GM1 promotion of BDNF activity via association with TrkB [89] Endogenous promotion of GDNF activity via association with GFRa1/Ret [90] Exogenous promotion of neurotrophic activities [83,84,132,133] Neuroprotection by semisynthetic GM1 analogs (LIGA) [80,82] Roles in neurological disorders Spinal cord injury; GM1 benefit to subgroup of patients [134,135] PD: GM1 benefit in animal models [93][94][95] PD: GM1 benefit in clinical trials [97,98] PD: GM1 deficit as risk factor [90,100] PD: GM1 prevents aggregation of a-synuclein [101,102]…”

“…(For a description of several such trials and GM1 relevance, see the supplementary material online.) PD has drawn interest in regard to GM1 therapy based on promising preclinical results showing partial restoration of depleted striatal dopamine and nigrostriatal neuron recovery in MPTP-treated mice [93,94] and primates [95]. LIGA20 proved superior to GM1 in the murine model and was shown to have the advantage of oral bioavailability [96].…”

GM1 ganglioside in Parkinson's disease: Results of a five year open study

“…Treatment with GM1 following a number of different types of central nervous system lesions in experimental animals [9][10][11][12][13][14] has resulted in significant biochemical and behavioral recovery and pretreatment with GM1 inhibits damage resulting from a variety of neurotoxic exposures [15][16][17]. GM1 administration has been effective in ameliorating neurochemical and behavioral alterations in murine and non-human primate models of PD [13,[18][19][20].…”

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

“…We previously suggested that the symptomatic effect from GM1 in PD may relate to functional improvement in residual dopaminergic neurons, a conclusion supported by data showing enhanced dopamine synthesis in residual dopamine neurons in a mouse model of Parkinsonism following GM1 treatment 17 . In Phase II, ES subjects maintained some of the initial benefit of GM1 treatment and DS subjects showed benefit after switching to GM1 use and both treatment groups fared better than the Comparison subjects.…”

“…GM1 is highly expressed in the adult brain 4 where it modulates Ca 2+ homeostasis 5 and signal transduction, may promote lysosomal integrity 6 and influence mitochondrial function 7, 8 . In a variety of preclinical studies, administration of GM1 following different types of lesions resulted in significant biochemical and behavioral recovery 9-15 , with results particularly impressive in animal models of PD 1614171819202122 .…”