Gangliosides: Treatment Avenues in Neurodegenerative Disease

Abstract

Gangliosides are cell membrane components, most abundantly in the central nervous system (CNS) where they exert among others neuro-protective and -restorative functions. Clinical development of ganglioside replacement therapy for several neurodegenerative diseases was impeded by the BSE crisis in Europe during the 1990s. Nowadays, gangliosides are produced bovine-free and new pre-clinical and clinical data justify a reevaluation of their therapeutic potential in neurodegenerative diseases. Clinical experience is greatest with monosialo-tetrahexosyl-ganglioside (GM1) in the treatment of stroke. Fourteen randomized controlled trials (RCTs) in overall >2,000 patients revealed no difference in survival, but consistently superior neurological outcomes vs. placebo. GM1 was shown to attenuate ischemic neuronal injuries in diabetes patients by suppression of ERK1/2 phosphorylation and reduction of stress to the endoplasmic reticulum. There is level-I evidence from 5 RCTs of a significantly faster recovery with GM1 vs. placebo in patients with acute and chronic spinal cord injury (SCI), disturbance of consciousness after subarachnoid hemorrhage, or craniocerebral injuries due to closed head trauma. In Parkinson's disease (PD), two RCTs provided evidence of GM1 to be superior to placebo in improving motor symptoms and long-term to result in a slower than expected symptom progression, suggesting disease-modifying potential. In Alzheimer's disease (AD), the role of gangliosides has been controversial, with some studies suggesting a “seeding” role for GM1 in amyloid β polymerization into toxic forms, and others more recently suggesting a rather protective role in vivo . In Huntington's disease (HD), no clinical trials have been conducted yet. However, low GM1 levels observed in HD cells were shown to increase cell susceptibility to apoptosis. Accordingly, treatment with GM1 increased survival of HD cells in vitro and consistently ameliorated pathological phenotypes in several murine HD models, with effects seen at molecular, cellular, and behavioral level. Given that in none of the clinical trials using GM1 any clinically relevant safety issues have occurred to date, current data supports expanding GM1 clinical research, particularly to conditions with high, unmet medical need.

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

“…is probably the most studied and its neuroprotective properties are well-known [63]. GM1 administration was shown to provide significant benefits in a variety of neurological conditions [38], including stroke [64,65], PD [66,67] and HD [32,41,42]. Some of the underlying mechanisms were neuronal-specific [63,68,69], but whether GM1 could also directly target microglia was not investigated.…”

“…A decrease in ganglioside levels and changes in the relative abundance of specific gangliosides also occur in ageing [28][29][30][31] and in common neurodegenerative conditions, including HD [32,33], PD [34] and AD [35,36]. On the other hand, therapeutic administration of one of the most abundant brain gangliosides, GM1, was shown to provide neuroprotection in models of neuronal injury and neurodegeneration [37][38][39][40] and in genetic models of HD [41,42].…”

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

“…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.…”

“…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, including the ABC transporters [11].In fact, to obtain positively relevant results in parkinsonian patients, a high dose of GM1 has been used in clinical trials in which GM1 was peripherally administered [12], and even for the treatment of patients with Alzheimer's, GM1 was administered via intracranial injection to obtain a beneficial effect [13], an administration route that is not compatible with an adequate quality of human life.Many unsuccessful efforts have been made by researchers to find a solution allowing GM1 to reach the brain's central areas.…”

“…Unfortunately, even this strategy cannot be performed in the clinic, and peripheral injection of the enzyme would result in it being blocked by the BBB if not properly conveyed to the brain. As reported in recent reviews, many efforts are still ongoing and seem to be concentrated on the possibility of using vehicles (i.e., liposomes) to drive the GM1 into the brain [2,7,8], however without any reported success to date at the best of our knowledge.In this context, which seems to be disadvantaging the therapeutic use of GM1, our studies have investigated the molecular mechanism underlying the neurotrophic properties of GM1. Indeed, we recently recognized that GM1 exerts its neurotrophic functions by interacting with and activating plasma membrane receptors throughout its oligosaccharide portion-GM1-oligosaccharide (OligoGM1) [22][23][24][25].…”