GM₁ Ganglioside for Acute Ischemic Stroke: Trial Design Issues

Abstract

GM1 ganglioside decreases the severity of ischemic brain lesions in experimental models, although the mechanism is uncertain. In clinical trials involving patients with stroke, efficacy has been reported in some but not in others. However, some of the latter also showed efficacy after analyses not planned before the trial began. Analyses of the trials done to date revealed design differences sufficiently large so as to preclude meta-analysis of the results. Moreover, flaws in these studies may account for some of their failure to demonstrate that GM1 therapy is efficacious in ischemic stroke. Several of these flaws are discussed, including small sample size; attrition of the study cohort; inclusion of stroke severity and type that made demonstrations of a beneficial effect difficult; use of inappropriate clinical and outcome measuring instruments; delay in enrollment; inappropriate statistical analyses; inadequate dose; inappropriate route of administration; a too short duration of treatment. Improvements in these design features in future clinical trials of GM1 may yet demonstrate efficacy of this drug in acute ischemic stroke.

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

“…In this regard, previous clinical trials in which the ganglioside was used for the treatment of other conditions (35,(53)(54)(55) demonstrated that GM1 is safe to use in patients, even when administered by intraventricular infusion (56), and potential adverse effects are rare (35).…”

“…Consistent with the pivotal role of gangliosides in the nervous system and in cell signaling, defects in their biosynthetic pathway lead to a severe infantile neurodegenerative disorder characterized by progressive brain atrophy, chorea, and epilepsy (35), symptoms that are also common to the juvenile form of HD (36).…”

Impaired Ganglioside Metabolism in Huntington's Disease and Neuroprotective Role of GM1

“…In HD, where endogenous levels of the ganglioside are reduced, GM1 is likely to have multiple beneficial effects, by restoring normal ganglioside content and by targeting multiple aspects of the HD pathology: from cell signaling and AKT activation to mHtt phosphorylation, susceptibility to apoptosis, and potentially also axonal transport and neurotrophin release and excitotoxicity. Importantly, previous clinical trials that have tested the effects of GM1 in patients with stroke (Alter, 1998), Parkinson's disease (Schneider, 1998), and spinal cord injury (Chinnock and Roberts, 2005) have shown that the compound is relatively safe to use. Possible potential adverse effects, such as the development of a peripheral neuropathy known as Guillain-Barré…”

Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins

“…Mocchetti Neurotrophic function of exogenous gangliosides extracellular events involved in apoptosis, which will be presented later. The use of gangliosides in humans is still limited despite the positive outcome of clinical trials showing that GM1 and other gangliosides, either alone or in combination with other neuroprotective agents, reduce neuronal damage after stroke [59] and spinal cord trauma [60]. Major setbacks preventing a wide use of gangliosides in human neurodegenerative disorders are concerns about side effects, such as the potential of GM1 to cause allergic reactions [61] or an acute Guillain-Barré syndrome [62,63].…”