g(m1)-ganglioside and Cerebrovascular-Disorders

Topics: Animals; Cerebral Infarction; Cerebrovascular Disorders; Clinical Trials as Topic; Disease Models, Animal; Fibrinolytic Agents; G(M1) Ganglioside; Glucocorticoids; Hemodilution; Humans; Neuroprotective Agents; Nimodipine; Tissue Plasminogen Activator

Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. The highest ganglioside concentration of any organ is found in the mammalian brain, where the gangliosides are enriched in the neuronal membrane, particularly in the synapses. There are four major brain gangliosides with the same neutral tetrasaccharide core to which one to three sialic acids are linked--the simplest being the GM1-ganglioside. These gangliosides have been shown to have neuritogenic and neuronotrophic activity and to facilitate repair of neuronal tissue after mechanical, biochemical or toxic injuries. Mixtures of native bovine brain gangliosides were adopted for pharmacological use in the treatment of peripheral nerve damage, and GM1-ganglioside has been applied for the treatment of CNS injuries and diseases. Beneficial effects of GM1 have been documented in the treatment of stroke and spinal cord injuries, particularly when the treatment has been initiated within a few hours of the acute event. Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).

Topics: Alzheimer Disease; Animals; Carbohydrate Sequence; Cerebrovascular Disorders; G(M1) Ganglioside; Humans; Molecular Sequence Data; Spinal Cord Injuries

Topics: Animals; Central Nervous System; Cerebrovascular Disorders; G(M1) Ganglioside; Humans; Nerve Regeneration; Neuronal Plasticity; Neurons

Nine double-blind, placebo-controlled clinical trials involving 784 patients with nonhaemorrhagic stroke have been reviewed to investigate the clinical efficacy of ganglioside GM1 in this disorder. The evaluated data show a statistically significant, but transient, acceleration in recovery from neurological deficits in 63% of all GM1-treated patients during the first 2 weeks after the event compared with placebo. Both studies in which the first administration of GM1 occurred within 48 hours after stroke demonstrated a statistically significant benefit in neurological recovery for the GM1-treated patients, suggesting an advantage of early administration. However, quantitative neurological assessments of GM1- and placebo-treated patients between 2 weeks and 6 months, disability scores and mortality rates failed to show significant differences. The problems and limitations of the trials (differences in patient populations studied, lack of standardised assessment criteria, etc.) are discussed, and potential mechanisms of GM1 action and factors that influence treatment results (e.g. early administration) are evaluated.

Topics: Adult; Aged; Animals; Cerebrovascular Disorders; G(M1) Ganglioside; Humans; Middle Aged

Topics: Adolescent; Adult; Animals; beta-Galactosidase; Cats; Cerebrovascular Disorders; Child, Preschool; Coronary Disease; Fabry Disease; Female; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycolipids; Hexosaminidases; Humans; Infant; Infant, Newborn; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Male; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

The Early Stroke Trial (EST) is a randomized, double-blind, placebo-controlled trial to assess the effect of monosialoganglioside GM-1 in improving recovery in patients who experienced an ischemic supratentorial stroke.. Sixteen clinical centers recruited 805 patients, of whom 792 were confirmed to be eligible. Treatment, consisting of a first dose of either 200 mg GM-1 or placebo, was initiated within 5 hours of the onset of stroke; a second dose of either 100 mg GM-1 or placebo was administered 12 hours later. Thereafter, patients received a daily injection of 100 mg GM-1 or placebo intravenously from day 2 through 10 and intramuscularly from day 11 through 21. Patients were followed up for a total of 4 months.. Survival was similar in the two treatment groups. Improvement in neurological status, as measured by the change in Canadian Neurological Scale score between baseline and 4-month assessments, was greater in the group receiving GM-1; the observed difference between treatment groups was 0.22 (P = .06). A post hoc analysis in the subgroup of patients treated within 4 hours showed a statistically significant difference, with Canadian Neurological Scale mean improvement of 0.41 (P = .016). GM-1 use was not associated with differences in frequency, nature, or severity of adverse experiences.. These findings suggest that GM-1 is safe in the dose and treatment schedule used and that its efficacy in ischemic stroke is greater when given soon after onset of stroke.

Topics: Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Double-Blind Method; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Safety

We sought to assess the safety and efficacy of ganglioside GM1 in acute (< or = 48 hours), anterior circulation ischemic stroke.. We screened more than 5000 patients at 13 centers in a randomized, double-blind, placebo-controlled, parallel-treatment, clinical trial and enrolled 287 patients. They received 100 mg GM1 or placebo intramuscularly daily for 28 days and were evaluated regularly for 84 days. Number of deaths, the Toronto Stroke Scale, and the Barthel Index were primary outcomes; improvements on the Fugl-Meyer Scale and on a neuropsychological battery were secondary outcomes.. The groups were balanced for severity, side of stroke, age, sex, race, years of schooling, prior illness, and depression scores. Analyzable data were available on 275 patients; 217 patients completed the trial. Protocol-specified primary and secondary outcome measures showed no significant difference between treatment arms. However, improvement from baseline in the motor component of the Toronto Stroke Scale favored the GM1-treated group at day 28 when GM1 treatment stopped (P = .020); at day 84, the difference still favored the GM1-treated group (P = .057). All 10 components of the Barthel Index, the Fugl-Meyer Scale, and four of the five tests in the neuropsychological battery also favored the GM1 group. Adverse experiences were similar in the two groups.. GM1 is safe. However, since only certain post hoc tests showed statistically significant differences or trends favoring GM1, another clinical trial is needed to demonstrate efficacy.

Topics: Activities of Daily Living; Acute Disease; Aged; Brain Ischemia; Cause of Death; Cerebrovascular Disorders; Double-Blind Method; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Injections, Intramuscular; Male; Motor Activity; Movement; Neurologic Examination; Neuropsychological Tests; Placebos

The Early Stroke Trial is a randomized, placebo-controlled, double-masked, multicenter study to assess the safety and efficacy of monosialoganglioside in patients who have suffered an ischemic stroke of the cerebral hemispheres.. Only patients who could be evaluated and treated within 5 hours after the onset of stroke were considered; within each center, subjects were stratified by age, sex, and clinical severity. Patients were randomly allocated to receive a specified sequence of intravenous and intramuscular doses of either monosialoganglioside or identical-appearing placebo for 21 days. Patients were followed up for 4 months after randomization. Neurological status was measured primarily by using the Canadian Neurological Scale. After assessing the effect of treatment on survival, the principal measure of efficacy will be the change in neurological status between baseline and the 4-month follow-up among survivors.. Sixteen clinical centers, 15 in Europe and one in North America, entered a total of 792 eligible patients during a 36-month recruitment period (from May 1987 to April 1990). In our series there were more men than women, and the relative frequency of patients increased with advancing age. The most frequently associated cardiovascular conditions were hypertension, atrial fibrillation, and peripheral vascular disease. Approximately 46% of the patients were admitted to a hospital within 1 hour and 81%, within 2 hours after the onset of stroke. About 22% first received the study treatment within 3 hours and 57%, within 4 hours.. This study demonstrates the feasibility of large-scale trials with the onset of treatment within 5 hours after an ischemic stroke.

Topics: Adult; Cerebral Angiography; Cerebrovascular Disorders; Cohort Studies; Double-Blind Method; Drug Administration Schedule; G(M1) Ganglioside; Humans; Male; Middle Aged; Time Factors; Ultrasonography

Nine double-blind, placebo-controlled clinical trials involving 784 patients with nonhaemorrhagic stroke have been reviewed to investigate the clinical efficacy of ganglioside GM1 in this disorder. The evaluated data show a statistically significant, but transient, acceleration in recovery from neurological deficits in 63% of all GM1-treated patients during the first 2 weeks after the event compared with placebo. Both studies in which the first administration of GM1 occurred within 48 hours after stroke demonstrated a statistically significant benefit in neurological recovery for the GM1-treated patients, suggesting an advantage of early administration. However, quantitative neurological assessments of GM1- and placebo-treated patients between 2 weeks and 6 months, disability scores and mortality rates failed to show significant differences. The problems and limitations of the trials (differences in patient populations studied, lack of standardised assessment criteria, etc.) are discussed, and potential mechanisms of GM1 action and factors that influence treatment results (e.g. early administration) are evaluated.

Topics: Adult; Aged; Animals; Cerebrovascular Disorders; G(M1) Ganglioside; Humans; Middle Aged

Eleven of 31 clinical centers participating in the Italian Acute Stroke Study--Hemodilution carried out a preliminary study on the effectiveness of ganglioside GM1 in acute stroke; 502 patients were randomized to GM1 (GM1, n = 121), GM1 plus hemodilution (GM1 + H, n = 128), placebo (P, n = 130), or placebo plus hemodilution (P + H, n = 123) groups less than or equal to 12 hours after onset of a hemispheric cerebral infarct. The patients were treated for 15 days and were evaluated on Days 21 and 120 after the onset of stroke. Intention-to-treat analysis failed to show any differences in neurologic deficit, mortality, or neurologic disability among the groups. Efficacy analysis showed a significantly higher degree of neurologic improvement in GM1 group patients compared with patients in the P group during the first 15 days. GM1-treated patients (GM1 and GM1 + H groups) showed a significantly higher degree of neurologic improvement during the first 10 days compared with the placebo-treated patients (P and P + H groups). These differences were no longer statistically significant at Day 120. Our results provide a rationale for the planning of a larger, multicenter trial of GM1 ganglioside in acute stroke.

Topics: Aged; Cerebrovascular Disorders; Clinical Trials as Topic; Combined Modality Therapy; Female; G(M1) Ganglioside; Hemodilution; Humans; Italy; Male; Middle Aged; Multicenter Studies as Topic; Random Allocation

A randomized, double-blind trial on the effects of GM1 ganglioside in cerebrovascular diseases was done on 40 patients; the treatment (40 mg/day i.m. injection) began after the acute phase and lasted 6 weeks. 18 cases took the drug and 16 the placebo. The evaluation of the cases was made by graduating the severity of the clinical signs, and some neurophysiological and morphological parameters, i.e., EEGs, flash-evoked potentials and computer tomography scans. We found that the drug, in comparison with the placebo treatment, improved the clinical signs and also the neurophysiological parameters, whereas it was ineffective for the morphological damage. These data seem of some interest in relation to the action of GM1 ganglioside in the processes of neurotransmission and neuronal plasticity as described in the experimental animal.

Topics: Adult; Aged; Cerebrovascular Disorders; Clinical Trials as Topic; Double-Blind Method; Electroencephalography; Evoked Potentials, Visual; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Nerve Regeneration

Topics: Acute Disease; Aged; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Disorders; Clinical Trials as Topic; Double-Blind Method; Electroencephalography; Female; G(M1) Ganglioside; Gangliosides; Humans; Male; Middle Aged

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled. Using sensitive ELISAs, we measured IgG and IgM antibody titers and absorbances to the three major gangliosides GD1a, GD1b and GM1, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P<0.04) and 18% of 32 ON patients (P<0.05) presented elevated IgG antibody titers to GD1a in serum compared to 9% of patients with OND. Six (40%) of the patients with malignant MS had elevated serum IgG antibody titers to GD1a compared to one (6%) of the patients with benign MS (P<0.04). In CSF, elevated IgG antibody titers to GD1a were measured in 13% of MS and 20% of ON patients compared to 4% of patients with OND (P<0. 03 and P<0.02, respectively). The augmented IgG response to GD1a in serum also separated MS from Guillain-Barré syndrome. Compared to OND increased IgM absorbances to sulfatides and cardiolipin were observed in CSF of patients with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patients' serum and MS, ON and AM patients' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD1a is common and more discriminative, and should be evaluated in future MS treatment studies.

Topics: Adult; Antibodies, Anticardiolipin; Autoantibodies; B-Lymphocytes; Cerebrovascular Disorders; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Immunoglobulin M; Male; Meningoencephalitis; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Optic Neuritis; Recurrence; Sulfoglycosphingolipids

The role of antiganglioside antibodies (AGAs) in late post-apoplectic epilepsy (LPAE) was studied. Serum AGAs from 8 patients with large lobar infarctions were serially checked for 2.5 months. Sera from another 30 patients with fronto-temporoparietal (FTP) or frontal (F) infarction were obtained 3 months to 3 years after a stroke for AGA analysis. These 30 patients were followed up for 3 years following their strokes to determine if LPAE developed. Results showed that 7/8 patients with large lobar infarction showed increase in either anti-GT1b or anti-GM1 (IgM or IgG) within a few weeks, but levels returned to the baseline 2-3 months after stroke. LPAE occurred in 9/21 patients with FTP infarction and 5/9 with F infarction. There was no difference in AGAs among patients with FTP and F infarctions. Pooled data from these 2 groups showed no correlation between AGAs and LPAE. These data document for the first time that anti-GT1b and anti-GM1 antibodies can transiently increase after stroke, but their late titers are not associated with LPAE.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Cerebrovascular Disorders; Epilepsy; G(M1) Ganglioside; Gangliosides; Humans; Middle Aged

The occurrence of sprouting by fibre systems in the neocortex following lesion is still a controversial issue. In previous studies, we showed a nerve growth factor (NGF)-induced sprouting and hypertrophy of presynaptic terminals in the cholinergic fibres of the rat neocortex following stroke-type lesions, effects that were potentiated by the monosialoganglioside GM1. The present study investigated whether exogenous NGF and/or GM1 treatment could also affect the noradrenergic and somatostinergic systems in the neocortex. Immediately following unilateral vascular decortication, adult rats received, via minipump, a 7-day infusion of vehicle, NGF (12 microg/day) and/or GM1 (1.5 mg/day) into the cerebroventricular space. Thirty days postlesion, the animals were perfused with histological fixatives, the brains were removed, and relevant sections were processed for dopamine beta-hydroxylase and somatostatin immunocytochemistry at the light and electron microscopic levels. A Quantimet 920 image analysis system was used for the quantification of fibre length and size of presynaptic boutons. The lesion caused a reduction in the dopamine beta-hydroxylase-immunoreactive fibre length, which was not attenuated by either NGF or GM1 treatment or both. The somatostatin-immunoreactive network, in contrast, was unaffected by the lesion, and there was no sprouting of somatostatin fibres following trophic factor therapy. We also found no significant differences in the size and number of synapses of both the dopamine beta-hydroxylase-immunoreactive and somatostatin-immunoreactive boutons following lesion and drug treatments. These results indicate that NGF and/or GM1 therapies do not cause regrowth in the noradrenergic and somatostatinergic cortical fibre networks or their presynaptic elements following a cortical devascularizing lesion.

Topics: Analysis of Variance; Animals; Cerebral Cortex; Cerebrovascular Disorders; G(M1) Ganglioside; Immunohistochemistry; Injections, Intraventricular; Male; Nerve Endings; Nerve Fibers; Nerve Growth Factors; Norepinephrine; Rats; Rats, Wistar; Somatostatin; Synapses

Many reports indicate that GM1 ganglioside is effective in reducing CNS ischemic injury in animal models. These models employ invasive surgery to induce ischemic damage in otherwise healthy animals. The purpose of this study was to determine if the beneficial effects of GM1 could be generalized to Spontaneously Hypertensive Rats-Stroke Prone (SHRSP). The SHRSP strain develops a pathology similar to those observed in patients with stroke. The SHRSP have "risk" factors that include hypertension, fibrinoid necrosis, and sensitivity to diet. Female SHRSP were randomly assigned to GM1- or saline-treatment conditions. Rats were fed a stroke-inducing diet. Daily body weights, weekly blood pressure, time of stroke onset, and age at death were recorded. Spontaneous activity and performance on a tail-hang test were assessed thrice weekly. The results indicate that GM1 treatment did not delay the time of stroke onset or death. GM1 did reduce hyperactivity in the initial stages of the ischemic pathology, but did not prevent the marked decline in behavioral activity observed at later time points. There were no differences in weight loss, performance on the tail-hang test, or number of CNS injury-related symptoms observed. These findings suggest that GM1 was not as effective in decreasing mortality, weight loss, or behavioral deficits in SHRSP as previously reported using other animal models of ischemia. Distinguishing between those animal models in which GM1 is more and less effective may be useful in determining under which clinical situations GM1 is likely to be most suitable.

Topics: Aging; Animals; Blood Pressure; Body Weight; Cerebrovascular Disorders; Female; G(M1) Ganglioside; Motor Activity; Random Allocation; Rats; Rats, Inbred SHR; Stereotyped Behavior; Weight Loss

The present study shows a novel administration form of the monoganglioside GM1, which following microencapsulation in human serum albumin was topically applied on cortical regions damaged by devascularization in rats. The effects of microencapsulated GM1 on extracellular levels of acetylcholine, choline and dopamine in the cortex and in the striatum were analyzed using in vivo microdialysis. Cholinergic neurons in the nucleus basalis magnocellularis were studied immunohistochemically using monoclonal antibodies raised against choline acetyltransferase (ChAT). It was found that cortical devascularizing lesions produced a decrease in extracellular levels of cortical acetylcholine and choline, and retrograde morphological changes in cholinergic neurons in the nucleus basalis magnocellularis. GM1 promoted (1) recovery of the retrograde morphological changes produced by the decortication in the nucleus basalis magnocellularis and (2) a parallel increase in cortical acetylcholine release. No changes were observed in the striatum, nor on cortical or striatal dopamine levels simultaneously measured in the same perfusates.

Topics: Acetylcholine; Animals; Capsules; Cerebral Cortex; Cerebral Decortication; Cerebrovascular Disorders; Choline; Choline O-Acetyltransferase; Corpus Striatum; G(M1) Ganglioside; Immunohistochemistry; Male; Microscopy, Electron, Scanning; Rats; Rats, Inbred Strains; Serum Albumin

Topics: Acute Disease; Brain Ischemia; Cerebrovascular Disorders; G(M1) Ganglioside; Humans

Topics: Acute Disease; Cerebrovascular Disorders; G(M1) Ganglioside; Humans