g(m1)-ganglioside and Cerebral-Infarction

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

This review focuses on the recent advances in the management of acute ischemic stroke. We highlight the best current treatment, as proposed by different authors, as well as future lines of treatment.

Topics: Acute Disease; Cerebral Infarction; Female; G(M1) Ganglioside; Humans; Male; N-Methylaspartate; Nimodipine; Tissue Plasminogen Activator; Treatment Outcome

The cholinergic pathway ascending from the nucleus basalis magnocellularis (NBM) to the cortex has been implicated in several important higher brain functions such as learning and memory. Following infarction of the frontoparietal cortical area in the rat, a retrograde atrophy of cholinergic cell bodies and fiber networks occurs in the basalocortical cholinergic system. We have observed that neuronal atrophy in the NBM induced by this lesion can be prevented by intracerebroventricular administration of exogenous nerve growth factor (NGF) or the monosialoganglioside GM1. In addition, these agents can upregulate levels of cortical choline acetyltransferase (ChAT) activity in the remaining cortex adjacent to the lesion site. Furthermore, an enhancement in cortical high-affinity 3H-choline uptake and a sustained in vivo release of cortical acetylcholine (ACh) after K+ stimulation are also observed after the application of neurotrophic agents. Moreover, these biochemical changes in the cortex are accompanied by an anatomical remodeling of cortical ChAT-immunoreactive fibers and their synaptic boutons.

Topics: Animals; Basal Ganglia; Brain; Cerebral Cortex; Cerebral Infarction; Choline; Choline O-Acetyltransferase; G(M1) Ganglioside; Nerve Fibers; Nerve Growth Factors; Neuronal Plasticity; Neurons; Rats; Receptors, Nerve Growth Factor

Ganglioside GM1 (100 mg) was given daily by intramuscular injection for 28 days in a double-blind placebo controlled trial of acute stroke. No significant difference was detected in a 6 month follow-up period between well matched control and active groups. Although the number of patients studied was small the findings are believed to indicate that GM1 is unlikely to be of value in the treatment of acute stroke in the dose and route of administration used.

Topics: Adult; Aged; Aged, 80 and over; Cerebral Infarction; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; G(M1) Ganglioside; Humans; Injections, Intramuscular; Middle Aged; Random Allocation

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

A bilateral photochemically induced thrombotic lesion of rat sensorimotor cortex (approximately 3 mm in diameter and 25 mm3 in volume) is associated with a persistent cognition (learning and memory) deficit, which was evaluated with water maze tasks. The N-dichloroacetylsphingosine derivative of lysoGM1 (LIGA20) administered after the lesion either i.v. or per or reduces the infarct size by 30-40% and attenuates the associated cognition deficits, presumably by limiting the extent of damage of neurons at risk located in the surroundings of the infarcted core (i.e., area penumbra). The LIGA20 protection is dose and time dependent. Maximal protection is afforded by a single dose of LIGA20 of 34 mumol/kg i.v. 1 hr after lesion or by a dose of 270 mumol/kg per os when administered 1 hr and 24 hr after the lesion. The protective effect of LIGA20 can be observed when the drug is administered i.v. up to 6 hr after the lesion. The protective efficacy of the oral administration of LIGA20 is related to its physiochemical properties, which, unlike those of GM1, allow absorption from the gastrointestinal tract. LIGA20 given orally reaches the brain promptly and rapidly inserts into the neuronal membranes. Here, by an unknown molecular mechanism, LIGA20 selectively reduces the pathological amplification of Ca2+ signaling elicited by persistent stimulation of ionotropic glutamate receptors in the area penumbra.

Topics: Administration, Oral; Animals; Antiparkinson Agents; Brain; Cerebral Cortex; Cerebral Infarction; Functional Laterality; G(M1) Ganglioside; Glycolipids; Intracranial Embolism and Thrombosis; Learning; Memory; Phospholipids; Rats; Somatosensory Cortex; Sphingosine; Time Factors

The efficacy of p.o. semisynthetic glycolipid LIGA20 (II3Neu5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-dichloro-aceta mide-4-trans- octadecene) treatment in stroke was studied in a permanent left middle cerebral artery occlusion model in the rat. A dose-dependent increase of plasma LIGA20 and its presence in the brain were documented after p.o. drug application. Oral administration of 50 to 200 mg/kg of LIGA20, initiated 24 hr before middle cerebral artery occlusion and continued for 7 days, reduced the motor and cognitive impairment after the stroke, measured by the rotarod and the passive avoidance test, respectively. The 10-mg/kg dose was effective when given i.v. but not p.o. Oral treatment with 100 mg/kg of LIGA20 reduced the infarct size in the cortex but not in the ischemic core (the striatum). No biochemical or behavioral adverse effects of LIGA20 treatment were observed. Further studies are needed to evaluate the full therapeutic potential of this compound.

Topics: Administration, Oral; Animals; Behavior, Animal; Brain Ischemia; Cerebral Infarction; Drug Evaluation, Preclinical; G(M1) Ganglioside; Learning; Male; Memory; Motor Activity; Rats; Rats, Sprague-Dawley; Sphingosine

The efficacy of monosialoganglioside GM1 treatment was evaluated in a model of experimental stroke. Cerebral ischemia was induced by permanent occlusion of left middle cerebral artery. GM1 was administered intravenously soon after the occlusion of the artery and then intramuscularly daily for 7 days. Results indicate that GM1 can reduce the extent of infarct volume and neurochemical deficits associated with the ischemic event. The protection was more evident in the cortex than in the caudate-putamen. These observations confirm and extend the evidence of the GM1 efficacy in experimental models of stroke and further support the usefulness of gangliosides in the treatment of these pathologies.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain Edema; Brain Ischemia; Caudate Nucleus; Cerebral Infarction; Choline O-Acetyltransferase; Dopamine; G(M1) Ganglioside; Isoquinolines; Male; Putamen; Rats; Rats, Sprague-Dawley

Neocortical infarction induces biochemical and morphological retrograde degenerative changes in cholinergic neurons of the rat nucleus basalis magnocellularis [Sofroniew et al. (1983) Brain Res. 289, 370-374]. In the present study, this lesion model has been reproduced in the non-human primate (Cercopithecus aethiops) to investigate whether degenerative changes affecting the cortex surrounding the lesioned area and the ipsilateral basal forebrain are prevented by the early administration of recombinant human nerve growth factor alone or in combination with the monosialoganglioside GM1. Six months after surgery and treatment, the monkeys were processed either for biochemistry (choline acetyltransferase assay) or immunocytochemistry. In lesioned vehicle-treated animals, choline acetyltransferase activity significantly decreased by 28% in the cortex surrounding the injured area and by 31% in the ipsilateral nucleus basalis of Meynert when compared with values of sham-operated monkeys. These biochemical changes were fully prevented with the administration of nerve growth factor alone or in combination with the monosialoganglioside GM1. The morphometrical analysis revealed a significant shrinkage of cholinergic neurons (61 +/- 1.4% of sham-operated cell size) and loss of neuritic processes (59 +/- 10% of sham-operated values) within the intermediate nucleus basalis region of lesioned vehicle-treated animals. Although a protection of the cholinergic cell bodies within the nucleus basalis was found with both treatments, a significant recovery of the neuritic processes (84 +/- 7.2% of sham-operated values) was assessed only in the double-treated monkeys. These results indicate that the early administration of nerve growth factor alone or in combination with the monosialoganglioside GM1 induces a long-term protective effect on the nucleus basalis cholinergic neurons in cortical injured non-human primates.

Topics: Animals; Basal Ganglia; Cerebral Cortex; Cerebral Infarction; Chlorocebus aethiops; Choline O-Acetyltransferase; G(M1) Ganglioside; Gelatin; Immunohistochemistry; Male; Nerve Degeneration; Nerve Growth Factors; Neurons; Parasympathetic Nervous System; Recombinant Proteins; Substantia Innominata

Cortical focal ischemia in the rat was induced by middle cerebral artery occlusion (MCAo) together with permanent occlusion of the ipsilateral common carotid artery (CCAo) and a temporary (1 hr) occlusion of the contralateral CCA. By using a defined cortical tissue sampling procedure at 3, 6, 24, 72, 96, and 120 hr after the MCAo + CCAo, patterns of edema and ion (Na+, K+, and Ca++) changes in a primary and three peri-ischemic cortical areas are described. Ionic imbalances and edema formation have distinct patterns, are time dependent, and are different when comparing primary and peri-ischemic areas. Calcium increases to "neurotoxic" levels appear temporally independent of edema formation, reaching magnitudes 20 times greater than basal levels in the primary infarct area. Na+ increases correlate with increases in water, while K+ losses do not appear to be directly related to edema formation of Na+ and Ca++ increases. K+ losses are only significant in the primary infarct area. Rats treated with GM1 ganglioside (10 mg/kg, i.m.) daily showed significant reductions in edema, Na+ and Ca++ increases. These ganglioside effects were evident as early as 24 hr after the ischemic injury. Ca++ increases, which was maximal at 72 hr after the ischemic injury, was reduced by greater than 50% in GM1-treated animals. The mechanism by which GM1 is an effective neuroprotective agent may be evidenced by its effects on Ca++ influx/efflux processes in injury.

Topics: Animals; Brain; Brain Edema; Calcium; Cerebral Infarction; Functional Laterality; G(M1) Ganglioside; Ischemic Attack, Transient; Male; Potassium; Rats; Rats, Inbred Strains; Sodium; Time Factors