g(m1)-ganglioside and Brain-Ischemia

Ganglioside GM1 is a member of the ganglioside family which has been used in many countries and is thought of as a promising alternative treatment for preventing several neurological diseases, including cerebral ischemic injury. The therapeutic effects of GM1 have been proved both in neonates and in adults following ischemic brain damage; however, its clinical efficacy in patients with ischemic stroke is still uncertain. This review examines the recent knowledge of the neuroprotective properties of GM1 in ischemic stroke, collected in the past two decades. We conclude that GM1 may have potential for stroke treatment, although we need to be cautious in respect of its complications.

Topics: Animals; Brain Ischemia; Clinical Trials as Topic; G(M1) Ganglioside; Humans; Neuroprotective Agents; Stroke

Gangliosides may have a protective effect on the central and peripheral nervous systems.. The objective of this review was to assess the effect of exogenous gangliosides in acute ischaemic stroke.. We searched the Cochrane Stroke Group trials register (last searched: May 2001) and contacted drug companies and main investigators of included trials.. Randomised trials of gangliosides compared with placebo or standard treatment in people with definite or presumed ischaemic stroke. Trials were included if people were randomised within 15 days of symptom onset and if mortality data were available.. One reviewer applied the inclusion criteria. Two reviewers independently extracted the data. Trial quality was assessed.. Twelve trials involving 2265 people were included. All the trials tested purified monosialoganglioside GM1. Only three trials described the randomisation procedure. Follow-up was between 15 to 180 days. Death at the end of follow-up showed no significant difference (odds ratio 0.91, 95% confidence interval 0.73 to 1.13). There was no difference shown between early (within 48 hours) and delayed treatment. For disability, three trials did not show any improvement in Barthel index score with gangliosides (weighted mean difference 2.1; 95% confidence interval -4.8 to 8.9). In two trials, eight patients experienced adverse effects that led to discontinuation of ganglioside treatment, seven had skin reactions and one developed Guillain-Barré syndrome.. There is not enough evidence to conclude that gangliosides are beneficial in acute stroke. Caution is warranted because of reports of sporadic cases of Guillain-Barré syndrome after ganglioside therapy.

Topics: Acute Disease; Brain Ischemia; G(M1) Ganglioside; Gangliosides; Humans; Stroke

Gangliosides may have a protective effect on the central and peripheral nervous systems.. The objective of this review was to assess the effect of exogenous gangliosides in acute ischaemic stroke.. We searched the Cochrane Stroke Group trials register (last searched: March 1999) and contacted drug companies.. Randomised trials of gangliosides compared with placebo or standard treatment in people with definite or presumed ischaemic stroke. Trials were included if people were randomised within 15 days of symptom onset and if mortality data were available.. One reviewer applied the inclusion criteria. Two reviewers independently extracted the data. Trial quality was assessed.. Eleven trials involving 2257 people were included. All the trials tested purified monosialoganglioside GM1. Only three trials described the randomisation procedure. Follow-up was between 15 to 180 days. Death at the end of follow-up showed no significant difference (odds ratio 0.91, 95% confidence interval 0.73 to 1.14). There was no difference shown between early (within 48 hours) and delayed treatment. For disability, two trials showed an improved Barthel index score with gangliosides (weighted mean difference 8.6, 95% confidence interval 1.2 to 16.0). In two trials, eight patients experienced adverse effects that led to discontinuation of ganglioside treatment, seven had skin reactions and one developed Guillain-Barré syndrome.. There is not enough evidence to conclude that gangliosides are beneficial in acute stroke. Caution is warranted because of reports of sporadic cases of Guillain-Barré syndrome after ganglioside therapy.

Topics: Brain Ischemia; G(M1) Ganglioside; Gangliosides; Humans; Stroke

1. At least two different groups of molecules can be considered neurotrophic factors because they exert a variety of effects upon neural cells. The first consists of the numerous families of polypeptide growth factors known to take part in almost all stages of neural cell growth and functioning, including development, differentiation, survival and pathology. The second group also is characterized by extensive complexity of multiple forms, and consists of the sialic acid-containing glycosphingolipids or gangliosides. These molecules also take part in the transfer of information from the extracellular milieu to the cell interior, and, similarly to growth factors, are participants in such aspects as development, differentiation and functioning. 2. In this short overview, we consider the existing data on the neuroprotective effects of growth factors [e.g., basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and brain-derived neurotrophic factor] and one species of ganglioside (GM1) against retinal ischemia in vivo and cerebral excitotoxicity in vitro. 3. We used three different experimental models to investigate their relevance to ischemic and excitotoxic conditions in the retina and have shown that: (a) both bFGF and EGF show highly effective neuroprotection for rat retinal neurons exposed to toxic levels of glutamate or its nonphysiological agonist kainate in vitro (b) retinal glial cells suffer morphological perturbations after glutamate or kainate treatment, and this effect depends on neuron-glial interactions; (c) these glial changes can also be corrected by posttreatment with either bFGF or EGF in vitro; (d) with the use of an in vivo animal model involving anterior chamber pressure-induced ischemia in adult rats, either pretreatment by intraperitoneal injection of GM1 or posttreatment by intraocular injection of the same ganglioside significantly reduces histological damage to inner nuclear regions. 4. Hence both groups of trophic molecules show interesting features for retinal ischemic treatment.

Topics: Animals; Brain Ischemia; G(M1) Ganglioside; Growth Substances; Ischemia; Neuroprotective Agents; Retinal Diseases; Retinal Vessels

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.

Topics: Activities of Daily Living; Animals; Brain Ischemia; Clinical Protocols; G(M1) Ganglioside; Humans; Motor Activity; Neuroprotective Agents; Randomized Controlled Trials as Topic; Recurrence

In vitro studies have shown that monosialoganglioside GM1 reduces excitatory amino acid-related neurotoxicity by limiting the downstream consequences of abusive excitatory amino acid receptor stimulation, while enhancing neuronotrophic factor action in a variety of neuronal cell types. Systemic administration of GM1 appears to be efficacious in reducing acute nerve cell damage and in facilitating medium- and long-term functional recovery after brain injury. Although the mechanism of action remains unclear, it appears likely that GM1 protective effects in the acute injury phase are at least in part due to the attenuation of excitotoxicity, while the long-term functional recovery might reflect GM1 potentiation of neuronotrophic factors. The potential therapeutic efficacy of GM1 administration in different conditions in humans, as suggested by pioneer clinical studies, is reviewed. Further larger, randomized, double-blind clinical studies are necessary to define the therapeutic efficacy.

Topics: Brain Ischemia; G(M1) Ganglioside; Humans

Increasing evidence is available indicating that systemically administered GM1 is able to provide for functional recovery in different experimental models of CNS injury, including cerebral ischemia. Current evidence indicates that the GM1 effects are associated, in the acute phase, with attenuation of secondary neuronal damage due to its capability to antagonize excitatory amino acid-related neurotoxicity in vivo as in vitro. Furthermore, the ganglioside is able to facilitate occurrence of long-term reparative processes, an effect most likely reflecting the potentiation of the action of neuronotrophic factors. This bifaceted action of GM1 makes the ganglioside ideally suited for clinical treatment of patients afflicted by cerebrovascular insufficiencies.

Topics: Animals; Brain Ischemia; G(M1) Ganglioside; Humans; Ischemic Attack, Transient; Neurons

Many neuroprotective agents (NPAs) are effective in acute experimental cerebral ischemia in animals. None have proven effective in human stroke trials. Even short treatment delays cause substantial efficacy loss. Cardiac surgery under cardiopulmonary bypass (CS-CPB) causes cerebral ischemia with cognitive impairment at a predeterminable time point and should permit efficient screening of NPAs for stroke benefit. We sought to develop sensitive methods to assess dysfunction from CS-CPB in a double-blind trial of the NPA GM1 ganglioside.. Eighteen GM1 and 11 Control patients received GM1 300 mg or placebo, two doses intravenously, before nonemergency CS-CPB. Independent examiners administered structured neurological examinations and neuropsychological test batteries at Baseline and 1 day (Acute Postop; neurological only), 1 week (Early F/U), and > or = 6 months (Long-term F/U) postoperatively; using defined procedures they employed ordinal Clinical Change Scores (CCSs) to quantify neurological cerebral, neurological noncerebral, and neuropsychological performance changes. Several methods to analyze CCSs and neuropsychological test score changes were evaluated.. The most sensitive indicators were the mean Acute Postop Neurologist's CCS-Cerebral (P < 10(-5)) and the mean Early F/U Neuropsychologist's CCS (P < .01), with statistically nonsignificant differences favoring GM1. No significant mean changes in Neurologist's CCS-Noncerebral or any Long-term F/U CCSs occurred. CCS distributions and neuropsychological test score mean changes showed similar temporal patterns, with less sensitivity to change. When, as usual in prior CS-CPB studies, impairment was defined by neuropsychological test score declines (increases ignored), results were spurious.. The strokelike cerebral dysfunction (maximal acutely, with eventual recovery) that occurs after CS-CPB is useful to screen NPAs for clinical efficacy. CCSs based on detailed neurological examination and neuropsychological testing are sensitive measures; refinement of this approach should enhance the efficiency of the CS-CPB model. Further testing of GM1 is warranted.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiopulmonary Bypass; Cognition; Cognition Disorders; Coronary Artery Bypass; Coronary Disease; Double-Blind Method; Female; Follow-Up Studies; G(M1) Ganglioside; Heart Valve Prosthesis; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Placebos; Postoperative Complications; Probability; Sensitivity and Specificity; Time Factors

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

Topics: Brain Ischemia; Clinical Trials as Topic; Double-Blind Method; G(M1) Ganglioside; Hemodilution; Humans; Italy; Random Allocation

Long-term memory impairment is reported in more than 50% of cardiac arrest survivors. Monosialoganglioside (GM1) provided neuroprotection in experimental models of stroke but failed to replicate its promise clinically for unknown reasons. GM1 stimulates the release of nerve growth factor (NGF), which is synthesized as a precursor protein (pro-NGF) that either mediates apoptosis through the p75 neurotrophin receptor (p75NTR) or is cleaved by the protease furin (FUR) to yield mature NGF, the latter supporting survival through tropomyosin kinase receptor (Trk). The flavanol epicatechin (EPI) inhibits p75NTR-mediated signaling and apoptosis by pro-NGF. The aim of the current work is to test whether these two drugs affect, or communicate with, each other in the setting of CNS injuries. Using the two-vessel occlusion model of global ischemia/reperfusion (I/R), we tested if pharmacological modulation of Trk, p75NTR, and NGF balance with GM1, EPI, and their combination, can correct the memory deficit that follows this insult. Finally, we tested if FUR insufficiency and/or p75NTR-mediated apoptosis negatively affect the neurotherapeutic effect of GM1. Key proteins for Trk and p75NTR, FUR, and both forms of NGF were assessed. All treatment regiments successfully improved spatial memory retention and acquisition. A week after the insult, most Trk and p75NTR proteins were normal, but pro/mature NGF ratio remained sharply elevated and was associated with the poorest memory performance. Pharmacological correction of this balance was achieved by reinforcing Trk and p75NTR signaling. GM1 increased FUR levels, while concomitant administration of EPI weakened GM1 effect on pro-survival Trk and p75NTR mediators. GM1 neuroprotection is therefore not limited by FUR but could be dependent on p75NTR. Graphical Abstract "."

Topics: Animals; Apoptosis; Brain Ischemia; Catechin; G(M1) Ganglioside; Male; Memory Disorders; Nerve Growth Factor; Nerve Tissue Proteins; Neuroprotective Agents; Rats; Rats, Wistar; Receptor, trkA; Receptors, Growth Factor; Receptors, Nerve Growth Factor; Signal Transduction

We aimed to assess the neuroprotective mechanism of monosialotetrahexosy-1 ganglioside (GM1) on focal cerebral ischemia/reperfusion (I/R) injury in rats with diabetes. A total of 54 male Wistar rats were induced with diabetes mellitus by administration of streptozotocin (STZ). The rats were then randomized into three groups, including sham group (n=18), I/R group (n=18), and GM1 group (n=18). Focal cerebral ischemia was modeled using the right middle cerebral artery occlusion method. In the GM1 group, diabetic rats were intraperitoneally administered with GM1 (15mg/kg) at 20min prior to reperfusion. GM1 was replaced by an equal volume of saline in the I/R group. Rats from the sham group accepted sham operation and normal saline. The neurological deficit and brain infarct volume and TUNEL-apoptosis were evaluated. The expression of endoplasmic reticulum (ER) stress-related proteins, including caspase-12, GRP78 and CHOP/GADD153, was examined by Western blot. GM1 notably reduced the cerebral infarct size and improved the neurological behavior. In addition, GM1 dramatically reduced TUNEL-positive cell numbers in the cerebral cortex. Furthermore, GM1 treatment modulated protein levels, increasing GRP78 and reducing CHOP/GADD153 expression along with activation of caspase-12 in the ischemic brain hemispheres. These results imply that GM1 attenuates diabetes-associated cerebral I/R injury by suppressing the ER stress-induced apoptosis.

Topics: Animals; Apoptosis; Brain Ischemia; Diabetes Mellitus, Experimental; Endoplasmic Reticulum Stress; G(M1) Ganglioside; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

Ganglioside GM1, which is particularly abundant in the central nervous system (CNS), is closely associated with the protection against several CNS disorders. However, controversial findings have been reported on the role of GM1 following ischemic stroke. In the present study, using a rat middle cerebral artery occlusion (MCAO) model, we investigated whether GM1 can protect against ischemic brain injury and whether it targets the autophagy pathway. GM1 was delivered to Sprague-Dawley male rats at 3 doses (25 mg/kg, 50 mg/kg, 100 mg/kg) by intraperitoneal injection soon after reperfusion and then once daily for 2 days. The same volume of saline was given as a control. Tat-Beclin-1, a specific autophagy inducer, was administered by intraperitoneal injection at 24 and 48 hours post-MCAO. Infarction volume, mortality and neurological function were assessed at 72 hours after ischemic insult. Immunofluorescence and Western blotting were performed to determine the expression of autophagy-related proteins P62, LC3 and Beclin-1 in the penumbra area. No significant changes in mortality and physiological variables (heart rate, blood glucose levels and arterial blood gases) were observed between the different groups. However, MCAO resulted in enhanced conversion of LC3-I into LC3-II, P62 degradation, high levels of Beclin-1, a large area infarction (26.3±3.6%) and serious neurobehavioral deficits. GM1 (50 mg/kg) treatment significantly reduced the autophagy activation, neurobehavioral dysfunctions, and infarction volume (from 26.3% to 19.5%) without causing significant adverse side effects. However, this biological function could be abolished by Tat-Beclin-1.. GM1 demonstrated safe and robust neuroprotective effects that are associated with the inhibition of autophagy following experimental stroke.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Brain; Brain Ischemia; Disease Models, Animal; Drug Administration Schedule; G(M1) Ganglioside; Gene Expression Regulation; Gene Products, tat; Heat-Shock Proteins; Infarction, Middle Cerebral Artery; Injections, Intraperitoneal; Male; Microtubule-Associated Proteins; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Sequestosome-1 Protein; Signal Transduction; Stroke; Survival Analysis

To explore the new mechanism of neuroprtection of monosialotetrahexosylganglioside and providing reliable theoretical foundation and experimental evidence for the emergency treatment and rehabilitation of cerebral ischemia/reperfusion injury. A rat model of cerebral ischemia/reperfusion injury was constructed and intervened with monosialotetrahexosylganglioside(5mg/kg) and lipid peroxidation inhibitor U-101033E(40mg/kg). TTC straining and neurobiological function score were used to evaluate brain injury. 4-HNE and MDA content were measured to evaluate lipid peroxidation. The expression of tyrosine hydroxilase at both mRNA and protein levels and enzyme activity were determined to evaluate the gene disfunction. Tyrosine content in brain and in serum and the DOPA content in plasma were measured to evaluate the metabolism of tyrosine. As the study shown, cerebral ischemia/reperfusion lead to brain infarction and neurobiological function losing accompany with upregulation of 4-HNE and MDA levels and downregulation of TH expression (mRNA and protein) and decreased enzyme activity. The results above mentioned can be reversed obviously by intervening with monosialotetrahexosylganglioside and lipid peroxidation inhibitor U-101033E. Toxic aldehyde accumulation leaded to disfunction of tyrosine hydroxylase and excessive tyrosine and decreased synthesis of catecholamine neurotransmitter such as dopamine and accelerated neuron cell injury. Both monosialotetrahexosylganglioside and U-101033E presented neuroprotecion by restoring the tyrosine/dopa pathway through reversing the function of tyrosine hydroxylase by inhibiting lipid peroxidation.

Topics: Animals; Brain Ischemia; Fatty Acids; G(M1) Ganglioside; Gene Expression Regulation, Enzymologic; Lipid Peroxidation; Male; Neuroprotective Agents; Pyrimidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tyrosine 3-Monooxygenase; Up-Regulation

The pathogenesis of cerebral ischemia-reperfusion injury (CIRI) is not completely clear and therapies are limited now. Therefore, our study aimed to investigate the possible pathogenesis and preventive approach of CIRI through analyzing changes of aspartate (Asp), glutamate (Glu), mitochondrial calcium (MCa), calmodulin (CaM), and malondialdehyde (MDA) contents and ultramicropathology in hippocampus and cerebral cortex of ischemic susceptible injured regions and the effect of monosialotetrahexosylganglioside (GM1) in the rat model of CIRI.. Contents of Asp, Glu, MCa, CaM, and MDA in hippocampus and cerebral cortex tissues were measured by a high-performance liquid chromatography, atomic absorption spectrophotometer, and ordinary spectrophotometer, respectively, changes of ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex were observed by a transmission electron microscope.. Contents of Asp and Glu in hippocampus and cerebral cortex tissues of CIRI groups significantly decreased and contents of MCa, CaM, and MDA significantly increased than those in control groups, and the ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex revealed a significant damaged change, and GM1 significantly ameliorated changes of Asp, Glu, MCa, CaM, and MDA contents in hippocampus and ultrastructural changes in neurons of the hippocampus CA1 region and frontal cerebral cortex.. Our findings further support that the abnormal release and/or reuptake of excitatory amino acid neurotransmitters, the disordered calcium homeostasis and the excessive production and/or reduced elimination of reactive oxygen species contribute to the pathogenesis of CIRI, and GM1 can partially prevent these pathogenesises to exert the protective effect on CIRI.

Topics: Animals; Biomarkers; Brain Ischemia; Calcium; Cerebral Cortex; Cytoprotection; Disease Models, Animal; Excitatory Amino Acids; G(M1) Ganglioside; Hippocampus; Homeostasis; Male; Neurons; Neuroprotective Agents; Oxidative Stress; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Time Factors

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer's disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain's response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aβ) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aβ toxicity, rats received intracerebralventricular (i.c.v.) injections of the toxic 25-35 fragment of the Aβ peptide (Aβ alone group). To model the combination of Aβ toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aβ25-35 (combined Aβ/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aβ. By 21 d, GM2 levels only remained elevated in the combined Aβ/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aβ/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aβ/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Brain Ischemia; G(M1) Ganglioside; G(M2) Ganglioside; G(M3) Ganglioside; Male; Peptide Fragments; Rats, Wistar; Reperfusion Injury; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

The ganglioside GM1 has neuroprotective effects but is not of therapeutic value because of its lack of bioavailability. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized 19 small GM1-like analogues whose simplified structure includes a hydrophobic saturated or unsaturated moiety linked to a hydrophilic moiety. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells. We found that several analogues protected the HT22 cells from death at concentrations ranging from 2 to 5 microM. Additional neuroprotective assays using cortical slices injured by glutamate confirmed these results. Since members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the GM1-like analogues. Interestingly, the results indicate that the compounds provide neuroprotection through distinct mechanisms of action.

Topics: Animals; Brain; Brain Ischemia; Cell Line; Cell Survival; Fatty Acids, Unsaturated; G(M1) Ganglioside; Hydrophobic and Hydrophilic Interactions; Mice; Neuroprotective Agents; Structure-Activity Relationship

To determine the protective effect of monosialoganglionside (GM1) and evaluate the influence of GM1 on expression of N-methyl-D-aspartate receptor subunit 1 (NMDAR1) in Sprague-Dawley (SD) rats with focal cerebral ischemia-reperfusion (I/R).. Left middle cerebral artery (MCA) was occluded by an intraluminal suture for 1 h and the brain was reperfused for 72 h in SD rats when infarct volume was measured, GM1 (10 mg/kg) was given ip (intraperitoneally) at 5 min (group A), 1 h (group B) and 2 h (group C) after MCA occlusion (MCAo). Expression of NMDAR1 was detected by Western blot at various time after reperfusion (4 h, 6 h, 24 h, 48 h and 72 h) in ischemic hemispheres of the rats with or without GM1 administered.. (1) Adjusted relative infarct volumes of groups A and B were significantly smaller than that of group C and the control group (P<0.01 and P<0.05, respectively). (2) Expression level of NMDAR1 was temporally high at 6 h after reperfusion, and dipped below the normal level at 72 h after reperfusion. GM1 at 5 min after MCAo significantly suppressed the expression of NMDAR1 at 6 h after reperfusion (P<0.05 vs the control). At 72 h after reperfusion, the NMDAR1 expression level of rats treated with GM1 administered (at 5 min or 2 h after MCAo) was significantly higher than that of the control (P<0.05).. GM1 can time-dependently reduce infarct volume in rats with focal cerebral I/R partly through stabilizing the expression of NMDAR1.

Topics: Animals; Brain Ischemia; G(M1) Ganglioside; Gene Expression Regulation; Male; Middle Cerebral Artery; Neurons; Protein Subunits; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Treatment Outcome

Cytidine-5'-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM(1) ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM(1) ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline.

Topics: Animals; Brain; Brain Infarction; Brain Ischemia; Cholesterol; Choline; Cytidine Diphosphate Choline; Disease Models, Animal; Drug Combinations; Drug Synergism; G(M1) Ganglioside; Liposomes; Male; Phagocytosis; Phosphatidylcholines; Rats; Rats, Inbred SHR; Reperfusion Injury; Stroke; Treatment Outcome

Neuronal damage subsequent to transient cerebral ischemia is a multifactorial process involving several overlapping mechanisms. Gangliosides, sialic acid-conjugated glycosphingolipids, reduce the severity of acute brain damage in vitro. However their in vivo effects on the cerebral cortex damaged by ischemic infarct are unknown. To assess the possible protective role of gangliosides we examined their expression in the cerebral cortex damaged by ischemic infarct in the rat. Ischemia was induced by middle cerebral artery (MCA) occlusion, and the resulting damage was observed by staining with 2, 3, 5-triphenylterazolium chloride (TTC). High-performance thin-layer chromatography (HPTLC) showed that gangliosides GM3 and GM1 increased in the damaged cerebral cortex, and immunofluorescence microscopy also revealed a significant change in expression of GM1. In addition, in situ hybridization demonstrated an increase in the mRNA for ganglioside GM3 synthase. These results suggest that gangliosides GM1 and GM3 may be synthesized in vivo to protect the cerebral cortex from ischemic damage.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Chromatography, Thin Layer; G(M1) Ganglioside; G(M3) Ganglioside; In Situ Hybridization; Infarction, Middle Cerebral Artery; Microscopy, Fluorescence; Middle Cerebral Artery; Rats; Rats, Wistar; Sialyltransferases; Tetrazolium Salts

Topics: Acute Disease; Animals; Antiparkinson Agents; Brain Ischemia; Drugs, Investigational; G(M1) Ganglioside; Humans; Neuroprotective Agents; Parkinson Disease; Stroke

Cerebral ischemia represents a serious therapeutic challenge. We investigated the therapeutic efficacy of CDP-choline-loaded liposomes against cerebral ischemia. The determination of post-ischemic brain recovery by EEG analysis was carried out to evaluate the effect of CDP-choline-loaded liposomes with respect to the free drug on the maturation of ischemic injury.. Long-circulating unilamellar liposomes were prepared by a freeze and thaw procedure followed by an extrusion through polycarbonate membranes. Wistar rats were ischemized by bilateral clamping of the common carotid arteries. Free or liposomally entrapped drug was administered (20 mg/kg) just after ischemia and thereafter once a day for six days. Post-ischemic survival, neuronal membrane peroxidation and brain recovery (EEG analysis) were evaluated.. The post-ischemic reperfused rats treated with CDP-choline-loaded liposomes showed a higher survival rate than animals treated with the free drug. The delayed cerebral neurodegenerative injury due to an ischemic event, referred to as maturation phenomenon, was substantially reduced with the administration of the liposomal formulation. The liposomal carrier showed a marked protection against lipoperoxidative damage.. Liposomes ensured a rapid recovery of the damaged membranous structure of the neuronal cells, allowing a significant improvement of brain functionality. The reduction of the maturation phenomenon may probably be of particular importance in humans, where a fundamental problem is the quality of life after an ischemic event.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Chemical Phenomena; Chemistry, Physical; Cytidine Diphosphate Choline; Drug Carriers; Electroencephalography; Freeze Fracturing; G(M1) Ganglioside; Lactates; Lipid Peroxidation; Liposomes; Male; Nootropic Agents; Rats; Rats, Wistar; Survival Analysis

Unilamellar liposomes made up of DPPC-DPPS-Chol (7:4:7 molar ratio) and ganglioside GM1 8% mol were used to deliver cytidine-5I-diphosphate choline (CDP-choline) to the brain. The liposomal suspension consisted of unilamellar vesicles with a mean size of 50 nm and a very narrow size distribution. The therapeutic effectiveness of CDP-choline-loaded liposomes was investigated by an in vivo model of cerebral ischemia on Wistar rats (320-350 g). The animals were made ischemic to different extents (5, 15 and 30 min) by bilateral clamping of the common carotid arteries. The effect of free and liposomally encapsulated CDP-choline on the survival rate of post-ischemic reperfused rats was evaluated. The liposome formulation was much more active against ischemic injury than the free CDP-choline, ensuring a noticeable improvement of the survival rate with regards to the free drug ranging from 45% to 100% as a function of the duration of the ischemic event.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Brain Ischemia; Carotid Artery, Common; Cholesterol; Constriction; Cytidine Diphosphate Choline; G(M1) Ganglioside; Liposomes; Male; Phosphatidylserines; Rats; Rats, Wistar; Survival Rate

The effects of a 20 min period of four-vessel occlusion cerebral ischemia followed by reperfusion on glutamate, aspartate, GABA and glycine efflux from the rat cerebral cortex were studied using a cortical cup technique. Cerebral ischemia increased amino acid concentrations in the cortical superfusates. When the cerebral cortices were exposed to topically applied GM1 ganglioside (50 microM) for 40 min prior to ischemia, the evoked efflux of all four amino acids was significantly inhibited. GM1 (1 microM) failed to inhibit amino acid release. The results support the concept that gangliosides have a cerebroprotective action.

Topics: Analysis of Variance; Animals; Brain Ischemia; Cerebral Cortex; G(M1) Ganglioside; Male; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley

Cytidine-5'-diphosphate choline (CDPc) was encapsulated in long-circulating unilamellar vesicles (SUVs) to improve the drug's biological effectiveness.. SUVs made up of diaplmitoylphosphatidylcholine/diaplmitoylphosphatidylserine /cholesterol (7:4:7 molar ratio) and 8 mol % of ganglioside GM1 were prepared by extrusion through polycarbonate filters (mean diameter 50 nm). The formulation effectiveness was evaluated by an in vivo model of cerebral ischemia on Wistar rats.. The enhanced delivery of CDPc into the brain improved the therapeutic effectiveness of the drug. CDPc-loaded SUVs improved the survival rate of ischemized and reperfused Wistar rats (320-350 g) by approximately 66% compared with the free drug. Liposome formulation was also able to effectively protect the brain against peroxidative damage caused by post-ischemic reperfusion. SUVs lowered the conjugated diene levels of the cerebral cortex. The liposomal delivery system did not alter the distribution patterns in the various cerebral lipid fractions of the drug, radiolabeled with 14C-CDPc.. CDPc-loaded SUVs were able to protect the brain against damage induced by ischemia. A possible clinical application is envisaged.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Cytidine Diphosphate Choline; Drug Carriers; G(M1) Ganglioside; Liposomes; Magnetic Resonance Spectroscopy; Male; Nootropic Agents; Particle Size; Rats; Rats, Wistar; Reperfusion Injury

In this study Mongolian gerbils were submitted to a normothermic bilateral carotid ligation lasting 5 min. A noncompetitive antagonist of NMDA receptors, MK-801, 0.8 mg/kg, was injected i.p. 30 min before ischemia, or the ganglioside GM1, 30 mg/kg, was given i.p. for 3 days, twice a day. The morphology of the hippocampal CA1 neurones and the brain content of cyclooxygenase metabolites of arachidonic acid: prostaglandin 6-keto PGF1 alpha and thromboxane Tx B2 were studied. Untreated ischemia induced the accumulation in brain of the 6-keto PGF1 alpha and Tx B2 immunoreactive materials, and resulted in a lesion of 70% of CA1 neurones. In the MK-801- and GM1-pretreated groups the postischemic levels of Tx B2 were significantly decreased. However MK-801 and GM1 did not prevent damage to the CA1 neurones in gerbils normothermic after ischemia, whereas a partial neuroprotection was observed in hypothermic, MK-801 treated gerbils. The results of this study indicate that NMDA receptors may participate in the mechanism of postischemic release of eicosanoids in brain. They also confirm a potential modulatory role of gangliosides. These results are discussed in terms of the involvement of cyclooxygenase metabolites of arachidonic acid in the mechanism of a selective delayed neuronal damage to the hippocampus CA1 after ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Dizocilpine Maleate; Female; G(M1) Ganglioside; Gerbillinae; Hippocampus; Male; Prostaglandins; Thromboxane B2

Rat pups, seven days old, with right carotid artery ligations were exposed to an atmosphere of oxygen 8% remainder nitrogen for 2 hr. The animals that survived for three weeks after the hypoxic-ischemic episode had clusters of darkly stained (hematoxylin-eosin) neurons in the cortex and reduced uptake of dopamine (frontal cortex) and choline (frontal cortex, hippocampus and striatum) in preparations of synaptosomes. Treatment with GM1 ganglioside partially corrected the loss of uptake activity and increased the number of darkly stained neurons.

Topics: Animals; Animals, Newborn; Brain; Brain Ischemia; Choline; Dopamine; Female; G(M1) Ganglioside; Hypoxia, Brain; Neurons; Pregnancy; Rats; Rats, Sprague-Dawley; Synaptosomes

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

This study aimed to investigate the effects of monosialoganglioside (GM1) when administered early in a model of cerebral focal ischemia, in the rabbit. The statistical evaluation of the electroencephalographic changes (quantified EEG analysis, QEEG) due to the ischemic event showed that the early treatment (1-3-24 h) with GM1 reduced the EEgraphic pattern typical of this model of cerebral ischemia. Considering the observation period, we hypothesized that it was due to the formation of an oedema of a lesser degree compared to the untreated group. Particularly, we did not obtain the increase in delta activity on the contralateral hemisphere, which we thought was expression of the diaschisi phenomenon.

Topics: Acute Disease; Animals; Brain Edema; Brain Ischemia; Cell Membrane; Electroencephalography; G(M1) Ganglioside; Intracranial Embolism and Thrombosis; Models, Biological; Rabbits

The purpose of this study was to determine whether prophylaxis with monosialoganglioside GM1 can protect the fetus from hypoxic-ischemic encephalopathy in utero. Because some protective strategies can compromise the fetus, the effect of GM1 treatment on metabolic status and blood pressure was also evaluated. Chronically instrumented near-term fetal sheep (119-133 d) were subjected to 30 min of severe cerebral ischemia. Six were given 30 mg/kg GM1 through the umbilical vein 2 h before insult followed by continuous infusion of 30 mg/kg/d over the next 60 h, and these were compared with seven vehicle-treated control sheep. The time course of electrocorticographic activity and cytotoxic edema within the parasagittal cortex were determined with real-time spectral analysis and continuous impedance measurements, respectively. Histologic outcome was assessed 72 h later. Pretreatment with GM1 improved recovery of primary edema, reduced the duration of epileptiform activity (15 +/- 2 versus 31 +/- 5 h; p < 0.05) and the magnitude of secondary edema (p < 0.05). At 72 h, histologic damage was reduced, particularly in the cortex (p < 0.05) and hippocampus (p < 0.01), and residual electrocorticographic activity was increased in the GM1-treated group (-5 +/- 1 versus -9 +/- 3 dB, p < 0.01). GM1 infusion did not alter arterial blood pressure or metabolic status. These results indicate that GM1 can protect the fetal brain against hypoxic-ischemic injury without causing hypotension or metabolic compromise.

Topics: Animals; Brain Injuries; Brain Ischemia; Electroencephalography; Female; Fetal Hypoxia; G(M1) Ganglioside; Gangliosides; Hypoxia, Brain; Pregnancy; Reperfusion Injury; Sheep

Using a consistent, reproducible and reliable cortical focal ischemia in rat (permanent unilateral occlusion of the left middle cerebral artery & the ipsilateral common carotid artery [MCAo + CCAo] with a 1 h temporary occlusion of the contralateral CCA), the levels of four major membrane fatty acids (palmitic, C16:0; stearic, C18:0; Oleic, C18:1 and arachidonic, C20:4) were analyzed at 3, 36 and 72 h, and 2 and 4 wk following ischemia to determine the critical point of irreversibility of the cellular plasma membrane disorganization in primary ischemic (Area 1, parietal cortex) and peri-ischemic (Area 2, tempero-occipital cortex) areas. The cortical focal ischemia resulted in time dependent differential loss in four of these major membrane fatty acids. The quantitative differences among primary and peri-ischemic areas reflected the different degree of ischemic injury inflicted to these regions. Acute treatment with ganglioside GM1 protected the further losses of all of these fatty acids and differentially restored their levels in these various injury sites over periods of time. The changes in levels of these membrane fatty acids indicate that the primary ischemic area suffers an irreversible injury and peri-ischemic area suffers reversible injury. After acute treatment (< 2 h) with ganglioside GM1, a partial recovery was observed in primary ischemic area and complete recovery was observed in peri-ischemic areas. These studies support the hypothesis that, ischemia leads to a irreversible plasma membrane disorganization which underlies the eventual cell death, and protection and restoration of these membrane changes by drugs, such as ganglioside GM1 leads to neuroprotection against ischemic injury.

Topics: Animals; Brain; Brain Ischemia; Cell Membrane; Fatty Acids; G(M1) Ganglioside; Male; Rats; Time Factors

The time course for the ischemia-induced changes in the subcellular distribution of protein kinase C (PKC) (alpha), (beta II), and (gamma) and the activity of PKC were studied in the neocortex of rats subjected to 1, 2, 3, 5, 10, and 15 min of global cerebral ischemia. In the particulate fraction, a 14-fold increase in PKC (gamma) levels was seen at 3 min of ischemia, which further increased at 5-15 min of ischemia. At 15 min of ischemia, PKC (alpha) and (beta II) levels had increased two- and six-fold, respectively. In the cytosolic fraction, a transient early 1.4-fold increase in PKC (beta II) and PKC (gamma) levels was seen, whereas no change in the levels PKC (alpha) was noted. PKC (gamma) levels then progressively declined, reaching 50% at 15 min of ischemia. At 5 min of ischemia, a 43% decrease in PKC activity was seen in the particulate fraction, reaching 50% at 15 min of ischemia concomitant with a 27% decrease in the cytosolic fraction. There was no change in the activator-independent PKC activity. Pretreatment with the ganglioside AGF2 prevented the redistribution of PKC (gamma) in the particulate fraction at 5 min, but not at 10 min of ischemia. The observed time course for the translocation of PKC (gamma) parallels the ischemia-induced release of neurotransmitters and increased levels of diacylglycerols, arachidonate, and increased levels of diacylglycerols, arachidonate, and intracellular calcium and delineates this subspecies as especially ischemia-sensitive. Ganglioside pretreatment delayed the translocation of PKC (gamma), possibly by counter-acting the effects of ischemia-induced factors that favor PKC binding to cell membranes.

Topics: Animals; Biological Transport; Brain Ischemia; G(M1) Ganglioside; Isoenzymes; Male; Protein Kinase C; Rats; Rats, Wistar; Subcellular Fractions; Time Factors

The efficacy of GM1 ganglioside treatment in stroke was studied in a permanent middle cerebral artery occlusion model in the rat. A dose-dependent attenuation of infarct size at 24 hr was documented with the maximum effective dose halving the volume of the experimental stroke. Delayed administration at 5 min, but not 15 min, after vessel occlusion was as effective as preocclusion drug administration. Morphologic sparing was confined to the cortical penumbra; no protection in the ischemic core was found. Morphologically salvaged cortex was also metabolically preserved as demonstrated by quantitative measurement of glucose utilization. In vivo microdialysis demonstrated an attenuation of ischemic-induced glutamate release in the cortex with GM1 administration but no effect was found in the caudate. Hypotension did not occur even with doubling of the maximally effective dose of GM1. Accordingly, GM1 may be a safe and effective treatment for stroke.

Topics: Animals; Behavior, Animal; Brain; Brain Ischemia; Cerebral Cortex; Deoxyglucose; Dialysis; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; G(M1) Ganglioside; Male; Rats; Rats, Sprague-Dawley

Alterations in cellular membrane structure and the subsequent failure of its function after CNS ischemia were monitored by analyzing changes in the plasma membrane marker enzyme (Na(+) + K(+)-ATPase. The levels of two isozymes of (Na(+) + K(+)-ATPase, alpha+ and alpha, which have distinct cellular and anatomical distributions, were studied to determine if differential cellular damage occurs in primary and peri-ischemic injury areas. The efficacy of monosialoganglioside (GM1) treatment was assessed, since this glycosphingolipid has been shown to reduce ischemic injury by protecting cell membrane structure/function. Using a rat model of cortical focal ischemia, levels of both ATPase isozyme activities were assayed in total membrane fractions from primary ischemic tissue (parietal cortex) and three peri-ischemic tissue areas (frontal, occipital, and temporal cortex) at 1, 3, 5, 7, and 14 days after ischemia. No significant loss of either isozyme's activity occurred in any tissue area at 1 day after ischemia. At 5 days, in the primary ischemic area, both isozyme activity levels decreased by 70-75%. The alpha+ enzyme activity loss persisted up to 14 days, while a 17% recovery in alpha activity occurred. In the three peri-ischemic tissue areas, enzyme activity losses ranged from 42%-59% at 3 days after ischemia. A complete restoration of both isozyme activities was seen at 14 days. After three days of GM1 ganglioside treatment there was no loss of total (Na*+) + K(+)-ATPase activity in the three peri-ischemic areas, and a significantly reduced loss in the primary infarct tissue. An autoradiographic analysis of brain coronal sections using 3H-ouabain supports the enzymatic data and GM1 effects. Reductions in 3H-ouabain binding in all cortical layers at 3 days after ischemia were visualized. GM1 treatment significantly reduced these 3H-ouabain binding losses. In summary, time-dependent quantitative changes in activity levels of ATPase isozymes (alpha+ and alpha) reflect the different degree of membrane damage that occurs in primary vs. peri-ischemic tissues (e.g., irreversible vs. reversible membrane damage), and that ischemia affects cell membranes of all neural elements in a largely similar fashion. GM1 ganglioside was found to reduce plasma membrane damage in all CNS cell types.

Topics: Animals; Autoradiography; Brain Ischemia; Cell Membrane; Cerebral Cortex; G(M1) Ganglioside; Isoenzymes; Male; Ouabain; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase

Transient forebrain ischemia induced in rats by the four-vessel occlusion method is known to produce severe neural damage in the hippocampus and striatum and a behavioral syndrome the major symptom of which is a working memory deficit. Recent evidence suggests that monosialogangliosides can ameliorate postischemic symptoms. Our purpose was to study the effect of siagoside, the inner ester of GM1 ganglioside, on some behavioral and morphological impairments induced by four-vessel occlusion in rats.. Rats were injected daily with 5 mg/kg i.p. siagoside starting 4 hours after the cerebral ischemia. After 14 days the rats were tested for working memory in a water T maze or scored for apomorphine-induced stereotypy. The rats were killed 21 days after the cerebral ischemia. Histological and computer-assisted morphometric analyses were performed on cresyl violet-stained brain sections, which were graded according to a neuropathologic score, and on sections stained with a monoclonal antiserum against dopamine and cyclic adenosine-3',5'-monophosphate-regulated phosphoprotein, a marker for striatal dopaminoceptive neurons.. Siagoside treatment reduced the stereotypy score induced by low doses of apomorphine and the extent of striatal lesions but did not affect the working memory deficit or the extent of hippocampal lesions.. Daily siagoside treatment after acute cerebral ischemia attenuates some morphological and functional deficits related to striatal damage. These effects can be interpreted as a selective protective action on striatal neural populations or as a modulatory action on neural systems involved in striatal control. These data are consistent with preliminary clinical reports showing that monosialogangliosides enhance motor recovery after acute ischemic stroke.

Topics: Animals; Apomorphine; Behavior, Animal; Brain; Brain Ischemia; Choice Behavior; Corpus Striatum; Dopamine and cAMP-Regulated Phosphoprotein 32; G(M1) Ganglioside; Germ-Free Life; Hippocampus; Male; Memory Disorders; Nerve Tissue Proteins; Phosphoproteins; Prosencephalon; Rats; Rats, Inbred Strains; Stereotyped Behavior

Reports of improved short-term (less than 72 hours) outcome in experimental models of mechanical and ischemic central nervous system injury suggest that exogenous ganglioside administration may confer a protective effect on neural tissue. We studied the effect of the monosialoganglioside GM1 on cerebral infarction and edema in spontaneously hypertensive rats subjected to permanent focal cerebral ischemia.. GM1 or normal saline was injected intramuscularly once a day for 3 days before and 30 and 120 minutes after occlusion of the right middle and common carotid arteries. Following a 24-hour survival period, the volume of infarction was measured by computer-assisted image analysis, and the extent of edema was assessed by measurements of tissue water content and hemispheric volume.. Infarct volume was similar among the GM1-treated (n = 10) and saline-treated (n = 10) rats (212 +/- 10 versus 220 +/- 13 microliters, respectively). In a second series of experiments, the brain water content and edema volume of the ischemic right hemisphere in GM1-treated rats (n = 10) did not differ from saline-treated controls (n = 10).. GM1 ganglioside does not effectively reduce cerebral infarction caused by permanent focal ischemia.

Topics: Animals; Body Water; Brain; Brain Edema; Brain Ischemia; G(M1) Ganglioside; Male; Osmolar Concentration; Rats; Rats, Inbred SHR; Reference Values

Systemic administration of monosialoganglioside GM1 is efficacious in reducing excitatory amino acid (EAA)-related neurotoxicity in vivo following intracerebroventricular injection of N-methyl-D-aspartate (NMDA) in 7-day-old rats. Five days later, NMDA-treated animals showed extensive brain damage which was accompanied by significant decreases in brain weight, choline acetyltransferase activity and 3H-ouabain binding. All these neurotoxic effects were significantly reduced with ganglioside treatment. Since excessive activation of EAAS is implicated in hypoxic-ischemic brain damage, these results favor the hypothesis that a similar effect is involved in the ability of ganglioside to ameliorate outcome following cerebral ischemia.

Topics: Animals; Brain; Brain Damage, Chronic; Brain Ischemia; Choline O-Acetyltransferase; G(M1) Ganglioside; Injections, Intraventricular; N-Methylaspartate; Organ Size; Ouabain; Rats

Topics: Animals; Behavior, Animal; Brain Ischemia; G(M1) Ganglioside; Male; Nervous System Diseases; Rats; Rats, Inbred Strains; Time Factors

The functional consequences of cortical focal ischemia and the effect of monosialoganglioside (GM1) treatment on learning/performance of a spatial reversal task were investigated. Cortical focal ischemia was induced by a permanent occlusion of the left common carotid artery and the ipsilateral middle cerebral artery, with a 1-h clamping of the contralateral carotid artery. Twenty-six rats were randomly assigned to three groups: sham controls, a saline-treated ischemic group, and a GM1 ganglioside-treated ischemic group (10 mg/kg/day: IM). Fifteen days after surgery rats were trained on a spatial reversal task in a two-lever operant chamber where food reward was contingent on lever pressing. Training continued from day 15 to day 21 after surgery. Cortical focal ischemia resulted in learning/performance deficits that were reduced by GM1 ganglioside treatment. The cognitive deficits were characterized by a significantly higher number of nonperseverative errors and number of responses to criterion. There was a significant difference between left and right lever performance in the saline-treated ischemic group, which was absent in shams and GM1-treated ischemic rats. On all measures GM1-treated rats were not different from sham controls.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cognition Disorders; Conditioning, Operant; Food; G(M1) Ganglioside; Male; Psychomotor Performance; Rats; Rats, Inbred Strains; Reversal Learning; Reward; Space Perception

Complete obstruction of the maternal blood flow to fetal rats at 20 days of gestation for a period of 10 min causes a significant shift of approximately 22% in protein kinase C (PKC) activity from a cytosolic to a membrane-bound form in the fetal brain. This translocation can be entirely reversed without losses in activity by a single intraperitoneal injection into the gravid rat of either a mixture of disialo- and trisialoganglioside [polysialoganglioside (PSG)] or by GM1 (50 mg/kg of body weight) given 3 h before onset of the ischemic episode. Cessation of blood flow for 15 min followed by a reperfusion period of 24 h results in a 47% loss in total PKC activity. This down-regulation can be almost entirely prevented upon intraperitoneal administration of GM1 3 h before, but also during and even 90 min after the onset of ischemia. The PSG mixture is also effective, particularly when given 3 h before the insult. Down-regulation of PKC is accompanied by an increase in a Ca2(+)-phosphatidylserine-independent kinase [protein kinase M (PKM)] activity, which rises from 30 pmol/min/mg of protein in control animals to a maximal value of 83.1 pmol/min/mg of protein after 15 min of ischemia and 6 h of reperfusion. By 24 h, PKM activity is 46.8 pmol/min/mg of protein. Administration of GM1 blocks completely the appearance of PKM, a result suggesting that PKC down-regulation and PKM activity elevation are intimately associated events and that both are regulated by GM1 ganglioside.

Topics: Animals; Brain; Brain Ischemia; Down-Regulation; G(M1) Ganglioside; Gangliosides; Protein Kinase C; Rats

In vitro studies have shown that monosialoganglioside GM1 reduces excitatory amino acid-related neurotoxicity by limiting the downstream consequences of abusive excitatory amino acid receptor stimulation. Systemic administration of GM1 appears to be efficacious in reducing acute neuronal damage and in facilitating medium- and long-term functional recovery after brain injury. We propose that GM1 protective effects in the acute injury phase results from attenuation of excitotoxicity, whereas the functional recovery seen at longer term could reflect GM1 potentiation of neuronotrophic factors. The potential therapeutic efficacy of GM1 administration in humans is suggested by clinical studies demonstrating improved neurologic outcome in stroke patients.

Topics: Amino Acids; Animals; Brain; Brain Ischemia; Central Nervous System; G(M1) Ganglioside; Hypoxia, Brain; Neurons

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

An examination was made of the effects of ganglioside GM1 (i.m.) on the losses of membrane fatty acids (palmitic, stearic, oleic, linoleic, and arachidonic), the plasma membrane enzyme Na+, K+-ATPase, and the mitochondrial membrane enzyme Mg2+-ATPase, associated with global ischemia 24 hr after permanent unilateral occlusion of the carotid artery in Mongolian gerbils. While there was a significant loss of fatty acids in saline controls, no loss was detected in membranes from GM1-injected gerbils. Rather, we found an increase in membrane fatty acid content, indicative of altered turnover. A 38% loss of Na+, K+-ATPase and a 36% loss of mitochondrial Mg2+-ATPase observed in membranes from saline controls was reduced in membranes from GM1-injected animals to losses of 15% and 8% respectively. These effects are further described by analyses of enzyme kinetics (apparent Vmax and apparent Km). After 1 week of storage, the activities of both membrane ATPases from saline controls decreased substantially more than from GM1-injected animals, suggesting that the GM1 membranes were better "preserved." Since there was a minimal loss in protein content after 24 hr of ischemia, these results indicate that systemically injected GM1 may protect structure and function of plama membranes during the acute phases of ischemic injury.

Topics: Adenosine Triphosphatases; Animals; Brain Ischemia; Ca(2+) Mg(2+)-ATPase; Cation Transport Proteins; Fatty Acids; G(M1) Ganglioside; Gerbillinae; Male; Mitochondria; Sodium-Potassium-Exchanging ATPase

The effect of the ganglioside GM1 was studied in a focal cerebral ischemia model in 30 cats consisting of 2 hours of middle cerebral artery occlusion followed by 4 hours of recirculation. The cerebrocortical electrical activity, extracellular potassium activity, and microcirculation indicated by NAD/NADH fluorescence were measured during occlusion as well as during recirculation in the core of the middle cerebral artery territory, while the cerebral metabolic rate for glucose (ICMRgl) was measured at the end of recirculation. The cats were classified into either mildly or moderately severe stroke groups based on the depression of the cerebrocortical electrical activity on the occluded side. Of 12 cats with only a mild stroke, six were administered GM1 intravenously 30 minutes after occlusion, while six cats were not treated. Of 12 cats with a moderate stroke, six were treated and six were left untreated. In six additional cats, only a sham insult was undertaken. In the cats with mild stroke, GM1 treatment significantly increased lCMRgl in the peripheral middle cerebral artery territory compared with the untreated cats; for the six treated cats, lCMRgl was normalized toward the control level, whereas it was depressed in the six untreated cats. There were no other significant effects of GM1 treatment on the other measured parameters. A potential protective effect of anesthesia is discussed.

Topics: Anesthesia; Animals; Blood Glucose; Brain; Brain Ischemia; Cats; Cerebral Arteries; Cerebrovascular Circulation; Constriction; G(M1) Ganglioside; Glucose; Halothane; Male; NAD; Oxidation-Reduction; Potassium; Reperfusion

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Brain; Brain Ischemia; Cell Membrane Permeability; G(M1) Ganglioside; Lactates; Male; Rats; Rats, Inbred Strains; Reperfusion; Thromboxane B2

The effect of the ganglioside GM1 on amplitude of the electroencephalogram, neurologic function, and histology has been studied in chronic middle cerebral artery occlusion in cats. Ischemia was produced by a 2-hour occlusion of the left middle cerebral artery and was followed by a 7-day observation period. GM1 was intravenously administered 30 minutes after occlusion and daily during the observation period. Using the reduction in the electroencephalogram amplitude to measure stroke severity, three cats with mild, three cats with moderate, and three cats with severe stroke were treated with 5 mg/kg GM1. Nine cats, three in each group, were treated with 30 mg/kg GM1, while nine cats, three in each group, received middle cerebral artery occlusion but no treatment. In all cats there was a precipitous fall in mean electroencephalogram amplitude during occlusion, followed by a secondary fall during the observation period. Treated cats showed better recovery of electroencephalogram amplitude during the first 4 hours of reperfusion and a smaller secondary fall than untreated cats. Treated cats, especially those treated with 5 mg/kg GM1, showed significant recovery of neurologic deficits compared with untreated cats. Histologic damage was less in treated cats than in untreated cats. Some cats treated with 30 mg/kg GM1 exhibited convulsions, whereas no untreated cat showed any seizure activity. Our findings suggest that gangliosides may improve the recovery of both neurologic deficits and morphologic damage in the central nervous system. These positive effects might be tentatively explained by stimulation of enzymatic activities such as Na+, K+-ATPase and adenyl cyclase.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Cats; Cerebral Arterial Diseases; Chronic Disease; Electroencephalography; G(M1) Ganglioside; Nervous System

Topics: Animals; Brain; Brain Ischemia; Calcium; Cebidae; Cerebrovascular Circulation; Dogs; G(M1) Ganglioside; Hyperemia; Ketoprofen; Potassium; Rats; Time Factors