g(m1)-ganglioside and Reperfusion-Injury

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

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

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

To investigate the protective effect of monosialoganglioside (GM1) on injury induced by oxygen glucose deprivation/reperfusion (OGD/Rep) in rat hippocampal slices.. The protective effects of GM1 on hippocampal slices after OGD/Rep were observed by detecting the light transmittance (LT) changes of rat hippocampal slices and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining of rat hippocampal slices.. (1) In four groups treated with 0 (control), 0.1, 1.0, 10 micromol/L GM1, the peak of light transmittance (LT) in the slices treated with 1.0 micromol/L GM1 was significantly lower than that of the control and the group treated with 0.10 micromol/L GM1 (P < 0.01, ANOVA), while the peak of LT in the slices treated with 10.0 micromol/L GM1 was significantly lower than that of the other groups (P < 0.01, ANOVA). The time to reach the peak of LT in four groups was significantly different from each other (P < 0.05, Kruskal-Wallis test). The time to reach the peak of LT in the group treated with 1 micromol/L GM1 was the significantly longer than that in the control (P < 0.01, Mann-Whitney U test). (2) There was characteristic dose-response relationship between GM1 and TTC staining of rat hippocampal slices. In the five groups, treated with 0 (control), 0.01, 0.1, 1.0, 10 micromol/L GM1 respectively, TTC staining in the group treated with 1 micromol/L GM1 was the deepest (P < 0.05 vs. control, 0.01 and 0.1 micromol/L GM1 group, ANOVA), and the next was in the group treated with 10 micromol/L GM1 (P < 0.05 vs. control and 0.01 micromol/L GM1 group, ANOVA).. GM1 could protect injury induced by OGD/Rep in rat hippocampal slices effectively in vitro.

Topics: Animals; G(M1) Ganglioside; Glucose; Hippocampus; Hypoxia; In Vitro Techniques; Male; Oxygen; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Gangliosides are normal components of cell membranes and contribute to structural rigidity and membrane function. They have been shown to protect against various insults in the brain. We have shown previously that GM1 administered intraperitoneally before the induction of retinal ischemia provides a protective effect. This study evaluates the protective effect of GM1 administered intravitreally after ischemia on retinal lesions.. We induced retinal ischemia unilaterally in Long-Evans rats by increasing intraocular pressure to 160 mm Hg for 60 minutes. GM1 (20 microL x 10(-5) mol/L) or saline (20 microL) was injected into the vitreous 15 minutes after ischemia, and the postischemic survival time was either 8 or 15 days. The degree of retinal damage was assessed by histopathological study.. Retinal ischemia led to reductions in thickness and cell number, principally in the inner retinal layers (39% to 80%) and to a lesser extent in the outer retinal layers (26% to 45%). Postischemic treatment with intravitreally injected GM1 conferred significant protection against retinal ischemic damage after both 8 and 15 days of survival time. After 8 days of reperfusion, the ischemia-induced loss in overall retinal thickness was reduced by 15% and those of the inner nuclear and plexiform layers by 44% and 17%, respectively. Ischemic-induced ganglion cell and inner nuclear cell density losses were reduced by 37% and 27%, respectively. After 15 days of reperfusion, approximately the same statistically significant differences could be observed in comparison with the 15-day saline-injected group.. GM1 protects the rat retina from pressure-induced ischemic injury when given intravitreally after the insult. The protection provided by GM1 after initiation of retinal damage could be of therapeutic interest.

Topics: Animals; Disease Models, Animal; Eye; G(M1) Ganglioside; Neuroprotective Agents; Rats; Rats, Inbred Strains; Reperfusion Injury; Retina; Sodium Chloride; Time Factors; Vitreous Body

Gangliosides are normal components of cell membranes, contribute to structural rigidity and membrane function, and have been shown to protect against various insults to the brain. This study evaluates the effect of exogenously administered monosialoganglioside GM1 on retinal damage induced by transient retinal ischemia and reperfusion.. Retinal ischemia was induced unilaterally in Long Evans rats by increasing intraocular pressure to 160 mm Hg for 60 minutes. GM1 (30 mg/kg, intraperitoneally) or buffer controls were administered at 48 hours, and 15 minutes before ischemia, and survival time after ischemia was either 8 or 15 days. The degree of retinal damage was assessed by histopathologic study according to Hughes' quantification of ischemic damage.. Retinal ischemia led to significant reductions in thickness and cell number, principally in the inner retinal layers (30% to 80%), and to a lesser extent in the outer retinal layers (18% to 42%). Pretreatment with intraperitoneally injected monosialoganglioside GM1 conferred significant protection against retinal ischemic damage either 8 or 15 days after ischemic survival time. After 8 days reperfusion, the ischemic-induced loss in overall retinal thickness was reduced by 70%, and those of the inner nuclear and plexiform layers were reduced by 77% and 44%, respectively. Ischemic-induced ganglion cell, inner nuclear, and outer nuclear layer cell density losses were reduced by 45%, 40%, and 57%, respectively. After 15 days of reperfusion, approximately the same statistically significant differences could be observed in comparison with the 15-day ischemic--reperfusion group.. Monosialoganglioside GM1 protects the rat retina from pressure-induced ischemic injury when administered intraperitoneally 2 days before insult. This protection afforded by GM1 can be observed even after 8 days or 15 days of reperfusion.

Topics: Animals; Apoptosis; Cell Count; Cell Death; Disease Models, Animal; G(M1) Ganglioside; Injections, Intraperitoneal; Ischemia; Rats; Reperfusion; Reperfusion Injury; Retina; Retinal Artery; Retinal Diseases

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

The present study was designed to investigate the possible participation of Kupffer cells in the development of reperfusion injury of the cold-stored liver graft. In the cold preservation of Kupffer cells with Euro-Collins solution, the proportion of asialo-GM1-positive cells was significantly increased at 12 and 24 hr of storage, and the TNF alpha-producing activity in these cells was approximately fivefold greater than control. Northern blot analysis demonstrated that TNF alpha mRNA was remarkably elevated in the reperfusion of the cold-preserved liver, although that of the prereperfused graft was only slightly induced. The reperfusion experiments of the cold-stored liver graft showed that addition of anti-TNF alpha antibody to the perfusate suppressed the elevation of the effluent levels of GOT and LDH significantly, and that pretreatment with a Kupffer cell inhibitor, gadolinium chloride, inhibited the increase of these enzymes in the effluents almost completely. Histological study revealed deposition of a fibrinlike substance in the sinusoid and the central veins extensively in the reperfused liver graft, whereas no apparent deposition was observed in the gadolinium-pretreated liver. Thus, the present study showed that Kupffer cells were primed by cold preservation with Euro-Collins solution, and then activated when the reperfusion was done. It seems likely that the Kupffer cell activation induced by cold preservation/reperfusion plays a major role in reperfusion injury with sinusoidal microcirculatory disturbance, and that TNF alpha is responsible for the impairment of the reperfused liver graft.

Topics: Alanine Transaminase; Animals; Antibodies; Cell Survival; Cold Temperature; G(M1) Ganglioside; Kupffer Cells; L-Lactate Dehydrogenase; Liver; Organ Preservation; Rats; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

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