The Neuroprotective Effect of GM-1 Ganglioside on the Amyloid-Beta-Induced Oxidative Stress in PC-12 Cells Mediated by Nrf-2/ARE Signaling Pathway.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, tau tangles, neuroinflammation, oxidative stress, and progressive memory deficits. Aß deposition could exacerbate oxidative damage and cellular apoptosis. GM-1 ganglioside (GM-1) has previously been reported to exhibit neuroprotective effects in rodents and patients with AD. However, the substantial impacts and mechanism of GM-1 on Aß-induced oxidative stress remain elusive. The present study used PC-12 pheochromocytoma cells treated with Aß25-35 peptide to construct the AD model in vitro. Aß25-35 administration alone inhibited cell viability and facilitated cell apoptosis in the range doses of 10 µM to 30 µM. At the same time, GM-1 supplementation promoted cell proliferation and rescued cell apoptosis in a dose-dependent fashion ranging from 5 to 30 µM. In parallel, GM-1 treatment alleviated Aß-induced oxidative stress by increasing the level of antioxidant enzymes and decreasing the content of malondialdehyde (MDA). The nuclear factor-E2-related factor 2 (Nrf2) is a crucial mediator of antioxidant response. We reported herein that GM-1 could activate Nrf-2 in the PC-12 cells co-treated with Aß25-35, following with the activated expression of antioxidant response elements (ARE)-mediated antioxidant and detoxifying genes. Consistently, knock-down of Nrf-2 via siRNA abolished the beneficial decrease of Aß-induced oxidative stress by GM-1 treatment, indicating that GM-1-improved oxidative stress was regulated by the Nrf-2 signaling pathway. Collectively, GM-1 could alleviate Aß25-35-induced oxidative damage mediated through the Nrf-2/ARE signaling pathway, which might be a potential agent for AD treatment.

Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis.

GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal ß-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline ß-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included ß-galactosidase and virus distribution, histological analysis and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. ß-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal ß-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of ß-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.

Ganglioside-monosialic acid (GM1) for prevention of chemotherapy-induced peripheral neuropathy: a meta-analysis with trial sequential analysis.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect that largely remains an unresolved clinical issue, leading to long-term morbidity. This meta-analysis aimed to evaluate the efficacy and safety of Ganglioside-monosialic acid (GM1) in preventing CIPN. METHODS: Systematic literature searches of PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were performed to identify randomized controlled trials and cohort studies that evaluated the efficacy of GM1 for preventing CIPN. Conventional meta-analysis with a random-effects model and trial sequential analysis (TSA) were performed. RESULTS: A total of five studies involving 868 participants were included. The results showed that GM1 did not reduce the overall incidence of grade ≥ 2 CIPN when the common terminology criteria for adverse events (CTCAE) was used (OR 0.34, 95% CI 0.34-1.11). Subgroup analyses showed that GM1 could not reduce the risk of CTCAE grade ≥ 2 CIPN (OR 0.63, 95% CI 0.35-1.13) and neurotoxicity criteria of Debiopharm (DEB-NTC) grade ≥ 2 CIPN (OR 0.25, 95% CI 0.01-7.10) in oxaliplatin-treated patients, despite that GM1 was associated with a reduced risk of CTCAE grade ≥ 2 CIPN in the taxane subgroup of one study (OR 0.003, 95% CI 0.00-0.05). These results were confirmed by the sub-analysis of randomized controlled trials (RCTs). In TSA, the z-curve for the taxane subgroup crossed the upper trial sequential monitoring boundary (TSMB) but do not reach the required information size (RIS). The z-curves for the oxaliplatin subgroup remained in the nonsignificant area and did not reach the RIS. Further, GM1 did not influence the rate of response to chemotherapy and CTCAE grade ≥ 2 adverse events such as fatigue, nausea, diarrhea, and rash. CONCLUSIONS: GM1 seemed to be well-tolerated and did not influence the anti-cancer effects of chemotherapeutic agents. Although the data did not confirm the effectiveness of GM1 in preventing oxaliplatin-induced peripheral neuropathy, GM1 might be able to prevent taxane-induced peripheral neuropathy. More studies are required in different ethnic populations receiving taxane-based chemotherapy to confirm these findings.

Autophagy-dependent removal of α-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson's disease.

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson's disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg-1·d-1, i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg-1·d-1, i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP+-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12α-Syn A53T) cells, treatment with GM1 ganglioside (40 µM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP+-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12α-Syn A53T cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12α-Syn A53T cells and the MPP+-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.

Cattle Encephalon Glycoside and Ignotin Protects Neurons Against Microglia-Induced Neuroinflammation via Elevating BDNF Expression and Inhibiting TLR4/NF-κB Pathway.

Neuroinflammation is involved in the pathology and progression of Alzheimer's disease (AD) and is closely related to microglial activation. We have previously reported that cattle encephalon glycoside and ignotin (CEGI) could inhibit the activation of microglia in APP/PS1 mice, a mouse model of familial AD. However, the anti-neuroinflammatory mechanisms of CEGI have not yet been fully elucidated. Here, we aimed to investigate the role of CEGI in microglia-mediated neuroinflammation in AD. APP/PS1 mice were treated with CEGI intraperitoneally for 30 days, and then their cognition was assessed. We showed that CEGI alleviated cognitive damage with higher nesting scores, preferential indices, and spontaneous alternation rates in APP/PS1 mice. Moreover, CEGI treatment effectively reduced microglial activation and Iba-1 levels in the cortex of APP/PS1 mice. Additionally, CEGI decreased pro-inflammatory factors production and neuroinflammation-mediated neuronal damage in vivo and in vitro. Finally, CEGI upregulated BDNF levels and downregulated TLR4 and p-NF-κB p65 levels in vivo and in vitro. Taken together, these findings indicated that CEGI could attenuate cognitive deficits in APP/PS1 mice and suppress microglia-induced neuroinflammation via increasing BDNF expression and inhibiting the TLR4/NF-κB pathway.

Pharmacological Manipulation of Trk, p75NTR, and NGF Balance Restores Memory Deficit in Global Ischemia/Reperfusion Model in Rats.

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 "."

Disease-modifying effects of ganglioside GM1 in Huntington's disease models.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L-Ser and D-Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric-like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease-modifying potential in HD.

Enhanced Autophagy Contributes to Protective Effects of GM1 Ganglioside Against Aß1-42-Induced Neurotoxicity and Cognitive Deficits.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The aggregation of Aß peptides, Aß1-42 in particular, is thought to be a fundamental pathogenic mechanism leading to the neuronal damage in AD. Recently, monosialoganglioside GM1 is reported to possess pivotal neuroprotection in neurodegenerative diseases. Previous studies have focused on the conformational dynamics and the biochemical interaction of the amyloid-peptide with the GM1 ganglioside, as well as the protective effect of GM1 on cognition. However, the phenomenon of autophagy with regard to neuronal dysfunction in AD is less investigated. In the present study, GM1 treatment were investigated in an AD mouse model and cultured PC12 dells to examine cognition-protective and neuroprotective effects of GM1. Furthermore, GM1 was found to induce autophagy via testing light chain 3 (LC3), Beclin1, neighbor of BRCA1 gene 1 protein and p62 (a substrate of LC3). Chloroquine, an inhibitor of lysosomal, was used to exclude the interference of lysosome, which could fuse with autophagosome and then clear it. In the presence of the inhibitor of autophagy (3-methyladenine; 3-MA), the protective effect of GM1 on PC12 cells in Aß (1-42) induced toxic conditions was diminished. Interestingly, the expression of histone deacetylase 1 was increased in PC12 cells when treated with GM1, indicating that autophagy might be activated by GM1 through a pathway integrates protein acetylation. This study provides a novel insight into the protective role of GM1 against Aß (1-42)-induced neurotoxicity via enhancing autophagy.

An in vivo study of hypoxia-inducible factor-1α signaling in ginsenoside Rg1-mediated brain repair after hypoxia/ischemia brain injury.

BACKGROUND: Hypoxia/ischemia (HI) brain injury is a common central nervous system insult in newborns. Studies have demonstrated bioactivity of ginsenoside Rg1 in increasing neural viability and promoting angiogenesis. However, there are few reports on roles of Rg1 in brain repair of neonatal HI, and the mechanisms involved are unclear. METHODS: a neonatal HI model was established by a modified Rice-Vannucci model (RVM) and pups received ginsenoside Rg1 or monosialotetrahexosyl ganglioside (GM1) treatment. Neurological function and pathologic damage of rats were evaluated. Cellular apoptosis was detected with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Immunohistochemistry for von willebrand factor (vwf) was used to label micro vessels. Expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and cleaved caspase 3 (CC3) were detected by western blot. RESULTS: Both Rg1 and GM1 reduced neurological impairment and pathologic damage after HI by enhancing neural survival. Rg1, but not GM1, could also facilitate angiogenesis after HI. These pharmacological effects of Rg1 may be attributed to regulation of expression level of VEGF and CC3 and HIF-1α signaling pathway was involved. CONCLUSION: Rg1 plays a neuroprotective role in brain repair following neonatal HI, and HIF-1α is a potential target for therapeutic intervention in neonates with HI brain injury.

Effects of ganglioside G(M1) and erythropoietin on spinal cord lesions in rats: functional and histological evaluations

OBJECTIVE: To evaluate the functional and histological effects of ganglioside G(M1) and erythropoietin after experimental spinal cord contusion injury. METHODS: Fifty male Wistar rats underwent experimental spinal cord lesioning using an NYU-Impactor device and were randomly divided into the following groups, which received treatment intraperitoneally. The G(M1) group received ganglioside G(M1) (30 mg/kg); the erythropoietin group received erythropoietin (1000 IU/kg); the combined group received both drugs; and the saline group received saline (0.9%) as a control. A fifth group was the laminectomy group, in which the animals were subjected to laminectomy alone, without spinal lesioning or treatment. The animals were evaluated according to the Basso, Beattie and Bresnahan (BBB) scale, motor evoked potential recordings and, after euthanasia, histological analysis of spinal cord tissue. RESULTS: The erythropoietin group had higher BBB scores than the G(M1) group. The combined group had the highest BBB scores, and the saline group had the lowest BBB scores. No significant difference in latency was observed between the three groups that underwent spinal cord lesioning and intervention. However, the combined group showed a significantly higher signal amplitude than the other treatment groups or the saline group (p<0.01). Histological tissue analysis showed no significant difference between the groups. Axonal index was significantly enhanced in the combined group than any other intervention (p<0.01). CONCLUSION: G(M1) and erythropoietin exert therapeutic effects on axonal regeneration and electrophysiological and motor functions in rats subjected to experimental spinal cord lesioning and administering these two substances in combination potentiates their effects.

Monossialogangliosídeo transdérmico com laser no tratamento de lesão medular espinal de ratos / Transdermal monosialoganglioside with laser in the treatment of spinal cord lesion in rats

Objetivos: Avaliar os efeitos de monossialogangliosídeos (GM1) administrados com laser por via transdérmica na recuperação da lesão da medula espinal de ratos. Métodos: Quarenta ratos Wistar machos foram submetidos a contusão da medula espinal usando NYU Impactor. No Grupo 1, os ratos receberam 0,2 ml de solução salina diária por via intraperitoneal; no Grupo 2, GM1 foi administrada intraperitonealmente em concentração de 30 mg/kg por dia; no Grupo 3, os ratos foram tratados diariamente com o laser a baixa temperatura sobre a pele, e no Grupo 4, a sessão de laser diária também continha GM1. Todos os grupos foram tratados durante 42 dias. Os animais foram avaliados pela escala funcional de Basso, Baettie e Bresnahan (BBB) nos dias 7, 14, 21, 28, 35 e 42 após a lesão, e por histopatologia e potencial motor evocado 42 dias depois da lesão. Resultados: Os animais do Grupo 4 apresentaram escores BBB mais elevados em comparação com os outros grupos. Não houve diferenças entre os grupos ou nas comparações ao longo do tempo. A avaliação histológica não mostrou diferenças, e tampouco foram encontradas diferenças significativas no potencial evocado. Conclusão: A GM1 associada ao uso de laser a baixa temperatura não mostra resultados superiores no tratamento de lesões da medula espinal de ratos. Nível de Evidência I, Experimental, Estudo Controlado de Animais.

Objectives: To evaluate the effects of monosialoganglioside (gm1) administered transdermally with laser in the recovery of spinal cord injury in rats. methods: forty male wistar rats underwent spinal cord contusion using the nyu impactor. in group 1, the rats received 0,2 ml of saline intraperitoneally daily; in group 2, GM1 was administered intraperitoneally at a concentration of 30 mg/kg per day; in group 3, rats were treated daily with laser at low temperature on the skin, and in group 4, the daily laser session also contained gm1. all the groups were treated for 42 days. the animals were evaluated by the Basso, Baettie and Bresnahan (BBB) functional scale on days 7, 14, 21, 28, 35 and 42 after the injury, and by histopathology and motor evoked potential after 42 days of injury. Results: the animals in group 4 had higher BBB scores compared with the other groups. there were no differences between the groups, or in the comparisons over time. Histological evaluation showed no differences, and no differences were found in the motor evoked potential tests either. conclusion: gm1 associated with the use of low-temperature laser shows no superior functional, neurological or histological results in the treatment of spinal cord lesions in rats. Evidence Level I, Experimental, Controlled, Animal Study.

Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors.

BACKGROUND: Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. METHODS: In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. RESULTS: The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann-Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). CONCLUSION: The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors.

Deficiency of ganglioside GM1 correlates with Parkinson's disease in mice and humans.

Several studies have successfully employed GM1 ganglioside to treat animal models of Parkinson's disease (PD), suggesting involvement of this ganglioside in PD etiology. We recently demonstrated that genetically engineered mice (B4galnt1(-/-) ) devoid of GM1 acquire characteristic symptoms of this disorder, including motor impairment, depletion of striatal dopamine, selective loss of tyrosine hydroxylase-expressing neurons, and aggregation of α-synuclein. The present study demonstrates similar symptoms in heterozygous mice (HTs) that express only partial GM1 deficiency. Symptoms were alleviated by administration of L-dopa or LIGA-20, a membrane-permeable analog of GM1 that penetrates the blood-brain barrier and accesses intracellular compartments. Immunohistochemical analysis of paraffin sections from PD patients revealed significant GM1 deficiency in nigral dopaminergic neurons compared with age-matched controls. This was comparable to the GM1 deficiency of HT mice and suggests that GM1 deficiency may be a contributing factor to idiopathic PD. We propose that HT mice with partial GM1 deficiency constitute an especially useful model for PD, reflecting the actual pathophysiology of this disorder. The results point to membrane-permeable analogs of GM1 as holding promise as a form of GM1 replacement therapy.

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

Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.

Potentializing the effects of GM1 by hyperbaric oxygen therapy in acute experimental spinal cord lesion in rats.

STUDY DESIGN: Experimental, controlled, animal study. OBJECTIVES: To evaluate the effect of GM1 ganglioside, hyperbaric oxygen and both in combination, in the treatment of experimental spinal cord lesions in rats. SETTING: Brazil. METHODS: Thirty-two Wistar rats with spinal cord lesions were divided into four groups: one group received GM1 ganglioside, one was submitted to hyperbaric oxygen therapy (HBOT), the third received both treatments and the fourth received no treatment (control). RESULTS: There were no significant differences between the groups in the histological analysis, for any of the variables (necrosis, hemorrhage, hyperemia, cystic degeneration, P>0.06). Neither were there any significant differences in the comparison of left and right sides in the functional tests (P>0.06 for all). No significant differences were found in the locomotor ratings, in the comparison of groups at 2, 7, 21 and 28 days after the surgical procedure. However, in the evaluation on day 14, group 3, which received the combined therapy, showed a significantly higher Basso Beattie and Bresnahan score than the other groups (P=0.015). CONCLUSION: The therapeutic effect of GM1 in locomotor evaluation of rats submitted to spinal cord lesion is anticipated by HBOT.

Effects of methylprednisolone and ganglioside GM-1 on a spinal lesion: a functional analysis

OBJECTIVES: The pharmacological effects of methylprednisolone (MP) and ganglioside GM-1 on spinal injuries have been thoroughly investigated, but only a few studies have evaluated the interaction between these two drugs. METHODS: Twenty-four Wistar rats were subjected to contusive injury of the spinal cord produced by the NYU system. These animals were divided into four groups: group I was injected with MP; group II was injected with GM-1; group III was injected with MP together with GM-1; and group control received physiological serum. The animals were evaluated with regard to their recovery of locomotive function by means of the BBB test on the second, seventh and fourteenth days after receiving the contusive injury to the spinal cord. They were sacrificed on the fourteenth day. RESULTS: This study demonstrated that the MP and GM-1 groups presented functional results that were better than those of the control group, although the enhanced recovery of group II (GM-1) relative to the control group was not statistically significant (p>0.05). The most notable recovery of locomotive function was observed in the group that received MP alone (p<0.05). The group that received MP together with GM-1 presented results that were better than those of the control group (p<0.05). CONCLUSION: Administration of methylprednisolone alone or with GM-1 was shown to be effective for recovery of locomotive function. Combined administration of these drugs resulted in better outcomes than administration of methylprednisolone alone.

Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin.

PURPOSE: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicity of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant. EXPERIMENTAL DESIGN: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production. RESULTS: Five of six patients at the 30-microg dose and three of five patients at the 10-microg dose mounted IgM responses of 1:80 or greater. These antibodies were confirmed by flow cytometry in seven of eight cases. None of the patients at the 3-microg dose had titers above 1:80. One patient at the 30-microg dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complement-mediated cytotoxicity of tumor cells. CONCLUSIONS: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing fucosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic fucosyl GM1 vaccine at a dose of 30 microg with vaccines against three other antigens-GM2, Globo H, and polysialic acid-to test in patients with SCLC after initial chemotherapy.

Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme.

Five patients with the early-onset form of Alzheimer disease (AD) received GM1 ganglioside by continuous injection into the frontal horns of the lateral ventricles for a period of 12 months. The optimal GM1 dose varied between 20 and 30 mg/24 h. The patients were trained twice a week for 4-5 h with an individually designed cognitive programme, which included the use of a word processor. Neurological, neuropsychological, psychiatric and neurochemical examinations were performed a week before surgery and on days 30, 90, 180, 270 and 365 after surgery. The cerebrospinal fluid levels of the monoamine metabolites homovanillic acid and 5-hydroxyindoleacetic acid and the neuropeptide somatostatin increased. The regional cerebral blood flow showed a tendency to increase. The progression of deterioration was stopped, and motor performance and neuropsychological assessments improved. The patients became more active and felt safer in relation to other people and performing various activities. They had improved reading comprehension and a better feeling for language. They were able to write reports and short letters on a word processor. When interviewed at the end of the study, all 5 patients stated that they felt better, and their relatives reported that they had regained integrity and their joie de vivre.

Recruitment and early treatment in a multicenter study of acute spinal cord injury.

STUDY DESIGN: Post hoc secondary analysis of data from 1992 to 1998 in the trial of Sygen in Acute Spinal Cord Injury. OBJECTIVES: Quasi-epidemiologic understanding of injury and treatment patterns and of recruitment in an SCI trial. No drug efficacy results. SUMMARY OF BACKGROUND DATA: The most recent large epidemiologic study was the National SCI Database by Stover and colleagues around 1980. METHODS: Emphasis on descriptive, rather than inferential, statistics: consistent with secondary analysis. RESULTS: The study involved 760 patients at 28 centers in North America. Cervical injuries were more common than thoracic, and complete injuries were more common than incomplete injuries. Recruitment in the complete cervical stratum was 332, but the incomplete thoracic strata had only 31 patients combined. Vital signs at arrival and on randomization show fair stability. Clock times show more injuries on weekends and nights but suggest immediate attention was given. Elapsed times to treatment (especially EMT and Medevac arrival) are short. The rate of direct admission to tertiary centers, traction weight, and time to surgery vary among centers. Inpatient rehabilitation appeared driven by insurance in addition to severity. CONCLUSIONS: The imbalances in favor of cervical and of complete injuries would make it hard for studies to attain results for SCI in general. The vital signs and time patterns suggest local protocol-driven stabilization to prevent secondary physiologic injury early after SCI. Some features of care vary among centers, but the sparseness of prospective data in specific injury and treatment categories suggests that treatment guidelines have limited empirical support and should be made cautiously.