g(m1)-ganglioside and Brain-Injuries

Gangliosides play important roles in the physiologic operations of the nervous system, in particular that of the brain. Changes in ganglioside composition occur in the mammalian brain not only during development, but also in aging and in several neuropathologic situations. Gangliosides may modulate the ability of the brain to modify its response to signals from the surrounding environment. For example, cultured neurons respond to exogenous gangliosides with changes characteristic of differentiation; these sialoglycosphingolipids also amplify the response of neurons to neurotrophic factors. Additional in vitro studies have shown that monosialogangliosides like GM1 protect against excitatory amino acid-related neurotoxicity by limiting the downstream consequences of receptor overstimulation. Systemic administration of GM1 is efficacious in reducing acute nerve cell damage and in facilitating medium- and long-term functional recovery following various types of injury to the adult mammalian central nervous system. The GM1 protective effects in the acute injury phase likely result, at least in part, from attenuation of excitotoxicity, while long-term functional recovery may reflect GM1 potentiation of neurotrophic factors. The potential therapeutic efficacy of GM1 is encouraged by recent positive clinical findings in acute human stroke, subarachnoid hemorrhage, and spinal cord injury.

Topics: Animals; Brain Injuries; Cell Differentiation; Central Nervous System; G(M1) Ganglioside; Gangliosides; Humans; Neurons; Neurotoxins; Spinal Cord Injuries

Systemic injections of GM1 gangliosides can enhance behavioral recovery from brain damage as measured by a number of cognitive tasks. The functional recovery is not due to GM1-induced alterations in activity, emotional arousal, or heightened sensitivity to mild, noxious stimulation. In addition, the recovery endures long after all treatments are terminated. Although the specific actions by which GM1 treatments facilitate recovery are unknown, evidence does suggest that both anomalous sprouting and protection of neurons from secondary consequences of injury may be involved in the repair process.

Topics: Animals; Avoidance Learning; Brain Damage, Chronic; Brain Injuries; Caudate Nucleus; Escape Reaction; G(M1) Ganglioside; Rats; Reinforcement, Psychology

Developmental lead (Pb) exposure involves various serious consequences, especially leading to neurotoxicity. In this study, we examined the possible role of monosialoganglioside (GM1) in lead-induced nervous impairment in the developing rat. Newborn male Sprague-Dawley rat pups were exposed to lead from birth for 30 days and then subjected to GM1 administration (0.4, 2, or 10 mg/kg; i.p.) or 0.9% saline. The results showed that developmental lead exposure significantly impaired spatial learning and memory in the Morris water maze test, reduced GM1 content, induced oxidative stress, and weakened the antioxidative systems in the hippocampus. However, co-treatment with GM1 reversed these effects. Moreover, GM1 counteracted lead-induced apoptosis by decreasing the expression of Bax, cleaved caspase-3, and by increasing the level of Bcl-2 in a dose-dependent manner. Furthermore, we found that GM1 upregulated the expression of SIRT1, CREB phosphorylation, and BDNF, which underlie learning and memory in the lead-treated developing rat hippocampus. In conclusion, our study demonstrated that GM1 exerts a protective effect on lead-induced cognitive deficits via antioxidant activity, preventing apoptosis, and activating SIRT1/CREB/BDNF in the developing rat hippocampus, implying a novel potential assistant therapy for lead poisoning.

Topics: Animals; Apoptosis; Brain Injuries; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Female; G(M1) Ganglioside; Hippocampus; Lead; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Sirtuin 1

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.. 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.. 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.. 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.

Topics: Animals; Animals, Newborn; Apoptosis; Brain Injuries; Caspase 3; Disease Models, Animal; Female; G(M1) Ganglioside; Ginsenosides; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Ischemia, Brain; Male; Neovascularization, Physiologic; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Signal Transduction; Vascular Endothelial Growth Factor A

To explore the mechanism of apoptosis after traumatic brain injury (TBI) in rats and elucidate the role of GM-1 by detecting the expression of Fas mRNA and apoptosis in hippocampi.. After creating the model of Marmarou cranio-cerebral trauma and offering GM-1 therapy, we observed the expression of Fas mRNA and apoptotic cell death using in situ hybridization and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) technique.. Increased expression of Fas mRNA and increased apoptotic cells in hippocampi after TBI were observed. GM-1 could decrease the expression of Fas mRNA and apoptotic cell death.. The increased expression of Fas mRNA may be a noteworthy cause of apoptotic cell death after traumatic brain injury. GM-1 may play a protective role by way of decreasing the expression of Fas mRNA and apoptotic cell death.

Topics: Animals; Apoptosis; Brain Injuries; fas Receptor; G(M1) Ganglioside; Hippocampus; Neuroprotective Agents; Random Allocation; Rats; RNA, Messenger

To explore the therapeutic approaches and observe their effects on primary traumatic injuries in the brainstem.. A summary analysis of the therapeutic effects was carried out in 126 cases of primary traumas in the brainstem, most of which were given controlled ventilation at early stages of the injury, mild hypothermia, Ca(2+) antagonist and ganglioside GM1 therapy.. Death occurred in 35 cases (27.78 %) within 2 weeks following brain trauma, mainly due to central respiratory failure. Six months after brain trauma, totally 50 deaths (39.68 %) occurred, with 12 cases (9.52 %) lapsing into vegetative state, 11 cases (8.73 %) severely disabled, 17 cases (13.40 %) moderately disabled, and 38 cases (30.16 %) enjoying favorable recovery.. Controlled ventilation at early stages of the injury, mild hypothermia, Ca(2+) antagonist and GM1 therapy can immensely reduce the mortality and disability rate of patients with primary traumas in the brainstem.

Topics: Adolescent; Adult; Aged; Brain Injuries; Brain Stem; Calcium Channel Blockers; Combined Modality Therapy; Female; G(M1) Ganglioside; Humans; Hypothermia, Induced; Male; Middle Aged; Respiration, Artificial; Survival Rate

The Hebb-Williams maze was used to examine spatial abilities of adult male Sprague-Dawley rats with unilateral electrolytic entorhinal cortex lesions. The injured rats were treated for 14 days with either saline or ganglioside GM1. Testing was begun 7 weeks following injury, and involved 12 maze problems with independent configurations, with immediate starting replacement used for the six trials per problem. Compared to sham-operated counterparts, the rats with lesion plus saline treatment were impaired in total number of errors, initial entry errors, and repeat errors over 12 consecutive problems. GM1-treated rats showed improved performance, making significantly fewer total and repeat errors, indicating that this substance may be potentially useful as therapy after entorhinal cortex injury.

Topics: Analysis of Variance; Animals; Brain Injuries; Cues; Disease Models, Animal; Entorhinal Cortex; G(M1) Ganglioside; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Neuronal Plasticity; Neuroprotective Agents; Orientation; Rats; Rats, Sprague-Dawley

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Electroencephalography; Fetal Diseases; Flunarizine; G(M1) Ganglioside; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Ischemic Attack, Transient; Microdialysis; Neuroprotective Agents; Sheep; Spectrophotometry, Infrared

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

Three- and fifteen-month old rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM) were used. In 3-month old rats, 4 days after the lesion a 34 and 33% decrease in high affinity choline uptake (HACU) rate was found in the ipsilateral frontal and parietal cortices, respectively. Twenty-one days later the lesioned rats showed a loss in the NBM choline acetyltransferase (ChAT)-positive cells, a marked decrease in ipsilateral cortical ChAT activity and an impairment of the acquisition of a passive avoidance conditioned response. If the lesioned rats received nerve growth factor (NGF) (10 micrograms i.c.v.) twice a week or daily administration of ganglioside GM1 (GM1) (30 mg/kg i.p.), beginning immediately after surgery, the decreases in the HACU rate and ChAT activity were significantly smaller and the behavioral performance was normal. A potentiation by GM1 of NGF effects on the cholinergic neurons of the NBM occurred since no differences were detected between sham-operated rats and rats trated with NGF plus either the active (30 mg/kg) or inactive (10 mg/kg) dose of GM1. The loss in the number of NBM ChAT-positive neurons was reduced by GM1 or prevented by NGF administrations, indicating that the two drugs prevent the cholinergic deficit by protecting the cholinergic neurons of the NBM from ibotenic acid neurotoxicity. GM1 had no effect on ChAT activity decrease and behavioral impairment in 15-month old rats. The latter finding indicates an age-related loss of the ability of GM1 to enhance neurotrophic activity in the NBM.

Topics: Animals; Brain Injuries; Cerebral Cortex; Choline; Choline O-Acetyltransferase; G(M1) Ganglioside; Male; Nerve Growth Factors; Neurons; Rats; Rats, Inbred Strains; Substantia Innominata

Cholinergic neurons of the forebrain respond trophically to nerve growth factor (NGF) in some experimental circumstances. The cholinergic cell system of the nucleus basalis magnocellularis (NBM) which projects to the cortex shows signs of cellular degeneration following limited devascularizing cortical lesions, while no apparent damage is observed in the remaining ipsilateral cortex. These cholinergic cells possess receptors for NGF and the administration of this peptide into the cerebroventricular space prevents cell shrinkage and loss of activity of the biosynthetic enzyme for acetylcholine, choline acetyltransferase (ChAT). Analogous trophic responses can be elicited in this system with the application of the sialoganglioside GM1. In addition, GM1 can increase the effects of NGF on ChAT activity in lesioned neurons of the NBM-to-cortex model system described above. This cooperative interaction is observed even when ineffective doses of GM1 are administered. Furthermore, an interaction between these two putative neurotrophic substances has been noted over other cholinergic parameters such as cortical high affinity choline uptake (HACU). These studies confirm the idea that trophic factors can be utilized to rescue degenerating neurons of the CNS and, in addition, lend support to the concept that gangliosides can facilitate actions of endogenously produced trophic factors.

Topics: Animals; Brain Injuries; Cerebral Cortex; Choline O-Acetyltransferase; Corpus Striatum; G(M1) Ganglioside; Nerve Growth Factors; Rats

In mature rats with unilateral cortical lesions, choline acetyltransferase activity was found to decrease by 40% in the ipsilateral nucleus basalis magnocellularis, compared with control animals. Intraventricular administration of the monosialoganglioside GM1 (5 mg/kg per day), via minipumps, over a period of 14 days prevented this fall in choline acetyltransferase activity. The activity of this enzyme in the sham operated subjects was not significantly different from that in the unoperated group. This biochemical data is in full agreement with regards to the protective action of monosialoganglioside GM1 on forebrain cholinergic neurons. In this study the behavioral effects of these cortical lesions were investigated for the first time. Results show that these lesions, with their associated retrograde neuronal degenerative effects, altered a variety of sensorimotor and memory-based behaviors. In particular, the limited unilateral devascularization of the neocortex increased baseline locomotor activity above control; affected motor coordination; impaired passive avoidance retention and reacquisition; and decreased the retention of learnt Morris water-maze information. Infusion of the monosialoganglioside into the ventricles, whilst having no effect on the increased motor activity or motor coordination deficit, did enhance the reacquisition of information in both memory-related tasks.

Topics: Animals; Brain Injuries; Choline O-Acetyltransferase; G(M1) Ganglioside; Injections, Intraventricular; Male; Memory Disorders; Movement Disorders; Rats; Rats, Inbred Strains

Topics: Afferent Pathways; Animals; Brain Injuries; Cell Survival; Corpus Striatum; Denervation; Dopamine; Drug Interactions; G(M1) Ganglioside; Nerve Growth Factors; Nerve Tissue Proteins; Neuronal Plasticity; Rats; Substantia Nigra; Tyrosine 3-Monooxygenase

Administration of exogenous gangliosides has been reported to accelerate neurite outgrowth in vitro, and to enhance peripheral nerve regeneration and central nervous system recovery subsequent to damage. After injury, facilitation of CNS recovery with GM1 ganglioside treatment has been postulated to be due to enhanced neuronal regeneration. Since maximal recovery is achieved when experimental animals are treated before injury with GM1 ganglioside, an alternative or parallel mechanism is that gangliosides are "protecting" the CNS by limiting the extent of damage (ie, cell loss, process degeneration, membrane disruption). This may be due to a reduction in the edema subsequent to injury. In this study, rats were treated for 2 days with 20 mg/kg/day of GM1 ganglioside. On the third day they were subjected to a unilateral lesion (mechanical) of one cerebral hemisphere and given another 20 mg/kg of GM1. On the fourth day brains were removed for analysis of edema resulting from the injury. In treated animals there was a significant reduction in edema as measured either in the entire injured hemisphere (23%) or in the area of injury (33%). No effect was seen outside the damaged area. Since exogenous gangliosides can spontaneously "insert" into membranes, it is postulated that the effect of the GM1 may be due to alterations of membrane processes (eg, lipid hydrolysis, phospholipase activation, levels and membrane action of arachidonic acid, ionic permeation) that are characteristic of edema.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain Edema; Brain Injuries; Cell Membrane; G(M1) Ganglioside; Gangliosides; Male; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase

Injections of GM1-gangliosides (30 mg/kg, i.p.) in adult rats were shown to reduce behavioral deficits after brain lesions. This was observed (1) after bilateral electrolytic lesions of the caudate nucleus in a learning task involving negative reinforcement; (2) following aspiration lesions of the mediofrontal cortex in a learning task involving positive reinforcement; and (3) when rotational behavior was assessed after amphetamine or apomorphine injections in animals with partial hemitransections of the nigro-striato-nigral fibers. A detailed anatomical analysis of the latter study, using a retrograde tract-tracing dye wheat germ agglutinin-horseradish peroxidase (WGA-HRP), provided evidence for ganglioside-stimulated, neuronal reorganization of connections to the caudate nucleus. Our findings support the notion that gangliosides reduce behavioral deficits following brain injury by preventing secondary neuronal degeneration and/or enhancing structural reorganization of remaining afferents, rather than by influencing denervation supersensitivity.

Topics: Animals; Brain Injuries; Caudate Nucleus; Corpus Striatum; Frontal Lobe; G(M1) Ganglioside; Gangliosides; Humans; Learning Disabilities; Male; Movement Disorders; Neural Pathways; Rats; Substantia Nigra

Adult rats with bilateral lesions of the caudate nucleus were treated with GM1 ganglioside. Although animals injected with a control solution were severely impaired in their ability to learn a complex spatial task, those treated with ganglioside were able to learn spatial reversals.

Topics: Animals; Behavior, Animal; Brain Injuries; Caudate Nucleus; G(M1) Ganglioside; Gangliosides; Humans; Learning; Male; Rats; Rats, Inbred Strains

The effect of GM1 ganglioside on the recovery of dopaminergic nigro-striatal neurons was studied in rats after unilateral hemitransection. GM1 treatment favoured the collateral sprouting of dopaminergic axons in the striatum as indicated by the induced increase of tyrosine hydroxylase (TH) activity and immunofluorescence. Concomitantly GM1 partially prevented the decrease of TH activity caused by the hemitransection in the substantia nigra ipsilateral to the lesion. A significant increase of TH immunoreactivity was also detected in the substantia nigra: GM1 prevented the disappearance of TH-positive cell bodies and increased the formation of TH-positive collaterals and dendrites with respect to the saline treatment. The addition of GM1 to embryonic dissociated mesencephalic cell cultures stimulates the expression of dopaminergic characteristics as suggested by the increase of 3H-DA uptake.

Topics: Animals; Brain; Brain Injuries; Cell Differentiation; Corpus Striatum; Dopamine; G(M1) Ganglioside; Gangliosides; Nerve Regeneration; Neurons; Rats; Spinal Cord Injuries

Reports indicate that exogenous gangliosides can accelerate neurite outgrowth in vitro and facilitate peripheral nerve regeneration in vivo. An experiment was designed to assess whether ganglioside administration alters functional recovery and neuronal regeneration after a CNS lesion. Rats trained on an alternation behavior and subjected to a unilateral entorhinal cortical lesion were given daily (i.m.) injections of either total brain ganglioside or GM1 ganglioside. Results show that ganglioside administration reduces the extent of behavioral deficit caused by the lesions and facilitated the course of functional recovery. It is hypothesized that gangliosides are enhancing hippocampal sprouting which occurs subsequent to the entorhinal lesion.

Topics: Animals; Brain Injuries; Cerebral Cortex; Conditioning, Psychological; G(M1) Ganglioside; Gangliosides; Learning; Male; Motor Activity; Rats; Rats, Inbred Strains