g(m1)-ganglioside and Nerve-Degeneration

To investigate the pathophysiological role of anti-GM1 antibody in Guillain-Barré syndrome (GBS), we reviewed sequential nerve conduction studies of 345 nerves in 34 GBS patients. Statistically significant correlation between IgG anti-GM1 antibodies and electrodiagnoses was found. Sixteen IgG anti-GM1-positive patients were classified as having acute motor or acute motor sensory axonal neuropathy (AMAN or AMSAN) (12 patients), as having acute inflammatory demyelinating polyneuropathy (AIDP) (3 patients), or as undetermined (1 patient) by electrodiagnostic criteria. Besides axonal features, there was rapid resolution of conduction slowing and block. In 3 patients initially diagnosed as having AIDP, conduction slowing was resolved within days, and 1 of them and 3 AMAN patients showed markedly rapid increases in amplitudes of distal compound muscle action potentials that were not accompanied by prolonged duration and polyphasia. The time courses of conduction abnormalities were distinct from those in IgG anti-GM1-negative AIDP patients. Rapid resolution of conduction slowing and block, and the absence of remyelinating slow components, suggest that conduction failure may be caused by impaired physiological conduction at the nodes of Ranvier. Reversible conduction failure as well as axonal degeneration constitutes the pathophysiological mechanisms in IgG anti-GM1-positive GBS. In both cases, immune-mediated attack probably occurs on the axolemma of motor fibers.

Topics: Adult; Axons; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Male; Middle Aged; Nerve Degeneration; Neural Conduction; Polyradiculoneuropathy

Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S-/- mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior.

Topics: Animals; Anxiety; G(M1) Ganglioside; Gene Deletion; Inflammation; Kainic Acid; Memory; Mice; Motor Activity; Nerve Degeneration; Neuraminidase; Neuroprotective Agents; Neurotoxins; Sialyltransferases; Skull; Vibrio cholerae

Monosialotetrahexosy-1 ganglioside (GM1) has been shown to reduce brain damage induced by cerebral ischemia. The objective of this study is to determine whether GM1 is able to ameliorate hyperglycemia-exacerbated ischemic brain damage in hyperglycemia-recruited areas such as the hippocampal CA3 sub regions and the cingulated cortex. Histologic stainings of Haematoxylin and Eosin, Nissl body, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and phospho-ERK1/2 were performed on brain sections that have been subjected to 15 min of forebrain ischemia with reperfusion of 0, 1, 3, and 6h in normoglycemic, hyperglycemic and GM1-pretreated hyperglycemic groups. The results showed that GM1 ameliorated ischemic neuronal injuries in the CA3 area and cingulated cortex of the hyperglycemic animals after ischemia and reperfusion. Immunohistochemistry of phospho-ERK1/2 revealed that the neuroprotective effects of GM1 were associated with suppression of phospho-ERK1/2. The results suggest that GM1 attenuates diabetic-augmented ischemic neuronal injuries probably through suppression of ERK1/2 phosphorylation.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; G(M1) Ganglioside; Hippocampus; Hypoxia, Brain; In Situ Nick-End Labeling; Male; Mitogen-Activated Protein Kinase 3; Nerve Degeneration; Neurons; Neuroprotective Agents; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Streptozocin; Time Factors

The mechanism underlying plaque-independent neuronal death in Alzheimer disease (AD), which is probably responsible for early cognitive decline in AD patients, remains unclarified. Here, we show that a toxic soluble Abeta assembly (TAbeta) is formed in the presence of liposomes containing GM1 ganglioside more rapidly and to a greater extent from a hereditary variant-type ("Arctic") Abeta than from wild-type Abeta. TAbeta is also formed from soluble Abeta through incubation with natural neuronal membranes prepared from aged mouse brains in a GM1 ganglioside-dependent manner. An oligomer-specific antibody (anti-Oligo) significantly suppresses TAbeta toxicity. Biophysical and structural analyses by atomic force microscopy and size exclusion chromatography revealed that TAbeta is spherical with diameters of 10-20 nm and molecular masses of 200-300 kDa. TAbeta induces neuronal death, which is abrogated by the small interfering RNA-mediated knockdown of nerve growth factor receptors, including TrkA and p75 neurotrophin receptor. Our results suggest that soluble Abeta assemblies, such as TAbeta, can cause plaque-independent neuronal death that favorably occurs in nerve growth factor-dependent neurons in the cholinergic basal forebrain in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Death; Cells, Cultured; G(M1) Ganglioside; Humans; Liposomes; Mutation; Nerve Degeneration; Neurons; Rats; Rats, Sprague-Dawley; Receptor, Nerve Growth Factor; Receptor, trkA; RNA Interference

The present study investigated cerebrospinal fluid (CSF) biomarkers for estimating degeneration of the central nervous system (CNS) in experimental dogs with GM1 gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 gangliosidosis using the biomarkers identified here. GM1 gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid beta-galactosidase activity. Pathogenesis of GM1 gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 gangliosidosis.

Topics: Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Biomarkers; Brain; Cerebrospinal Fluid Proteins; Disease Models, Animal; Dogs; G(M1) Ganglioside; Gangliosidosis, GM1; L-Lactate Dehydrogenase; Myelin Basic Protein; Nerve Degeneration; Phosphopyruvate Hydratase; Predictive Value of Tests; Prednisolone; Treatment Outcome; Up-Regulation

Previous studies have shown that electrical stimulation of the cochlea by a cochlear implant promotes increased survival of spiral ganglion (SG) neurons in animals deafened early in life (Leake et al. [1999] J Comp Neurol 412:543-562). However, electrical stimulation only partially prevents SG degeneration after deafening and other neurotrophic agents that may be used along with an implant are of great interest. GM1 ganglioside is a glycosphingolipid that has been reported to be beneficial in treating stroke, spinal cord injuries, and Alzheimer's disease. GM1 activates trkB signaling and potentiates neurotrophins, and exogenous administration of GM1 has been shown to reduce SG degeneration after hearing loss. In the present study, animals were deafened as neonates and received daily injections of GM1, beginning either at birth or after animals were deafened and continuing until the time of cochlear implantation. GM1-treated and deafened control groups were examined at 7-8 weeks of age; additional GM1 and no-GM1 deafened control groups received a cochlear implant at 7-8 weeks of age and at least 6 months of unilateral electrical stimulation. Electrical stimulation elicited a significant trophic effect in both the GM1 group and the no-GM1 group as compared to the contralateral, nonstimulated ears. The results also demonstrated a modest initial improvement in SG density with GM1 treatment, which was maintained by and additive with the trophic effect of subsequent electrical stimulation. However, in the deafened ears contralateral to the implant SG soma size was severely reduced several months after withdrawal of GM1 in the absence of electrical activation.

Topics: Age Factors; Animals; Cats; Cell Differentiation; Cell Survival; Cochlea; Cochlear Implants; Deafness; Electric Stimulation; Evoked Potentials, Auditory; G(M1) Ganglioside; Neomycin; Nerve Degeneration; Neurons; Neurons, Afferent; Spiral Ganglion

Ethanol exposure induces apoptotic neurodegeneration in the developing rodent brain during synaptogenesis. This process has been studied as a model for fetal alcohol syndrome. Previously, we have shown that gangliosides and LIGA20 (a semisynthetic derivative of GM1 ganglioside) attenuate ethanol-induced apoptosis in cultured neurons. In the present study, the effects of GM1 and LIGA20 on ethanol-induced apoptotic neurodegeneration were examined using an in vivo neonatal mouse model.. Seven-day-old C57BL/6By (B6By) mice were pretreated twice with intraperitoneal administration of GM1 (30 mg/kg), LIGA20 (2.5 mg/kg), or saline, followed by subcutaneous injection of either saline or ethanol (2.5 g/kg) twice with a 2 hours interval. Then the brains were: (1) perfusion-fixed 24 hours after the first ethanol injection, and the extent of neurodegeneration was assessed by cupric silver staining of the brain sections, or (2) perfusion-fixed 8 hours after the first ethanol injection, and the sections were immunostained with anti-cleaved (activated) caspase-3 antibody to evaluate caspase-3 activation.. The comparison of cupric silver stained coronal sections indicates that ethanol-induced widespread neurodegeneration in the forebrains of B6By mice was reduced overall by GM1 and LIGA20 pretreatments. The extent of neurodegeneration detected by silver impregnation and activated caspase-3 immunostaining was quantified in the cingulate and retrosplenial cortices, which were the regions most severely affected by ethanol. The results indicate that GM1 and LIGA20 pretreatments induced statistically significant reductions-approximately 50% of the ethanol-treated samples-in silver impregnation and activated caspase-3 immunostaining. No significant differences were observed between saline controls and samples treated with GM1 or LIGA20 alone.. These results indicate that GM1 and LIGA20, which have been shown to be neuroprotective against insults caused by various agents, partially attenuate ethanol-induced apoptotic neurodegeneration in the developing mouse brain.

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Caspase 3; Central Nervous System Depressants; Enzyme Activation; Ethanol; Fluorescent Antibody Technique; G(M1) Ganglioside; Gangliosides; Mice; Mice, Inbred C57BL; Nerve Degeneration; Perfusion; Silver Staining; Sphingosine; Tissue Fixation

The expression of ganglioside-mimicking structures of Campylobacter jejuni lipooligosaccharides (LOS) is considered essential for the induction of antiganglioside antibodies that lead to Guillain-Barré syndrome (GBS). The galE gene in C. jejuni is involved in the biosynthesis of the LOS outer-core oligosaccharide structures. We have demonstrated that the C. jejuni HB9313 (HS:19) parental strain expresses a LOS structure containing GM1-like epitopes, and the C. jejuni knockout mutant of the galE gene expresses a truncated LOS structure without GM1-like epitopes. To clarify whether the ganglioside-like structures in Campylobacteri LOS are crucial for induction of antiganglioside antibody responses and neuropathy, we performed immunization experiments in guinea pig models using the parental strain HB9313 and its galE mutant derivative. The anti-GM1 IgG antibody responses in immunized animals were measured by enzyme-linked immunosorbent assay. Sciatic nerve specimens were evaluated pathologically. High levels of the anti-GM1 IgG antibody were induced in guinea pigs immunized with HB9313, but not in those immunized with the galE mutant. The mean percentage of abnormality of sciatic-nerve teased fibers from animals sensitized with C. jejuni HB9313 was significantly higher than from animals immunized with the galE mutant. Furthermore, significant changes were found in semithin sections of the sciatic nerve from animals inoculated with C. jejuni HB9313. The major pathological finding was axonal degeneration; no significant morphological findings, except for occasional demyelination, were observed in animals immunized with the galE mutant. These results indicate that ganglioside-mimicry structures in C. jejuni LOS are necessary for induction of antiganglioside antibody response and neuropathy.

Topics: Animals; Autoantibodies; Bacterial Proteins; Blotting, Western; Campylobacter jejuni; Electrophoresis, Polyacrylamide Gel; Epitopes; Female; G(M1) Ganglioside; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Guillain-Barre Syndrome; Guinea Pigs; Immunoglobulin G; Lipopolysaccharides; Molecular Mimicry; Nerve Degeneration; Nerve Fibers, Myelinated; Sciatic Nerve; UDPglucose 4-Epimerase

Topics: Autoantibodies; Axons; Campylobacter Infections; Campylobacter jejuni; Female; G(M1) Ganglioside; Humans; Middle Aged; Motor Neurons; Nerve Degeneration; Neural Conduction; Peripheral Nervous System Diseases

Hippocampal neurogenesis is thought to play a functional role in hippocampal-dependent learning and memory. The neurogenic capability of the hippocampus declines with age and may be associated with a decline in cognitive function. In the present study, an established model of ageing in mice was used to test the protective effects of GM1 ganglioside on hippocampal neurogenesis. This model uses D-galactose treatment to cause neuronal injury and reduced neurogenesis. GM1 significantly increased the proliferation, long-term survival and neuronal differentiation of hippocampal progenitors that had been injured with D-galactose. This study demonstrates that GM1 can protect hippocampal neurogenesis from D-galactose injury. Therefore, GM1 may protect neurogenesis in the ageing brain.

Topics: Analysis of Variance; Animals; Bromodeoxyuridine; Cell Count; Cell Death; Cell Proliferation; Disease Models, Animal; Doublecortin Domain Proteins; G(M1) Ganglioside; Galactose; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Nerve Degeneration; Neuropeptides; Neuroprotective Agents; Phosphopyruvate Hydratase; Random Allocation; Regeneration

Pathological studies, including novel teased peripheral nerve fiber studies, were performed in a patient who presented with a rapidly progressive, lower motor neuron syndrome and high titer of immunoglobulin M anti-GM1 ganglioside antibody. In the central nervous system, there was a severe loss of motor neurons and central chromatolysis with ubiquitin immunopositive cytoplasmic inclusions in residual motor neurons. In the peripheral nervous system, axonal degeneration of myelinated fibers in the anterior nerve roots was evident. Pathologic evidence of sensory nerve involvement was also found despite the absence of clinical or electrophysiological sensory abnormalities. Sectional studies of single myelinated nerve fibers from an antemortem sural nerve biopsy showed remyelination and globular paranodal swellings due to focal complex myelin folding and degeneration in 13% of fibers. Postmortem studies of the sural nerves 4 weeks later showed paranodal demyelination (90% of fibers), but no paranodal swellings and similar findings were present in samples of the ulnar, radial, median, tibial, and common peroneal nerves. Paranodal abnormalities of enlargement of the adaxonal space, myelin degeneration, and axonal compaction were found on cross-sectional studies of individual teased fibers, which on conventional light microscopic assessment appeared normal. These changes suggest a disturbance of paranodal axonal-myelin adhesion due to binding of the anti-GM1 ganglioside antibody to the common epitope known to be present on the myelin sheath and nodal axolemma in the paranodal region of both motor and sensory nerves.

Topics: Adult; Central Nervous System; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Microscopy, Electron; Motor Neuron Disease; Myelin Sheath; Nerve Degeneration; Peripheral Nervous System

Immune responses against gangliosides are strongly implicated in the pathogenesis of some variants of Guillain-Barré syndrome (GBS). For example, IgG antibodies against GM1, GD1a, and related gangliosides are frequently present in patients with post-Campylobacter acute motor axonal neuropathy (AMAN) variant of GBS, and immunization of rabbits with GM1 has produced a model of AMAN. However, the role of anti-ganglioside antibodies in GBS continues to be debated because of lack of a passive transfer model. We recently have raised several monoclonal IgG anti-ganglioside antibodies. We passively transfer these antibodies by intraperitoneal hybridoma implantation and by systemic administration of purified anti-ganglioside antibodies in mice. Approximately half the animals implanted with an intraperitoneal clone of anti-ganglioside antibody-secreting hybridoma developed a patchy, predominantly axonal neuropathy affecting a small proportion of nerve fibers. In contrast to hybridoma implantation, passive transfer with systemically administered anti-ganglioside antibodies did not cause nerve fiber degeneration despite high titre circulating antibodies. Blood-nerve barrier studies indicate that animals implanted with hybridoma had leaky blood-nerve barrier compared to mice that received systemically administered anti-ganglioside antibodies. Our findings suggest that in addition to circulating antibodies, factors such as antibody accessibility and nerve fiber resistance to antibody-mediated injury play a role in the development of neuropathy.

Topics: Animals; Antibodies, Monoclonal; Antibody Formation; Blood-Brain Barrier; Blotting, Western; Capillary Permeability; Disease Models, Animal; G(M1) Ganglioside; Gangliosides; Hybridomas; Immunoglobulin G; Immunohistochemistry; Ki-67 Antigen; Male; Mice; Mice, Inbred Strains; Nerve Degeneration; Peripheral Nerves; Peripheral Nervous System Diseases; Species Specificity; Spinal Cord

GM1-ganglioside (GM1) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of GM1 due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease GM1-gangliosidosis, but whether the accumulation of GM1 is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis. GM1 loading of wild-type neurospheres recapitulated the phenotype of beta-gal-/- cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal-/-/GalNAcT-/-, which do not accumulate GM1. These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid GM1 and this causes a novel mechanism of neuronal apoptosis.

Topics: Animals; Animals, Newborn; Apoptosis; beta-Galactosidase; Calcium; Caspase 12; Caspases; CCAAT-Enhancer-Binding Proteins; Cell Death; Cells, Cultured; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; G(M1) Ganglioside; Gangliosidosis, GM1; Heat-Shock Proteins; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinases; Molecular Chaperones; N-Acetylgalactosaminyltransferases; Nerve Degeneration; Neurons; Polypeptide N-acetylgalactosaminyltransferase; Protein Folding; Transcription Factor CHOP; Transcription Factors

This study examined the combined effects of administration of exogenous GM1 ganglioside and electrical stimulation on the cochlear nucleus (CN) of cats deafened neonatally by ototoxic drugs. Five normal hearing adult cats served as controls. Another 12 cats were deafened bilaterally by daily injections of neomycin sulfate (60 mg/kg) for 17-21 days after birth until auditory brainstem testing demonstrated profound hearing loss. Six of the deaf animals comprised the GM1 group, which received daily injections of GM1 ganglioside (30 mg/kg) for 28-38 days during the period after profound deafness was confirmed, and prior to receiving a cochlear implant. The non-GM1 group (n=6) received no treatment during this interim period. All the deafened animals underwent unilateral cochlear implantation at 6-9 weeks postnatal and received several months (mean duration, 32 weeks) of chronic electrical stimulation (4 h/day, 5 days/week). Stimulation was delivered by intracochlear bipolar electrodes, using electrical signals that were designed to be temporally challenging to the central auditory system. Results showed that in the neonatally deafened animals, both the GM1 and non-GM1 groups, the volume of the CN was markedly reduced (to 76% of normal), but there was no difference between the animals that received GM1 and those that did not. The cross sectional areas of spherical cell somata in both GM1 and non-GM1 groups also showed a highly significant reduction in size, to < or =75% of normal after neonatal deafening. Moreover, in both the GM1 and non-GM1 groups, the spherical cells in the CN ipsilateral to the implanted cochlea were significantly larger (6%) than cells in the control, unstimulated CN. Again, however, there was no significant difference between the GM1 group and the non-GM1 group in spherical cell size. These results contrast sharply with previous reports that exogenous GM1 prevents CN degeneration after neonatal conductive hearing loss and partially prevents spiral ganglion cell degeneration when administered immediately after ototoxic drug deafening in adult animals. Taken together, findings to date suggest that GM1 may be effective in preventing degeneration only if the GM1 is administered immediately at the time hearing loss occurs.

Topics: Animals; Animals, Newborn; Cats; Cochlear Implants; Cochlear Nucleus; Deafness; Electric Stimulation Therapy; G(M1) Ganglioside; Nerve Degeneration

To investigate the pathophysiology of selective absence of F waves and its relation with antiganglioside antibodies in Guillain-Barré syndrome (GBS). Some patients with GBS show the absence of F waves as an isolated conduction abnormality, which has been interpreted as demyelination in the proximal nerve segments.. In 62 consecutive patients with GBS, sequential nerve conduction and F wave studies were reviewed, and antibodies against ganglioside GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, and GQ1b were measured by an enzyme linked immunosorbent assay.. In the first electrophysiological studies, isolated absence of F waves was found in 12 (19%) patients. Sequential studies in 10 of these patients showed two electrophysiological sequel patterns; rapid restoration of F waves (six patients), and persistent absence of F waves with distal motor nerve degeneration (acute motor axonal neuropathy, four patients). None of the 10 patients showed evidence of demyelination in the proximal, intermediate, or distal nerve segments throughout the course. Of the 62 patients, IgG antibodies against GM1, GM1b, GalNAc-GD1a, or GD1b were significantly associated with the electrodiagnosis of acute motor axonal neuropathy, and patients with these antibodies more often had isolated absence of F waves than patients without them (11 of 36 (31%) v one of 26 (4%); p<0.01). Eleven of the 12 patients with isolated absence of F waves had positive serology for one or more antiganglioside antibodies.. In GBS with antiganglioside antibodies, isolated absence of F waves is a frequent conduction abnormality especially in the early phase of the disease, and may be caused by axonal dysfunction, such as physiological conduction block or axonal degeneration at the nerve roots.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Anti-Idiotypic; Axons; Child; Child, Preschool; Demyelinating Diseases; Electrophysiology; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Male; Middle Aged; Motor Neurons; Nerve Degeneration; Neural Conduction; Peripheral Nerves; Time Factors

A 19-year-old male student with Guillain-Barré syndrome (GBS) was described. Neurologic examination revealed severe and moderate degrees of weakness in the distal and proximal muscles, respectively, in both upper and lower limbs. He was unable to walk even with support. Both superficial and deep sensations were normal. Serial electrophysiologic studies indicated that the predominant pathologic process of the peripheral nerve was axonal degeneration of motor nerves. Enzyme-linked immunosorbent assay showed that serum from the patient had markedly high titer of IgG antibody to Ga1NAc-GD1a (1:204,800). Thin-layer chromatography with immunostaining revealed that his serum IgG strongly reacted with Ga1NAc-GD1a prepared from both bovine brain and cauda equina, and additionally with unidentified acidic glycolipids prepared only from bovine cauda equina. Serum containing antibody to Ga1 NAc-GD1a and the unidentified acidic glycolipids may be responsible for axonal degeneration of motor nerves in this patient.

Topics: Acetylgalactosamine; Adult; Animals; Autoantibodies; Axons; Cattle; G(M1) Ganglioside; Glycolipids; Humans; Immunoglobulin G; Male; Motor Neurons; Nerve Degeneration; Neural Conduction; Polyradiculoneuropathy

Ruthenium red (RR) is an inorganic polycationic dye able to exert several effects on the nervous system, including neurodegeneration, both in vivo and in cell cultures. Gangliosides have been shown to protect cultured neurons against several damaging conditions, and it has been postulated that RR can interact with the negative charges of the sialic acid residues of these molecules. In the present work we have tested the effect of the trisialoganglioside GT1b and the monosialoganglioside GM1 on the RR-induced neuronal damage in primary cortical cultures, as well as on the binding of RR to synaptosomes. GT1b at 100-200 microM concentrations partially protected against RR-induced neurodegeneration, as judged by light microscopy and by measurement of the reduction of a tetrazolium salt, while GM1 was ineffective. GT1b, but not GM1, also partly blocked both RR binding and its diminution in the culture medium occurring during incubation. These results suggest that the three negative charges of GT1b enable it to interact with RR and as a consequence the entrance of the dye into the cells is blocked and neurotoxicity is diminished, although other mechanisms of protection cannot be excluded. Endogenous polysialic acid-containing molecules do not seem to be involved in RR effects, since the removal of sialic acid residues by treatment with neuraminidase did not prevent the cell damage.

Topics: Animals; Biological Transport; Cells, Cultured; Cerebral Cortex; G(M1) Ganglioside; Gangliosides; N-Acetylneuraminic Acid; Nerve Degeneration; Neuraminidase; Neurons; Neuroprotective Agents; Neurotoxins; Rats; Rats, Wistar; Ruthenium Red; Synaptosomes

The acute motor axonal neuropathy (AMAN) form of the Guillain-Barre syndrome is a paralytic disorder of abrupt onset characterized pathologically by motor nerve fiber degeneration of variable severity and by sparing of sensory fibers. There is little demyelination or lymphocytic inflammation. Most cases have antecedent infection with Campylobacter jejuni and many have antibodies directed toward GM1 ganglioside-like epitopes, but the mechanism of nerve-fiber injury has not been defined. In 7 fatal cases of AMAN, immunocytochemistry demonstrated the presence of IgG and the complement activation product C3d bound to the axolemma of motor fibers. The most frequently involved site was the nodal axolemma, but in more severe cases IgG and C3d were found within the periaxonal space of the myelinated internodes, bound to the outer surface of the motor axon. These results suggest that AMAN is a novel disorder caused by an antibody- and complement-mediated attack on the axolemma of motor fibers.

Topics: Acute Disease; Adolescent; Adult; Axons; Campylobacter jejuni; Child, Preschool; Complement Activation; Complement C3d; Demyelinating Diseases; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunohistochemistry; Male; Middle Aged; Motor Neuron Disease; Nerve Degeneration; Severity of Illness Index

Immune mechanisms have been implicated in the pathogenesis of motor neuropathy with conduction blocks and of acute axonal neuropathy, and GM1 ganglioside has been identified as a potential target antigen. In these experiments, the B subunit of cholera toxin (CT-B), which binds to GM1, was used to target an antibody response to GM1 in peripheral nerve. CT-B was injected into the sciatic nerves of rats, in which anti-CT antibodies were previously induced by immunization, so that the circulating anti-CT-B antibodies bound to the CT-B-GM1 complex in the nerve. Electrophysiological studies revealed the presence of conduction block, and in pathological studies there was axonal degeneration with little demyelination. Control animals, in which keyhole limpet hemocyanin was substituted for CT, did not develop conduction block or axonal degeneration. These studies indicate that antibodies directed at GM1 sites in peripheral nerve could cause an axonal neuropathy with conduction block.

Topics: Animals; Antigen-Antibody Reactions; Axons; Cholera Toxin; Electrophysiology; Female; G(M1) Ganglioside; Injections; Nerve Degeneration; Neural Conduction; Rats; Sciatic Nerve

The glial fibrillary acidic protein (GFAP) content was investigated using immunoblotting techniques in the septum and hippocampus of the rat after bilateral lateral fimbria transection. Seven days after surgery GFAP content increased significantly both in the septum (140% of control) and hippocampus (120% in dorsal, the less denervated, and 145% in the most denervated ventral part), indicating the occurrence of reactive gliosis. The GM1 treatment caused statistically significant attenuation of GFAP increment in all hippocampal parts. In contrast, GM1 treatment has no influence on the increase of GFAP content in the septum. Results suggest a differential effect of GM1 on the two gliotic reactions formed as a consequence of the lesion at the level of the source of innervation (septum) and the target (hippocampus).

Topics: Animals; Denervation; G(M1) Ganglioside; Glial Fibrillary Acidic Protein; Gliosis; Hippocampus; Immunoblotting; Male; Nerve Degeneration; Nerve Fibers; Neural Pathways; Rats; Rats, Wistar; Septum Pellucidum; Staining and Labeling

Basic fibroblast growth factor (bFGF), a polypeptide originally identified as a mitogen for a variety of cells including astroglial cells, also exhibits neurotrophic (survival) effects on a number of neuronal populations, among the latter being hippocampal pyramidal cells. The present study investigated the effects of bFGF on the sensitivity of pyramidal neurons to the excitatory neurotransmitter, glutamate, and possible modulation by monosialoganglioside GM1. Cultures were generated from embryonic day 18 rat hippocampus, and first treated with bFGF at 4-5 days in vitro. Twenty-four hours later, cells were exposed to glutamate (100 microM-1 mM) for a further 24 h in the continued presence of bFGF. The cytotoxic action caused by 200-500 microM glutamate, which normally is present at this culture stage, was reduced by bFGF in a concentration- and time-dependent manner. GM1 (100 microM), given alone 2 h prior to glutamate, also limited this neuronal loss by 50-80%. At lower concentrations, neither bFGF (0.3 ng/ml) nor GM1 (1-10 microM) alone for 24 h was effective in altering neuronal sensitivity to glutamate. However, given together for 24 h these levels of bFGF and GM1 were almost as efficacious as bFGF alone at 3-10 ng/ml. Similar results were obtained with more mature (12 day) cultures. The ability of GM1 to modulate trophic factor actions towards excitatory amino acids makes gangliosides useful tools in the study of central nervous system plasticity and repair processes.

Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Fibroblast Growth Factor 2; G(M1) Ganglioside; Glutamates; Glutamic Acid; Hippocampus; Kinetics; Nerve Degeneration; Neurons; Neurotoxins; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; Time Factors

Brain-derived neurotrophic factor (BDNF) supports the survival of sensory neurons as well as retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro. Here we examined the ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6-hydroxyDOPA (TOPA or 2,4,5-trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease. Cells prepared from embryonic day 14-15 rat mesencephalon were maintained with 10-50 ng/ml BDNF for 7 days prior to addition of TOPA (10-30 microM) for 24 hr. In BDNF-treated cultures, the extensive loss (> 90%) of tyrosine hydroxylase immunopositive cells was virtually (< 10%) eliminated, while the equally drastic loss (> 90%) of the overall cell population was limited to only a 25-30% recovery. Furthermore, the monosialoganglioside GM1 (1-10 microM), although inactive alone, acted synergistically with subthreshold amounts of BDNF to rescue tyrosine hydroxylase-positive cells against TOPA neurotoxicity. These results add impetus to exploring the therapeutic potential of gangliosides and BDNF in Parkinson's disease.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Survival; Cells, Cultured; Dihydroxyphenylalanine; Dopamine; Female; G(M1) Ganglioside; gamma-Aminobutyric Acid; Mesencephalon; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Pregnancy; Rats; Recombinant Proteins; Tyrosine 3-Monooxygenase

Brain-derived neurotrophic factor (BDNF) has recently been shown to enhance the survival of dopaminergic neurons in cultures derived from the embryonic rat mesencephalon. In the present study BDNF was found to protect cultured dopaminergic neurons from injury induced by acute exposure to the dopaminergic-selective neurotoxin 6-hydroxydopamine. The BDNF effect was concentration (ED50 approximately 10 ng/ml) and time-dependent, as determined by tyrosine hydroxylase immunocytochemistry. More importantly, subthreshold amounts of BDNF were rendered efficacious in the presence of ganglioside GM1: loss of tyrosine hydroxylase positive cells was reduced from 80% to only 20%. Thus GM1 may provide a fruitful treatment strategy for disorders of dopamine function such as Parkinson's disease.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Dopamine; Female; G(M1) Ganglioside; Nerve Degeneration; Nerve Growth Factors; Nerve Tissue Proteins; Neurons; Oxidopamine; Pregnancy; Rats; Recombinant Proteins

Gangliosides have been shown to be capable of protecting nerve tissue from mechanical and biochemical insults and promoting their repair. The present study provides morphologic evidence that monosialogangliosides attenuate the degenerative process at the distal stump of the rat optic nerve after crush injury. Injured rat optic nerves were treated for 7 days after injury with daily intraperitoneal injections of monosialogangliosides (30 mg/kg/day), and compared with untreated injured controls with respect to the number of viable axons 2 and 4 weeks after injury, as indicated by transmission electron microscopy. After 2 weeks, the mean number of viable axons in the treated optic nerves (n = 5) was slightly higher than in the controls (n = 5). Four weeks after injury, although the absolute number in both the experimental and the control groups had dropped, it was about seven-fold higher in the treated animals (1696 +/- 1149, n = 7) than in the untreated animals (216 +/- 65, n = 6); this difference was statistically significant. These findings, which offer some insight as to how monosialogangliosides affect injured nerves, may have important implications for treatment in cases of optic nerve injury.

Topics: Animals; Axons; Cell Count; G(M1) Ganglioside; Injections, Intraperitoneal; Male; Nerve Degeneration; Optic Nerve; Optic Nerve Injuries; Rats; Rats, Sprague-Dawley

Nerve growth factor (NGF) and monosialoganglioside GM1 were microencapsulated in biodegradable co-polymer poly(L-lactide):co-glycolide and administered locally to rats with unilateral cortical devascularizing lesions. Microcapsules were placed directly onto the lesioned cortical surface and rats were sacrificed 30 days post-operatively. Biochemical and quantitative immunocytochemical analyses revealed effective protection from degenerative changes of nucleus basalis magnocellularis (NBM) cholinergic neurones on the lesioned side as well as a significant increase in choline acetyltransferase activity in the frontoparietal cortex surrounding the lesion. Results of this study strongly suggest that the topical application of microcapsules of a biodegradable polymer containing a mixture of two neuroprotective factors is a viable alternative to the use of osmotic minipumps for delivery of these agents into the CNS. Indeed, this approach might find clinical applications.

Topics: Animals; Basal Ganglia; Cerebral Cortex; Choline O-Acetyltransferase; Drug Compounding; Drug Implants; Emulsions; G(M1) Ganglioside; Immunohistochemistry; Lactic Acid; Male; Microspheres; Nerve Degeneration; Nerve Growth Factors; Parasympathetic Nervous System; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rats; Rats, Wistar

A 76-yr-old male patient with carcinomatous neuropathy associated with hepatic cell carcinoma, whose initial symptom was deep sensory disturbance followed by muscle weakness is described. The onset was subacute, followed by slow progression. Sural nerve biopsy, as well as electrophysiological examinations, revealed severe axonal degeneration without any evidence of demyelination. The autopsy findings were similar to findings described in the literature on carcinomatous neuropathy. Although carcinomatous neuropathy is usually associated with lung cancer, this report describes an association with hepatic cell carcinoma. The patient also had motor nerve involvement with positive serum anti-GM1 ganglioside antibody which decreased after immunosuppressant therapy in parallel with recovery of muscle weakness. The anti-GM1 ganglioside antibody may be involved in the pathogenesis of motor disturbance in the present case.

Topics: Aged; Antibodies; Carcinoma, Hepatocellular; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Liver Neoplasms; Male; Nerve Degeneration; Neural Conduction; Neurons, Afferent; Peripheral Nervous System Diseases

The effects of unilateral devascularizing lesions of the neocortex in primates (Cercopithecus aethiops) on the immunoreactivity of choline acetyltransferase and the low-affinity nerve growth factor receptor (p75NGFR) were investigated in cell bodies of the nucleus basalis of Meynert. Choline acetyltransferase enzymatic activity was measured in the dissected ipsi- and contralateral nucleus basalis of Meynert as well as in the remaining cortex adjacent to the lesion. Cortically lesioned animals displayed a shrinkage of p75NGFR-immunoreactive cholinergic cell bodies in only the intermediate portion of the nucleus basalis of Meynert as well as a depletion of choline acetyltransferase activity in this cellular complex. In contrast, cortically lesioned monkeys treated with monosialoganglioside did not reveal a significant loss of choline acetyltransferase activity or shrinkage of nucleus basalis of Meynert cholinergic neurons, but rather a modest hypertrophy. These results are discussed in relation to a possible use of putative trophic agents in the repair of the damaged central nervous system.

Topics: Animals; Cerebral Cortex; Chlorocebus aethiops; Choline O-Acetyltransferase; G(M1) Ganglioside; Immunohistochemistry; Male; Nerve Degeneration; Nerve Growth Factors; Neurons; Parasympathetic Nervous System; Receptors, Nerve Growth Factor; Substantia Innominata

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

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

This study demonstrates the earliest reported effects of GM1 treatment on crush-injured axons of the mammalian optic nerve. GM1, administered intraperitoneally immediately after injury, was found to reduce the injury-induced metabolic deficit in nerve activity within 2 hr of injury, as measured by changes in the nicotine-amine adenine dinucleotide redox state. After 4 wk, transmission electron microscopy 1 mm distal to the site of injury revealed a sevenfold increase in axonal survival in GM1-treated compared to untreated injured nerves. These results emphasize the beneficial effect of GM1 on injured optic nerves as well as the correlation between immediate and long-term consequences of the injury. Thus, these results have implications for treating damaged optic nerves.

Topics: Animals; Axons; Cell Count; Cell Survival; Disease Models, Animal; G(M1) Ganglioside; Injections, Intraperitoneal; Male; NAD; Nerve Degeneration; Optic Nerve; Optic Nerve Injuries; Rats; Rats, Sprague-Dawley; Spectrometry, Fluorescence

We found high titers of anti-GM1 antibodies (1/1280 or more) in 3 of 14 consecutive patients (21%) with Guillain-Barré syndrome (GBS) and in 2 additional patients who developed GBS, 10-11 days after starting parenteral treatment with gangliosides. Antibodies were IgG in 4 patients and IgM in one, and they all bound to asialo-GM1, and, in 3, to GD1b as well. Although the clinical features in all the patients with high anti-GM1 titers fulfilled the criteria for the diagnosis of GBS and in 4 of them, proteins but not cells were elevated in cerebrospinal fluid, electrodiagnostic studies in 3 patients showed prominent signs of axonal degeneration, that in one case were confirmed by morphological studies on sural nerve biopsy. No recent antecedent infection was reported by these patients, but in 3, including patients treated with gangliosides, anti-Campylobacter jejuni antibodies were elevated. In 3 patients a consistent decrease in anti-GM1 levels was observed after the acute phase of the disease suggesting that the frequent occurrence of these antibodies in patients with GBS and their frequent association with a prominent axonal impairment may have pathogenetic relevance.

Topics: Adolescent; Adult; Aged; Antibodies; Chromatography, High Pressure Liquid; Electromyography; Electrophysiology; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Nerve Degeneration; Neural Conduction; Polyradiculoneuropathy

Topics: Autoantibodies; Axons; G(M1) Ganglioside; Humans; Nerve Degeneration; Polyradiculoneuropathy

Rat cerebellar granule cells, when subjected to a glucose-free environment for 4 h, developed extensive degeneration of neuronal cell bodies and their associated neurite network over the following 24 h. This neuronal damage was quantitated with a colorimetric assay using the metabolic dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Hypoglycemic neuronal injury could be markedly reduced by the presence of both competitive (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and non-competitive (phencyclidine) N-methyl-D-aspartate receptor antagonists, but not by kainate/quisqualate preferring antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Glucose deprivation neuronal injury was also reduced by adding glutamate-degrading enzymes to the incubation medium. Monosialoganglioside GM1, but not its asialo derivative (lacking sialic acid), was also effective in protecting against hypoglycemic neurodegeneration when included during the period of glucose deprivation. These results suggest that the neuronal injury to cerebellar granule cells resulting from glucose deprivation is mediated predominantly by activation of the N-methyl-D-aspartate type of excitatory amino acid receptor, perhaps through the action of endogenously released glutamate. Furthermore, the monosialoganglioside GM1, a member of a class of naturally occurring sialoglycosphingolipids, is able to attenuate this neuronal injury--as already observed for glutamate neurotoxicity and anoxic neuronal death in cerebellar granule cells. Gangliosides may thus prove to be of therapeutic utility in excitatory amino acid-associated neuropathologies.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cerebellum; G(M1) Ganglioside; Gangliosides; Hypoglycemia; Nerve Degeneration; Neurons; Piperazines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate

The rubrospinal tract (RST) was cut unilaterally at C2-3 segment in 21 rats that were killed 3, 7, 10, 14, 28, 60, and 90 days later. Additionally, 14 rats, killed 14 or 28 days after lesioning, were treated postoperatively by daily intraperitoneal injections of GM1 ganglioside. Six unoperated, untreated rats served as controls. In untreated animals, axotomized neurons of the magnocellular division of the red nucleus (RN) exhibited cytoplasmic, nuclear, and nucleolar atrophy 7-10 days postoperatively. Atrophy progressed through the 90th postoperative day. Regression analyses disclosed a bimodal pattern to cytoplasmic and nucleolar atrophy, with an initial rapid phase changing to a slower but progressive mode from 14 days postoperatively. Nuclear atrophy proceeded in a unimodal manner. GM1 treatment did not affect these atrophic processes. Neuronal loss did not occur in the axotomized RN through the 60th postoperative day. Axotomized neurons of untreated rats showed significant and progressive reductions in mean somal (cytoplasmic) and nucleolar RNA from, respectively, the 7th and 14th postoperative day. GM1 partly prevented these RNA losses. Both in treated and untreated rats, spinal cord lesions contained many axonal sprouts 2 to 4 weeks after surgery, but newly generated axons did not traverse the rostro-caudal extent of any lesion.

Topics: Animals; Atrophy; Female; G(M1) Ganglioside; Nerve Degeneration; Rats; Rats, Inbred Strains; Red Nucleus; RNA; Spinal Cord; Time Factors

Developing and adult hamsters received unilateral neocortex aspiration lesions and were then treated daily with exogenous ganglioside (GM1, 30 mg/kg, i.p.). When lesions were made at the age of two weeks, GM1-treated animals had less shrinkage of the dorsal lateral geniculate nucleus of the thalamus compared to controls. Although a similar observation was made in adults, the effect was not as striking. Thus, GM1-treatment reduces retrograde degeneration after neocortical lesions and this effect is most pronounced during early development.

Topics: Animals; Cerebral Cortex; Cricetinae; G(M1) Ganglioside; Male; Mesocricetus; Nerve Degeneration

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; G(M1) Ganglioside; Mice; Mice, Inbred C57BL; Nerve Degeneration; Pyridines; Receptors, Dopamine; Substantia Nigra

The observation of generalized GM1 gangliosidosis type 1 (Norman-Landing disease) is reported. The case is typical, featuring all the main clinical and biological signs of the disease. Diagnosis was established by the demonstration of a severe deficit in beta-galactosidase activity in leucocytes, by the demonstration of oligosaccharides in the urine, and by the histological examination after the fatal outcome before the age of two with severe respiratory distress.

Topics: Cerebral Cortex; G(M1) Ganglioside; Gangliosidoses; Humans; Infant; Male; Nerve Degeneration; Oligosaccharides

Topics: Adrenal Gland Neoplasms; Animals; Brain; Cell Line; G(M1) Ganglioside; Gangliosides; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neurons; Peripheral Nerves; Pheochromocytoma; Rats

Postsurgical injections of GM1 gangliosides (30 mg/kg IP) reduced neither behavioral deficits in rats following bilateral ablation of the visual cortex nor the extent of retrograde degeneration of neurons in the dorsolateral geniculate nucleus that typically accompanies large lesions of the visual cortex. Our findings are in contrast to previous research, in which ganglioside treatments have been shown to enhance the rate of functional recovery after lesions in other parts of the central nervous system. The negative findings in the present experiment may be due to the disruption of normal circadian rhythms caused by occipital cortex injury.

Topics: Animals; G(M1) Ganglioside; Injections, Intraperitoneal; Male; Nerve Degeneration; Pattern Recognition, Visual; Photic Stimulation; Rats; Visual Cortex; Visual Perception

Adult male Fischer-344 rats were given bilateral injections of 2.5 micrograms colchicine or artificial cerebrospinal fluid into caudal and rostral sites of the dentate gyrus of the hippocampus. One group of rats received 21 consecutive daily injections of 20 mg/kg GM1 gangliosides, i.p., beginning the day prior to surgery. Another group received saline. Colchicine-induced hypermotility was not seen in animals repeatedly handled 21 d after surgery, in spite of significant decreases in granule cell number and decreases in the volume of hippocampal mossy fibers. Pretreatment with GM1 had no effect on behavior and it did not protect against the hippocampal damage produced by colchicine. Rats given colchicine, but not handled for 21 d, showed significant hypermotility, which was associated with decreases in hippocampal granule cells. These data underscore the importance of handling in postlesion functional recovery.

Topics: Animals; Colchicine; G(M1) Ganglioside; Hippocampus; Male; Microinjections; Motor Activity; Nerve Degeneration; Rats; Rats, Inbred F344

Gangliosidoses are very rare neurological diseases based on specific enzyme defects. They constitute models for the disruption of specific metabolic pathways and cellular functions with the ultimate consequence of manifest clinical symptoms. The investigation of the various steps involved in the generation of a given syndrome can therefore lead to a more profound understanding of the cell biology of the nervous system. In the present synopsis we try to briefly summarize some aspects of the present knowledge of pathophysiological mechanisms in GM1- and GM2-gangliosidoses.

Topics: beta-Galactosidase; beta-N-Acetylhexosaminidases; Brain; Child; G(M1) Ganglioside; G(M2) Activator Protein; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Glycoproteins; Hexosaminidases; Humans; Lysosomes; Nerve Degeneration; Protein Deficiency; Proteins; Saposins; Sphingolipid Activator Proteins; Synaptic Transmission

Topics: Axons; Cell Line; Child; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Motor Endplate; Motor Neurons; Muscles; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neuromuscular Junction; Neurons; Peripheral Nerves; Synaptic Transmission

GM1 and GM2 gangliosidoses are progressive neurodegenerative diseases which accumulate intralysosomal gangliosides--and to a lesser extent oligosaccharides--chiefly in the central and peripheral nervous system owing to deficiencies of beta-galactosidase and hexosaminidases A or/and B, respectively. This intralysosomal "storage" in neuronal pericarya and their processes, and subsequent loss of such nerve cells provide the background for clinical symptoms of the central nervous system and the retina, while involvement of the peripheral nervous system and the visceral organs largely remains free of clinical findings. The morphological involvement of the latter organs is widespread though varying, thus allowing morphological investigations of lymphocytes, skin, or rectum for morphological diagnosis and as a screening procedure.

Topics: Astrocytes; Brain; Child; Dendrites; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Inclusion Bodies; Lysosomes; Microscopy, Electron; Nerve Degeneration; Neurons; Peripheral Nerves; Sandhoff Disease; Spinal Cord; Synaptic Membranes; Tay-Sachs Disease; Vacuoles

The effect of GM1 ganglioside on the recovery of dopaminergic nigro-striatal neurons was studied in rats after unilateral hemitransection. GM1 treatment partially prevented the decrease of tyrosine hydroxylase (TH) activity caused by hemitransection in the substantia nigra ipsilateral to the lesion. Concomitantly a significant increase of TH-immunoreactivity in the substantia nigra was also detected. In particular, chronic treatment with GM1 prevented the disappearance of TH-positive cell bodies in the substantia nigra and induced the appearance of longer TH-positive dendrites with respect to the saline treatment. These data indicate that GM1 treatment maintains the number of dopaminergic cell bodies in the substantia nigra after hemitransection by protecting against retrograde neuronal degeneration.

Topics: Animals; Corpus Striatum; Dominance, Cerebral; Dopamine; G(M1) Ganglioside; Gangliosides; Glial Fibrillary Acidic Protein; Intermediate Filament Proteins; Nerve Degeneration; Nerve Regeneration; Neural Pathways; Neurons; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substantia Nigra; Tyrosine 3-Monooxygenase

By means of computer assisted morphometry and microdensitometry the effects of chronic GM-1 ganglioside treatment have been further evaluated on the degenerative and regenerative features of mesostriatal DA neurons in the rat brain. In this study mainly a rostrocaudal morphometrical analysis was performed in the substantia nigra of the lesioned side. The specificity of the action of the GM-1 ganglioside on the substantia nigra DA cells was evaluated by a comparison with antiinflammatory drugs such as betametazon and acetylsalicylic acid. In the rostrocaudal analysis it was demonstrated that chronic GM-1 treatment preferentially protected the caudally located dopamine nerve cells from degeneration after partial hemitransection, while instead this chronic GM-1 treatment increased tyrosine hydroxylase immunoreactivity mainly within the rostrally located DA nerve cells present close to the site of the lesion. Furthermore, the specificity of the GM-1 action was demonstrated by the absence of protective effects of chronic treatment with betametazon and acetylsalicylic acid on the dopamine nerve cells of the lesioned side. These results open up the possibility that chronic GM-1 treatment, by exerting a stimulatory metabolic action on the DA nerve cells located close to the lesion, can enhance the production of neurotrophic factors in these cells, which in turn can diffuse out to increase the survival of the less severely lesioned DA nerve cells located in the caudal part of the substantia nigra. These results indicate that chronic GM-1 treatment may be beneficial in the treatment of neurons undergoing degeneration, which takes place e.g. in Parkinson's disease and after mechanical injury to the brain due to accidents or neurosurgical operations.

Topics: Animals; Brain; Computers; Corpus Striatum; Dendrites; Densitometry; Dopamine; G(M1) Ganglioside; Gangliosides; Male; Nerve Degeneration; Nerve Regeneration; Neurons; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substantia Nigra

The effects of chronic ganglioside treatment GM-1 (10 mg/kg, i.p., once daily for 56 days) have been evaluated on the degenerative and regenerative features of nigrostriatal dopamine (DA) neurons following a partial lesion by tyrosine hydroxylase immunocytochemistry in combination with morphometrical analysis and by quantitative DA receptor autoradiography. Chronic GM-1 treatment resulted in the maintenance in the number of DA cell bodies, terminals and striatal area on the lesioned side and also increased dendrite length of the DA nerve cells in the zona reticulata on that side. The lesion induced DA receptor supersensitivity was counteracted by chronic treatment with GM-1 and the apomorphine induced rotational behaviour was significantly reduced. The hypothesis is introduced that following ganglioside treatment some lesioned DA nerve cells do not degenerate, but elongate their dendrites to give increased trophic support to DA cell bodies with intact DA axons. These increased dendro-dendritic interactions may enable the unlesioned DA cells to increase the density of their striatal nerve terminal networks via collateral sprouting leading to recovery of dopaminergic synaptic function as evidenced in the receptor autoradiographical and behavioural analysis. Gangliosides may therefore possibly represent a new type of drug in the treatment of Parkinson's disease and aging processes in DA systems.

Topics: Animals; Cell Survival; Dendrites; G(M1) Ganglioside; Gangliosides; Male; Nerve Degeneration; Nerve Endings; Nerve Regeneration; Neurons; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone; Substantia Nigra; Synapses; Tyrosine 3-Monooxygenase