Administration Of GM1 Ganglioside Research Articles

GM1 ganglioside modifies microglial and neuroinflammatory responses to α-synuclein in the rat AAV-A53T α-synuclein model of Parkinson's disease

Among the pathological events associated with the dopaminergic neurodegeneration characteristic of Parkinson's disease (PD) are the accumulation of toxic forms of α-synuclein and microglial activation associated with neuroinflammation. Although numerous other processes may participate in the pathogenesis of PD, the two factors mentioned above may play critical roles in the initiation and progression of dopamine neuron degeneration in PD. In this study, we employed a slowly progressing model of PD using adeno-associated virus-mediated expression of human A53T α-synuclein into the substantia nigra on one side of the brain and examined the microglial response in the striatum on the injected side compared to the non-injected (control) side. We further examined the extent to which administration of the neuroprotective ganglioside GM1 influenced α-synuclein-induced glial responses. Changes in a number of microglial morphological measures (i.e., process length, number of endpoints, fractal dimension, lacunarity, density, and cell perimeter) were indicative of the presence of activated microglial and an inflammatory response on the injected side of the brain, compared to the control side. In GM1-treated animals, no significant differences in microglial morphology were observed between the injected and control striata. Follow-up studies showed that mRNA expression for several inflammation-related genes was increased on the A53T α-synuclein injected side vs. the non-injected side in saline-treated animals and that such changes were not observed in GM1-treated animals. These data show that inhibition of microglial activation and potentially damaging neuroinflammation by GM1 ganglioside administration may be among the many factors that contribute to the neuroprotective effects of GM1 in this model and possibly in human PD.

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 andalleviated 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.

GM1 Ganglioside Modifies \u03b1-Synuclein Toxicity and is Neuroprotective in a Rat \u03b1-Synuclein Model of Parkinson\u2019s Disease

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD.

Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson's Disease.

BackgroundPreclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson’s disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration.ObjectiveTo assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach.MethodsWe used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection.ResultsVCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration.ConclusionThe results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system.

Factors affecting the prognosis of patients with delayed encephalopathy after acute carbon monoxide poisoning

Objective Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a disease with poor prognosis. The present study was conducted to determine the factors that affect the prognosis of DEACMP patients. Methods In a retrospective study, 46 DEACMP patients were chosen by the following criteria: (1) a clear history of acute carbon monoxide poisoning, a distinct “lucid interval,” and neuropsychologic symptoms; (2) first-time admittance to a hospital (within 1 week of onset of disease); and (3) completion of standard treatment period in our hospital. All patients received hyperbaric oxygen (HBO 2) treatments. Results Fifty percent (23 of 46) of the DEACMP patients showed improvements after HBO 2 treatments. Age, lucid interval, danger–activities of daily living scores (assessed at worst conditions), and complications were related ( P < .05) to the prognosis of DEACMP patients, whereas sex, fundamental diseases, HBO 2 treatment in acute stage, intoxication time, unconsciousness duration, and GM1 ganglioside administration were not ( P > .05) related to prognosis. Conclusion Hyperbaric oxygen treatment appears useful in treating DEACMP patients; and patients with greater age and more complications, but shorter lucid interval and less danger–activities of daily living scores, are more likely to have poor prognosis.

Parenteral administration of GM1 ganglioside to presenile Alzheimer patients

The pharmacokinetic parameters of GM1 ganglioside were examined in 16 patients (mean age 64 +/- 5 years) with Alzheimer's disease. The ganglioside was given intramuscularly and subcutaneously. The maximum GM1 blood level was reached after 48-72 h, the subcutaneous route leading to the highest blood levels, but the individual variability was relatively large. When 100 mg GM1 ganglioside was given daily for a week, maximum serum values of 15 to 20 mumol/l were found in 3 patients. The elimination half-life from serum was 60-75 h.

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

Research in animal models has demonstrated that electrical stimulation from a cochlear implant (CI) may help prevent degeneration of the cochlear spiral ganglion (SG) neurons after deafness. In cats deafened early in life, effective stimulation of the auditory nerve with complex signals for several months preserves a greater density of SG neurons in the stimulated cochleae as compared to the contralateral deafened ear. However, SG survival is still far from normal even with early intervention with an implant. Thus, pharmacologic agents and neurotrophic factors that might be used in combination with an implant are of great interest. Exogenous administration of GM1 ganglioside significantly reduces SG degeneration in deafened animals studied at 7–8 weeks of age, but after several months of stimulation, GM1-treated animals show only modestly better preservation of SG density compared to age-matched non-treated animals. A significant factor influencing neurotrophic effects in animal models is insertion trauma, which results in significant regional SG degeneration. Thus, an important goal is to further improve human CI electrode designs and insertion techniques to minimize trauma. Another important issue for studies of neurotrophic effects in the developing auditory system is the potential role of critical periods. Studies examining animals deafened at 30 days of age (rather than at birth) have explored whether a brief initial period of normal auditory experience affects the vulnerability of the SG or cochlear nucleus (CN) to auditory deprivation. Interestingly, SG survival in animals deafened at 30-days was not significantly different from age-matched neonatally deafened animals, but significant differences were observed in the central auditory system. CN volume was significantly closer to normal in the animals deafened at 30 days as compared to neonatally deafened animals. However, no difference was observed between the stimulated and contralateral CN volumes in either deafened group. Measurements of AVCN spherical cell somata showed that after later onset of deafness in the 30-day deafened group, mean cell size was significantly closer to normal than in the neonatally deafened group. Further, electrical stimulation elicited a significant increase in spherical cell size in the CN ipsilateral to the implant as compared to the contralateral CN in both deafened groups. Neuronal tracer studies have examined the primary afferent projections from the SG to the CN in neonatally deafened cats. CN projections exhibit a clear cochleotopic organization despite severe auditory deprivation from birth. However, when normalized for the smaller CN size after deafness, projections were 30–50% broader than normal. After unilateral electrical stimulation there was no difference between projections from the stimulated and non-stimulated ears. These findings suggest that early normal auditory experience may be essential for the normal development (or subsequent maintenance) of the topographic precision of SG-to-CN projections. After early deafness, the CN volume is markedly smaller than normal, and the spatial precision of SG projections that underlie frequency resolution in the central auditory system is reduced. Electrical stimulation over several months did not reduce or exacerbate these degenerative changes. If similar principles pertain in the human auditory system, then findings in animal models suggest that the basic cochleotopic organization of neural projections in the central auditory system is probably intact even in congenitally deaf individuals. However, the reduced spatial resolution of the primary afferent projections in our studies suggests that there may be inherent limitations for CI stimulation in congenitally deaf subjects. Spatial (spectral) selectivity of stimulation delivered on adjacent CI channels may be poorer due to the greater overlap of SG central axons representing nearby frequencies. Such CI users may be more dependent upon temporal features of electrical stimuli, and it may be advantageous to enhance the salience of such cues, for example, by removing some electrodes from the processor “map” to reduce channel interaction.

Titration of serum anti-ganglioside antibodies in patients with chronic medular injury previous to treatment with GM1 ganglioside

Anti-ganglioside serum titers were evaluated by ELISA in 150 patients with complete spinal cord lesion for 6 to 12 months (IgG monosialo GM1, IgM monosialo GM1, IgG asialo GM1, IgM asialo GM1, IgG disialo GD1b e IgM disialo GD1b) prior to treatment with GM1 100 mg/day i.m. Only 4 patients showed positive titers for anti-asialo-GM1 (IgM) antibodies . All patients were clinically examined during and after treatment. No important side effects were observed with GM1 therapy. These results suggest that GM1-ganglioside administration in patients with chronic spinal cord injury is safe.

Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [3H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [3H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism. Synapse 36:120–128, 2000. © 2000 Wiley-Liss, Inc.

Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys.

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [(3)H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [(3)H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism.

GM1 ganglioside restores abnormal responses to acute thermal and mechanical stimuli in aged rats

We investigated the effect of aging on the responses to thermal and mechanical stimuli in rats. Young (3–5 months old) and aged (22–24 months old) male Sprague–Dawley rats were tested in the hot plate, high- and low-intensity radiant heat tail flick, and von Frey hair assays. Compared to young rats, aged rats displayed longer latencies in the hot plate and the high-intensity tail flick assays (hypoalgesia), but there was no difference in the low-intensity tail flick assay. In addition, aged rats had decreased thresholds to mechanical stimuli produced by von Frey hairs compared with young rats (mechanical allodynia). Administration of GM1 ganglioside, 30 mg/kg, i.p., once daily for 30 days, to aged rats partially restored the responses in the hot plate and von Frey hair assays. GM1 had no effect on the altered responses in the tail flick test in aged rats, and in general, had no effect on any sensory modality tested in young rats.

Differential recovery of sensorimotor function in GM1 ganglioside-treated vs. spontaneously recovered MPTP-treated cats: partial striatal dopaminergic reinnervation vs. neurochemical compensation

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome characterized by rigidity, akinesia, bradykinesia, decreased response to external sensory stimuli and depletion of nigrostriatal dopamine. Cats spontaneously recover gross sensorimotor functions despite little recovery of the dopaminergic innervation of the striatum. In contrast, GM1 ganglioside administration accelerates gross behavioral recovery and causes an increased dopaminergic innervation of the striatum. This study examined whether these two recovery conditions are characterized by different degrees of functional recovery. Cats were trained to perform a sensorimotor reaching task prior to MPTP exposure and were then re-tested on the task 6 weeks later after spontaneously recovering gross motor functioning or after 6 weeks of GM1 treatment. Gross motor recovery was similar in both groups. However, the spontaneously recovered cats had significant difficulty in performing the task while GM1-treated cats performed normally. GM1-treated cats also had significant increases in striatal [ 3 H ]mazindol binding compared to spontaneously recovered cats. These results suggest that while gross motor functions may improve to a similar extent with spontaneous and GM1-induced recovery from experimental parkinsonism, complex sensorimotor behavior recovers to different extents under the different recovery conditions. More complete behavioral recovery may depend upon at least a partial recovery of striatal dopaminergic terminals rather than neurochemical compensation.

GM1 and the aged brain.

Aging is associated with the loss of brain neurotransmitter function, which apparently is the substrate for an adverse constellation of age-associated symptoms. In particular, cholinergic deficits have been associated with cognitive impairment in aging. Systemic administration of GM1 ganglioside, 30 mg/kg, i.p., for 30 days, enhances the cholinergic neurochemical presynaptic markers, choline acetyltransferase, choline uptake, and acetylcholine, in the brain and spinal cord of aged 22-24-month-old Sprague-Dawley rats. In addition to correcting cholinergic neurochemistry, it improves spatial learning and memory impairment, and restores the number and the size of the cholinergic neurons in the basal forebrain and striatum. The induced neuronal recovery by GM1 is long-lasting.

The role of GM1-ganglioside in the injured spinal cord of rats: an immunohistochemical study using GM1-antisera.

The effect of GM1-ganglioside (GM1) administration was investigated in the injured spinal cord of rats. Immunohistochemistry using GM1-antisera was applied in the study of GM1 distribution, and locomotor recovery was also evaluated. A total of 86 rats, subdivided into four groups, were used in the study. The SI + GM1 group (n = 30) underwent a thoracic cord injury, and then received daily intraperitoneal injections of GM1 (10 mg/kg) from 0 to 13 days after injury. The SI group (n = 30) also underwent thoracic cord injury, but did not receive GM1 treatment. The GM1 group (n = 20) received daily injections of GM1 in the absence of any spinal cord injury. The control group (n = 6) neither underwent spinal cord injury nor received GM1 treatment. The animals were sacrificed at 1, 3, 5, 7, and 14 days after injury for immunohistochemical evaluation. GM1 immunoreactive axons, myelin sheaths, and glial cells were counted in 5 light microscopic fields of spinal white matter. Immunohistochemical studies of the spinal cord revealed that GM1 treatment significantly increased both GM1-positive axons and GM1-positive myelin sheaths in the lateral funiculus surrounding the lesion site. The exogenous GM1 was incorporated predominantly into the myelin sheath rather than the axon. This distribution was detectable by day 1 of injury and persisted until day 14, and was significantly different from that of the control group on days 1 and 7. Moreover, GM1 treatment significantly accelerated the recovery of motor function. Collectively, these results suggest that exogenous GM1 administration after a spinal cord injury results in the rapid transfer of GM1 to the lateral funiculus where the motor transmission pathway is located. Furthermore, exogenous GM1 was shown to be specifically incorporated into the myelin sheath. Thus GM1 treatment may prevent demyelination and may contribute to motor function recovery.

GM1 ganglioside administration partially counteracts the morphological changes associated with haloperidol treatment within the dorsal striatum of the rat.

Haloperidol, a typical antipsychotic drug, causes an increase in the mean percentage of synapses within the situation containing a discontinuous, or perforated, postsynaptic density (PSD) following 1 month of treatment (Meshul et al. 1994). This effect is not observed with the atypical antipsychotic drug, clozapine, following subchronic administration (Meshul et al. 1992a). This morphological change is also associated with an increase in the density of dopamine D2 receptors. The synapses containing the perforated PSD are asymmetrical and the nerve terminals contain the neurotransmitter, glutamate, as demonstrated by immunocytochemistry. We have also shown that subchronic treatment with haloperidol (0.5 mg/kg per day, 30 days) results in a decrease in the density of glutamate immunoreactivity within asymmetric nerve terminals associated with perforated and non-perforated PSDs (Meshul and Tan 1994). This could be due to an increase in glutamate release, perhaps due to activation of corticostriatal synapses. Agnati et el. (1983a) reported that administration of GM1 ganglioside blocks the increase in dopamine D2 receptors following haloperidol treatment. GM1 has also been shown to attenuate the release of glutamate (Nicoletti et al. 1989). In order to determine if similar treatment with ganglioside could block the haloperidol-induced ultrastructural changes notes above, rats were co-administered GM1 (10 mg/kg per day) and haloperidol (0.5 mg/kg per day) for 30 days. We report that GM1 blocked the haloperidol-induced increase in striatal asymmetric synapses containing a perforated PSD, but had no effect on the increase in dopamine D2 receptors or the decrease in nerve terminal glutamate immunoreactivity. GM1, either alone or co-administered with haloperidol, also caused a small, but significant, increase in the density of all asymmetric synapses within the striatum. It is possible that the effect of GM1 in attenuating the haloperidol-induced change in glutamate synapses with perforated PSDs is primarily postsynaptic, since GM1 did not block the change in density of glutamate immunoreactivity within asymmetric nerve terminals.

Auditory brainstem responses of CBA/J mice with neonatal conductive hearing losses and treatment with GM1 ganglioside

Exogenous administration of GM1 ganglioside to CBA/J mice with a neonatal conductive hearing loss ameliorates the atrophy of spiral ganglion neurons, ventral cochlear nucleus neurons, and ventral cochlear nucleus volume. The present investigation demonstrates the extent of a conductive loss caused by atresia and tests the hypothesis that GM1 ganglioside treatment will ameliorate the conductive hearing loss. Auditory brainstem responses were recorded from four groups of seven mice each: two groups received daily subcutaneous injections of saline (one group had normal hearing; the other had a conductive hearing loss); the other two groups received daily subcutaneous injections of GM1 ganglioside (one group had normal hearing; the other had a conductive hearing loss). In mice with a conductive loss, decreases in hearing sensitivity were greatest at high frequencies. The decreases were determined by comparing mean ABR thresholds of the conductive loss mice with those of normal hearing mice. The conductive hearing loss induced in the mice in this study was similar to that seen in humans with congenital aural atresias. GM1 ganglioside treatment had no significant effect on ABR wave I thresholds or latencies in either group.

Systemic administration of GM1 ganglioside increases choline acetyltransferase activity in the brain of aged rats

In the brain of aged rats (22–24 months old) choline acetyltransferase (ChAT) activity in striatum and frontal cortex is lower than in young rats (4–5 months old). In contrast, ChAT activity in the hippocampus is similar in the two groups. Treating old animals with GM1 ganglioside, 30 mg/kg ip, for 30 or 45 days enhances ChAT activity in the striatum and frontal cortex, but has no effect on activity in the hippocampus. ChAT activity remains elevated in the striatum and frontal cortex for 15 days after discontinuing treatment with GM1.

Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats.

A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 micrograms twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained. Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.

Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy.

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.

Oral administration of semisynthetic sphingolipids promotes recovery of striatal dopamine concentrations in a murine model of parkinsonism

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to young C57/B16J black mice caused a striatal dopamine depletion that could be at least partially reversed by chronic intraperitoneal administration of GM1 ganglioside. The present study shows that the semisynthetic sphingolipids LIGA 4 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-acetamide-4-t rans-octadacene) and LIGA 20 (II3Neu-5-AcGgOse4-2-d-erythro-1,3-dihydroxy-2-chloro-acetam ide-4- trans-octadacene) are also effective in at least partially reversing MPTP-induced striatal dopamine depletions in mice after oral administration. These results suggest that semisynthetic ganglioside derivatives may be superior to the parent GM1 ganglioside for human clinical use.