GM1 ganglioside protects nucleus basalis from excitotoxin damage: Reduced cortical cholinergic losses and animal mortality

Mahadik, Sahebarao P.; Vilim, Ferdinand S.; Korenovsky, Anna; Karpiak, Stephen E.

doi:10.1002/jnr.490200411

Cited by 41 publications

(7 citation statements)

References 36 publications

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“…Based on their neural regenerative effect, gangliosides have been used successfully in animal models for the treatment of certain neurological disorders, such as diabetic neuropathy (18)(19)(20), and for acceleration of functional recovery after central nervous system damage (21)(22)(23) (24,25) and is capable of spontaneously differentiating or maturing to a benign ganglioneuroma (26 therefore agents that modify its activity might be of importance in the treatment of certain neuropathies and tumors, especially neuroblastomas.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of protein kinase C induces differentiation in Neuro-2a cells.

Miñana

Felipo

Grisolı́a

1990

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACT1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a potent inhibitor of protein kinase C, induced neuritogenesis in Neuro-2a cells, whereas N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), which inhibits more efficiently cAMP-and cGMP-dependent protein kinases, did not. The effect, noticeable after 3 hr, was maximum (13-fold increase at 500 ,tM H7) between 1 and 3 days and was maintained over 2 months. In controls, 90% of the cells were undifferentiated, whereas after 3 hr with 500 FIM H7 only 25% of the cells remained undifferentiated. DNA synthesis decreased as the number of differentiated cells increased. Differentiation is also functional since acetylcholinesterase activity increased =7-fold after 48 hr with 500 IAM H7. Phorbol 12-myristate 13-acetate, a specific activator of protein kinase C, prevented or reversed the induction of neuritogenesis and the inhibition of DNA synthesis by H7. There is a good correlation between the level of protein kinase C and the percentage of differentiated cells. The results indicate that protein kinase C may play a key role in the control of differentiation of neural cells. Some possible clinical implications are briefly discussed.The molecular regulation of cellular growth and differentiation is one of the fundamental problems of cell biology. It was shown some years ago that addition ofgangliosides induces the differentiation of neuroblastoma cell lines with concomitant sprouting and extension of neurites (1-3). However, the underlying mechanism of ganglioside-modulated neuritogenesis remained unknown (4, 5). It has been reported by others that gangliosides are inhibitors of protein kinase C (PKC) (6-8). It therefore appeared possible that the two findings might be related and that gangliosides might stimulate neuritogenesis by inhibiting PKC. To test this hypothesis we have studied the effect of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (17), a potent inhibitor ofPKC (9, 10), on differentiation in Neuro-2a cells. We find that H7 induces neuritogenesis and that this effect is prevented and reversed by phorbol 12-myristate 13-acetate (PMA), an activator ofPKC (11). It is further shown that there is a good correlation between the level ofthe enzyme and the percentage of differentiated cells. The results indicate that PKC may play an important role in the control of differentiation of neural cells. MATERIALS AND METHODS

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Section: Resultsmentioning

confidence: 99%

Inhibition of protein kinase C induces differentiation in Neuro-2a cells.

Miñana

Felipo

Grisolı́a

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Gangliosides have been used successfully in animal models for the treatment of certain neurological disorders. The following beneficial effects have been reported for gangliosides: stimulation of the regeneration of the nervous system and facilitation of recovery after CNS damage [8], acceleration of reinnervation [9], facilitation of learning performance [10], decreased mortality after induction of global ischemia [11], counteraction of the slowing of nerve conduction in diabetic neuropathy [12], reduction of retrograde degeneration after neocortical lesions [13], protection against excitotoxin damage [14] and reduction of vincristineinduced neuropathy [15]. The findings reported here suggest that similar effects might be obtained by using specific inhibitors of protein kinase C.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of protein kinase C induces differentiation of neuroblastoma cells

1989

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It is shown that 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), a specific inhibitor of protein kinase C, induces neuritogenesis in neuro 2a cells. The percentage of differentiated cells was 9%, 20%, 59% and 85% at 0, 17, 85 and 500 ~tM H7, respectively. The number of neurites/cell increased 2-, 8-and 14-fold over the controls for 17, 85 and 500 gM H7, respectively. These results indicate that protein kinase C plays a key role in the control of differentiation of neural cells and that its specific inhibition may be of basic as well as of practical importance.

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“…These latter compounds have recently been reported to reduce glutamate and kainate toxicity (Favaron et a]., 1988) and anoxic neuronal death (Skaper et al ~ 1989) in cultured cerebellar granule cells, as well as direct excitotoxin damage in vivo (Mahadik et al, 1988;Lipartiti et al, 1989;Lombardi et al, 1989).…”

Section: Cell Culturementioning

confidence: 99%

“…Gangliosides represent a class of naturally occurring, sialic acid-containing glycosphingolipids (Svennerholm, 1963) highly concentrated in ncuronal plasma membranes (Ledeen, 1983). The administration of monosialogangliosides like GM 1 has been described to reduce glutamate and kainate neurotoxicity (Favaron et al, 1988) and anoxia-induced neuronal injury (Skaper et al, 1989) in cultured cerebcllar granule cells, and cxogemus excitotoxin damage in the CNS (Mahadik et al, 1988;Lipartiti et a]., 1989; Lombardi et a]., 1989). Ganglioside was examined here for an effect on glutamate receptor agonist-mediated retinal neuron injury.…”

Section: Effect Of Ganglioside Gm1 On Eaa-induced Retinal Neuronal Dementioning

confidence: 99%

Excitatory amino acid neurotoxicity in cultured retinal neurons: Involvement of N‐methyl‐D‐Aspartate (NMDA) and Non‐NMDA receptors and effect of ganglioside GM1

Facci

Leon

Skaper

1990

J of Neuroscience Research

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Cultures of chicken day 8 embryo retinal cells, essentially free of contaminating non-neuronal elements, were used to examine the neurotoxicity of various excitatory amino acid transmitter receptor agonists. At 7 days in vitro, N-methyl-D-aspartate (NMDA), following 24 hr exposure to 0.1-1.0 mM, destroyed 60-70% of the multipolar neurons, but apparently spared photoreceptors. The cytotoxic effect of NMDA was prevented by extracellular Mg2+ or phencyclidine, suggesting a role for the NMDA ion channel; competitive NMDA antagonists were also neuroprotective. The mixed excitatory amino acid receptor agonist glutamate (0.1-1.0 mM) was also neurotoxic (approximately 70% loss of multipolar neurons) and strongly blocked by NMDA (but weakly by non-NMDA) antagonists and Mg2+, indicating a major action at NMDA receptors. As with NMDA, glutamate did not appear to affect photoreceptors. The neurotoxic action of kainate against multipolar retinal neurons, as reported by others, was confirmed here. Kainate neuronal injury was sensitive to the quinoxalinedione non-NMDA antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyanoquinoxaline-2,3-dione (CNQX), but not to Mg2+ or phencyclidine. Ibotenate and quisqualate, even at millimolar concentrations, were not neurotoxic. The monosialoganglioside GM1 was also effective in reducing NMDA and non-NMDA agonist neurotoxicity to retinal neurons. Maximal ganglioside benefit required 1-2 hr of pretreatment with 100-200 microM GM1. The percentage of multipolar neurons remaining after the neurotoxin insult approximately doubled with GM1 treatment. Gangliosides may thus have a therapeutic potential in excitatory amino acid-initiated neuropathologies.

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GM1 ganglioside protects nucleus basalis from excitotoxin damage: Reduced cortical cholinergic losses and animal mortality

Cited by 41 publications

References 36 publications

Inhibition of protein kinase C induces differentiation in Neuro-2a cells.

Inhibition of protein kinase C induces differentiation in Neuro-2a cells.

Inhibition of protein kinase C induces differentiation of neuroblastoma cells

Excitatory amino acid neurotoxicity in cultured retinal neurons: Involvement of N‐methyl‐D‐Aspartate (NMDA) and Non‐NMDA receptors and effect of ganglioside GM1

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