Growth Factors and Gangliosides as Neuroprotective Agents in Excitotoxicity and Ischemia*

Hicks, David; Heidinger, Valérie; Mohand‐Saïd, Saddek; Sahel, José‐Alain; Dreyfus, H.

doi:10.1016/s0306-3623(97)00356-x

Cited by 50 publications

(27 citation statements)

References 49 publications

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“…Actually, neurite extension, synaptogenesis, or regeneration of damaged nerves was enhanced in the presence of gangliosides (29). If this is the case, the hyperplastic nerve fibers found in Ho/Ho mice skin seem to be a paradox.…”

Section: Discussionmentioning

confidence: 98%

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Inoue

Fujii

Furukawa

et al. 2002

Journal of Biological Chemistry

108

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We generated double knock-out mice lacking the GM2/ GD2 and the GD3 synthase gene by mating single gene mutants, and we analyzed the abnormal phenotypes of the mutant mice expressing only the GM3 ganglioside. We observed a refractory skin lesion that appeared primarily on the face of the mutant mice at 25 weeks after birth or later. Frequent scratching of the wound sites was observed in mutant mice with the skin injury, suggesting that it is a triggering factor that exacerbates the injury. This was confirmed by isolating mice in special cages for metabolic study in which the skin injury developed more rapidly. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites of the mutants, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching and the resulting skin lesion. The fact that sensory response to mechanical stimuli decreased while that to hot stimuli increased in the mutant mice supports this interpretation. Thus, only GM3-expressing mice displayed the important role of gangliosides in maintaining skin integrity via regulation of the peripheral nerves.Acidic glycosphingolipids, gangliosides, are ubiquitously expressed in the various tissues of vertebrates and play important roles in the regulation of highly organized multicellular systems (1). In particular, they are very much enriched in the nervous system and have been considered to control development, proliferation, differentiation, and maintenance of the neural tissues and cells (2, 3). Expression patterns of various ganglioside species in the nervous system vary during development and are strictly regulated in a spatio-temporal manner (4), suggesting that individual structures of gangliosides contain significant implications for individual situations.A number of studies have been performed to demonstrate the biological function of gangliosides primarily by modifying their structures with enzymes or using inhibitors to block some steps of synthesis (5). Otherwise, the effects of addition of gangliosides to the culture medium or injection into the conditioned animals have been the primary approaches in addressing the significance of gangliosides. However, recent success in the molecular cloning of glycosyltransferase genes brought about an evolutional change in the experimental approaches for carbohydrate function analysis. Availability of glycosyltransferase genes responsible for the synthesis of gangliosides enabled us to remodel ganglioside compositions of cells and tissues in vivo (6, 7) and in vitro (8).Because we isolated GM2/GD2 synthase (EC 2.4.1.92) cDNA (9) and GD3 synthase (EC 2.4.99.8) cDNA (10), we established gene knock-out mice lines of the individual glycosyltransferases. GM2/GD2 synthase gene knock-out mice lacking all complex gangliosides showed almost normal morphogenesis of the nervous system and no definite abnormal behaviors (11), although they showed nerve degene...

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Section: Discussionmentioning

confidence: 98%

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Inoue

Fujii

Furukawa

et al. 2002

Journal of Biological Chemistry

108

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“…Representative tissue specimens were fixed in buffered Table 1. Ten patients with ischaemic stroke-clinical details and relative fibroblast growth factor-2 protein expression in different brain areas of the same patient (for patients [1][2][3][4][5][6][7][8][9][10] formalin and paraffin embedded for in situ hybridisation and IHC or snap frozen then stored at )70°C for Western blotting and IHC.…”

Section: Human Brain Tissuesmentioning

confidence: 99%

“…Neurotrophic factors, for instance nerve growth factor (NGF), brain-derived, neurotrophic factor (BDNF) and basic fibroblast growth factor (FGF-2) are involved in the regulation of nerve cell survival and differentiation during development and in the functional maintenance of adult neurones [4,5]. FGF-2 is also thought to be important for regeneration and restoration of function in pathophysiological situations, such as chemical neurotoxicity, mechanical trauma and brain ischaemia [6][7][8][9] and more specifically can protect cortical synaptic terminals from amyloid and oxidative stress-induced impairment of glucose, glutamate transport and mitochondrial function [10].…”

Section: Introductionmentioning

confidence: 99%

Expression of Basic Fibroblast Growth Factor mRNA and Protein in the Human Brain following Ischaemic Stroke

et al. 2005

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Our previous work has demonstrated that angiogenesis occurs in the damaged brain tissue of patients surviving acute ischaemic stroke and increased microvessel density in the penumbra is associated with longer patient survival. The brain is one of the richest sources of FGF-2 and several studies have noted its angiogenic and neuroprotective effects in the nervous system. These findings led us to investigate the expression and localisation of both FGF-2 mRNA and protein in brain tissue collected within 12 h of death from 10 patients who survived for between 24 h and 43 days after acute stroke caused by thrombosis or embolus. Western blot analysis demonstrated increased FGF-2 protein expression in both grey and white matter in the infarcted core and the penumbra region compared to the normal contralateral hemisphere of all 10 patients studied. Using indirect immunoperoxidase staining of paraffin embedded sections, we observed the presence of FGF-2 in neurones, astrocytes, macrophages and endothelial cells. In situ hybridisation was used to localise and quantify mRNA expression in ischaemic brain tissue of the same 10 patients. The expression of FGF-2 in the penumbra of all patients was significantly raised compared with infarcted tissue and normal-looking contralateral hemisphere. In addition, serum FGF-2 was significantly increased between 1 and 14 days (P<0.001) in many patients with both ischaemic stroke (n=28) and intra-cerebral haemorrhage (n=16) compared with age-matched control subjects undergoing routine medical examinations (n=20). We suggest that up-regulation of FGF-2 is one of the mechanisms that leads to angiogenesis and neuro-protection in the penumbra region after acute stroke in man.

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“…Administration of clonidine, an a 2 adrenergic agonist, induces bFGF expression in the rat retina (Wen et al, 1996;Chao et al, 2000), and bFGF attenuates hypoxia-induced retinal cell loss (Unoki and La Vail, 1994;Zhang et al, 1994;Hicks et al, 1998). Thus, it is conceivable that BMD exerts its neuroprotective effect through increased levels of bFGF in the retina (Chao et al, 2000), although the exact mechanism by which bFGF protects neurones from insults such as hypoxia is not known.…”

Section: Mann±whitney Test)mentioning

confidence: 99%

Neuroprotective Effects of Brimonidine against Transient Ischemia-induced Retinal Ganglion Cell Death: a Dose Response in Vivo Study

Lafuente

Villegas‐Pérez

Mayor

et al. 2002

Experimental Eye Research

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Growth Factors and Gangliosides as Neuroprotective Agents in Excitotoxicity and Ischemia*

Cited by 50 publications

References 49 publications

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Expression of Basic Fibroblast Growth Factor mRNA and Protein in the Human Brain following Ischaemic Stroke

Neuroprotective Effects of Brimonidine against Transient Ischemia-induced Retinal Ganglion Cell Death: a Dose Response in Vivo Study

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