Gangliosides: Overview | ScienceDirect Topics (2023)

Gangliosídeo

Gangliosídeoextracted from bovine brain tissue (Cronassial, Sygen) are widely used in Western Europe and South America for various neurological diseases.

Reported side effects of gangliosides include, in addition to injection site discomfort, motor neuron disease-like disorders, rash (with or without fever and nausea), and anaphylaxis. After evaluating the reported associations between ganglioside use and Guillain-Barré syndrome [29,30] In September 1994, the Committee on Proprietary Medicinal Products (CPMP) of the European Commission recommended that the marketing authorizations for Cronassial (a mixture of gangliosides for the treatment of peripheral neuropathies) be withdrawn. At the same time, the CPMP recommended the suspension of marketing authorizations for Sygen (a monosialoganglioside known as GM-1, used to treat cerebrovascular insufficiency).

In 65 patients with ischemic stroke treated intramuscularly with Sygen (monosialoganglioside 40 mg/day) for 6 weeks in a double-blind, placebo-controlled study, there were no significant differences between groups [31]. A subsequent double-blind, sequential, multicentre, randomized, placebo-controlled study of two doses of Sygen did not provide convincing evidence of efficacy.32].

3.2.1 General distribution

Gangliosídeothey are present in most if not all mammalian tissues.197]. The highest concentration of total gangliosides is found in the gray matter of the brain.200]. While the gangliosides of the central nervous system are mainly derived from the gangliosidesGanglion-Peripheral nerve series (about 0.11 µmol Neu per g wet weight [197]) and extraneural tissue (about 0.1–0.35 μmol Neu per g wet weight [200]) contain a high proportion of gangliosides from theleite-[88.461.464.496] ÖGlobus-Series [462.463]. Gangliosides ofGanglion-However, series have also been detected at extraneural sites. If in fact the presence of ganglioside G_tet1 confers sensitivity to a cell to cholera toxin (cf.Section 6.4) then a ganglioside from theGanglion- The series should be pretty ubiquitous.

Use of methylprednisolone and GM-1 ganglioside

Pharmacological neuroprotection is an ongoing area of ​​research in the field of SCI. There is currently no drug approved by the US Food and Drug Administration (FDA) to treat patients with irritable bowel syndrome. Current recommendations do not support the use of methylprednisolone or GM-1Gangliosídeo.⁶⁸

The use of methylprednisolone was mainly reported in three publications by Bracken et al. are reported, collectively referred to as Studies I, II, and III of the National Acute Spinal Cord Injury Study (NASCIS).^69-72Although the initial results of NASCIC II⁷⁰in particular they were reported to be promising, dubious post-manipulation of the data resulted in the results being only Class III recommendations.⁶⁸Furthermore, the use of steroids has been associated with a higher incidence of wound ruptures and infections, VTE phenomena, dyspnea, pneumonia, sepsis and gastrointestinal bleeding, among others. Current recommendations warn against the routine use of methylprednisolone in patients with spinal cord injury; However, there are some controversies, mainly regarding its use in incomplete injuries and in extremely healthy people, such as: B. Professional athletes who may be less prone to side effects.

Ganglioside GM-1 (monosialotetrahexosylganglioside) is a mammalian cell membrane component believed to play a role in cell repair. A small study by Geisler et al. and released in 1991⁷³provided promising results for improvement in ASIA motor skill test scores at 1-year follow-up. However, Geisler's multicenter follow-up study was published in 2001⁷⁴could not confirm these results and no difference was found between GM-1 ganglioside and placebo at final follow-up.^74a–74d). The usefulness of GM-1 ganglioside has not been studied as extensively as methylprednisolone; However, based on these 2001 results, the current recommendation is that the routine use of ganglioside GM-1 in patients with spinal cord injury be discouraged.⁶⁸

Abstract

Gangliosídeo, Glycosphingolipids, which contain one or more sialic acids in the glycan chain, are involved in several important biological processes in the plasma membranes (PM) of cells. However, the behavior and functions of gangliosides are poorly understood, mainly due to the lack of fluorescent analogues that correspond to native gangliosides that can be used as chemical and physical probes. In this study, we developed fully chemical methods to synthesize fluorescent gangliosides (GM3, GM2, GM1 and GD1b) in which the glucan moieties are specifically labeled with different fluorescent dyes. Functional evaluations of the synthesized fluorescent gangliosides revealed the strong influence of the fluorescent dye on the physical properties of the gangliosides in PMs and showed that the fluorescent ganglioside analogues behave similarly to the native gangliosides.

corticosteroids and gangliosides

Several studies have shown improved neurological recovery in animals with SCI given dexamethasone or methylprednisolone.^10-13Corticosteroid treatment initially showed promise as a potential therapeutic for its putative role in reducing white matter edema and inflammation. However, current evidence suggests that the main mechanism of action is to reduce the effects of secondary injury, specifically the destructive effects of lipid peroxidation on cell membranes.³Other effects include improving blood flow to the spinal cord and increasing Na activity after injury.⁺/K⁺-ATPase and facilitates extracellular calcium ion recovery.^13,14

The first NASCIS study (NASCIS I) evaluated low (100 mg) and high (1000 mg) doses of methylprednisolone given to patients with acute SCI for 10 days. Unfortunately, this study had no control group and no significant difference in outcome was found, except for a higher number of wound infections in patients in the high-dose group.¹⁵The second NASCIS study (NASCIS II) was a prospective, randomized, double-blind, multicenter study that demonstrated improved neurological outcomes at 6 weeks, 6 months, and 1 year in patients with nonpenetrating spinal cord injury who received methylprednisolone treatment for a period of 30 years mg/kg bolus.^sixteenImprovements in motor and sensory scores were observed associated with administration of methylprednisolone compared with naloxone or placebo, but only when the drug was administered within 8 hours of injury. The results of this study have been criticized.^17,18Some of the issues relate to difficulties with randomization, reporting methods, analysis of benefit limited to small subgroups within the larger study, and lack of replication of results by an independent group of investigators, among others. NASCIS III results suggest that patients seen within 3 hours of injury should receive a bolus dose of methylprednisolone (30 mg/kg intravenously [IV]) followed by 23 hours of treatment (5 0, 4 mg/ kg/hr i.v.). ). Patients treated for 3 to 8 hours should receive the same bolus followed by a longer (48 hour) dosing schedule. Complications within 48 hours of treatment included a significant increase in severe sepsis and pneumonia.¹⁹The latest neurosurgical guidelines for the management of spinal cord injury do not recommend methylprednisolone as a treatment option because the risks of its use have been more clearly established than the benefits.²⁰A prospective, randomized, double-blind, single-center study found a beneficial effect on functional neurological outcomes when theGangliosídeoGM-1¹was administered within 72 hours of human spinal cord injury.²¹However, a multicenter study showed no statistically significant benefit from this drug at 26 and 52 weeks after injury.²²

4 perspectives

Gangliosídeothey are the major molecular determinants of nerve cell surfaces throughout the central and peripheral nervous system, and major ganglioside structures in the brain have been well conserved during mammalian and avian evolution.¹The discovery of human CDGg demonstrates the importance of gangliosides in brain development, motor and sensory function, cognition, and axon-myelin stability. The spectrum of clinical outcomes of altered ganglioside expression likely encompasses the multiple ways in which gangliosides affect cellular function. As recognition molecules on the surface of nerve cells, certain gangliosides can couple to complementary receptors on side-by-side cells, such as MAG; while other gangliosides can interact laterally at the plasma membrane level to regulate cell signaling receptors and ion channels.^2,52,67,68As deletion of genes in the mouse ganglioside biosynthetic pathway leads to accumulation of gangliosides behind the blockade, some clinical findings in human CDGg may be due to higher levels of simpler structures as well as reduced levels of key brain gangliosides. As experimental insight into the functions of gangliosides in the nervous system emerges, a better understanding of the subsequent results of specific increases and decreases in ganglioside expression in the brain will follow.

The correlation between ganglioside expression and nervous system function in human diseases is currently limited by the lack of postmortem brain tissue from individuals with different diseases.B4GALNT1jST3GAL5Mutations At this time, it is not possible to correlate specific changes in ganglioside expression in the brain with variations in clinical outcomes. Likewise, results from specific mutations in the enzymatic activities of GM2/GD2 synthase and GM3 synthase are insufficient to predict clinical outcomes. In the absence of clinical specimens that shed more light on the structure-function relationships of gangliosides, the availability of patient fibroblasts provides valuable but limited information, as the ganglioside expression profile of human fibroblasts is very simple compared to that of fibroblasts. human neurons.⁶⁹Using technologies to restore fibroblast pluripotency and induce neuronal differentiation,⁷⁰It is expected that additional cellular materials (if not tissue) will be within reach for future studies.

As knowledge of human CDGg advances, a better understanding of the physiological and pathological role of gangliosides will emerge. This knowledge is expected to provide clinical insights beyond these rare congenital disorders and provide information that could lead to therapeutic interventions in these and other neurological diseases and disorders.

5.1 GAβ production in animal models of Alzheimer's

GAβ was discovered in a human brain with early AD pathological changes⁴; however, GAβ production in the brain was not confirmed experimentally until the development of mAb 4396C.⁵To date, using the conformation-specific immunoreactivity of mAb 4396C, GAβ production in various animal models of Alzheimer's disease has been confirmed as follows. First, GAβ production was studied in the brains of non-human primates, all of which had amyloid deposits over 25 years of age.⁷¹In particular, GAβ immunoreactivity was readily observed as a granular pattern in neurons from older monkey brains, suggesting that GAβ is generated and accumulated in specific organelles with age.⁵This possibility was later investigated in brains obtained from animals of the same species in different age groups and it was concluded that GAβ accumulation with age occurs exclusively in endosomes.⁷²Second, GAβ production was examined in the brains of transgenic mice engineered to express the genes responsible for familial AD and to develop extensive amyloid deposition.⁷³In this study, GAβ was readily detected in young mouse brains before amyloid deposition became evident, in good agreement with the detection of GAβ in human brains with early but not advanced AD.⁷³

Ganglioside-Induced Differentiation Associated Protein 1 (GDAP1)

GDAP1 is another factor associated with mitochondrial fission and is localized to the MOM via a C-terminal hydrophobic transmembrane domain that extrudes most of the N-terminal domain into the cytoplasm.Niemannand others, 2005). GDPP1 is involved in thisGangliosídeoMaturation. Mutations in GDAP1 result in peripheral Charcot-Marie-Tooth neuropathy (CMT) affecting Schwann cells, myelinating glia in the peripheral nervous system, and neurons.casseroleand others, 2011). Although it is unclear how GDAP1 is involved in mitochondrial fission, these data suggest the importance of membrane lipid compositions, such as gangliosides, in mitochondrial fission. GDAP1 mutants found in patients with CMT disease do not target mitochondria and lack mitochondrial fragmentation activity (Niemannand others, 2005). GDAP1-induced mitochondrial fragmentation is inhibited by knockdown of Drp1 or expression of the dominant negative Drp1 K38A mutant, indicating that GDAP1 is a Drp1-dependent regulator of mitochondrial fission.Niemannand others, 2005).Huberand others(2013)recently reported that GDAP1 also targets peroxisomes through the action of the peroxisomal import receptor Pex19 and mediates Drp1 and Mff-dependent peroxisomal cleavage, such as in mitochondrial cleavage. GDAP1 has two domains of the glutathione S-transferase family, and overexpression of wild-type GDAP1, but not CMT disease mutants, increases cellular glutathione levels and mitochondrial membrane potential, although the relationship to functional regulation of mitochondrial morphology remain unknown.noackand others, 2012).

Biochemistry of endogenous and exogenous gangliosides

Gangliosídeoare sialo-oligosaccharides attached to a ceramide moiety⁸⁷They are synthesized in the cytoplasm and transported to the plasma membrane. The lipophilic ceramide unit is inserted into the membrane.in the lipid bilayer and the hydrophilic oligosaccharide group with its sialic acid residues projects into the extracellular space. Ganglioside-dependent events leading to morphological and functional recovery likely involve surface modification of the plasma membrane as a result of stable insertion of exogenous gangliosides. Studies on artificial and natural membranes have shown that the distribution of gangliosides within the membrane depends on interactions between polar groups of gangliosides and cell surface proteins.⁸⁹Exogenous gangliosides are spontaneously incorporated into the phospholipid bilayer and exhibit considerable lateral mobility.⁷⁷Depending on the microenvironment, e.g. for example, temperature, exogenous.,⁸⁴o Endogenous GM1 (Monosyaloganglyoside)^23,84can concentrate in clusters and change the composition and local stability of the membrane.⁵⁴The concentration of gangliosides in nerve membranes is particularly high in synaptic structures, probably due to clustering. How ganglioside cluster formation depends on intact actin⁴⁴and because cytoskeletal function is restored in neurons damaged by GM1,^67,83It has been suggested that GM1 may be associated with membrane and cytoskeletal proteins. Once incorporated into the membrane, exogenous gangliosides are functionally active and exhibit behavior similar to endogenous gangliosides.^26,58Its location and structural diversity (more than sixty different types of molecules are now known) make the ganglioside molecule a suitable candidate as a membrane receptor or modulator of membrane-bound receptors.^32,64This could explain why exogenous gangliosides have such diverse effects after brain injury.

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