RESUMEN

It is known that sialyllactose (SL) in mammalians is a major source of sialic acid (Sia), which can further form cytidine monophosphate sialic acid (CMP-Sia), and the final product is polysialic acid (polySia) using polysialyltransferases (polySTs) on the neural cell adhesion molecule (NCAM). This process is called NCAM polysialylation. The overexpression of polysialylation is strongly related to cancer cell migration, invasion, and metastasis. In order to inhibit the overexpression of polysialylation, in this study, SL was selected as an inhibitor to test whether polysialylation could be inhibited. Our results suggest that the interactions between the polysialyltransferase domain (PSTD) in polyST and CMP-Siaand the PSTD and polySia could be inhibited when the 3'-sialyllactose (3'-SL) or 6'-sialyllactose (6'-SL) concentration is about 0.5 mM or 6'-SL and 3 mM, respectively. The results also show that SLs (particularly for 3'-SL) are the ideal inhibitors compared with another two inhibitors, low-molecular-weight heparin (LMWH) and cytidine monophosphate (CMP), because 3'-SL can not only be used to inhibit NCAM polysialylation, but is also one of the best supplements for infant formula and the gut health system.

RESUMEN

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1ß, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Asunto(s)

Degeneración Macular , Nanopartículas , Degeneración Retiniana , Ratones , Humanos , Animales , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Degeneración Macular/tratamiento farmacológico , Macrófagos , Inflamación/tratamiento farmacológico

RESUMEN

[This corrects the article DOI: 10.3389/fncel.2023.1207540.].

RESUMEN

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Spontaneous restoration of myelin after demyelination occurs, but its efficiency declines during disease progression. Efficient myelin repair requires fine-tuning inflammatory responses by brain-resident microglia and infiltrating macrophages. Accordingly, promising therapeutic strategies aim at controlling inflammation to promote remyelination. Polysialic acid (polySia) is a polymeric glycan with variable chain lengths, presented as a posttranslational modification on select protein carriers. PolySia emerges as a negative regulator of inflammatory microglia and macrophage activation and has been detected on oligodendrocyte precursors and reactive astrocytes in multiple sclerosis lesions. As shown recently, polySia-modified proteins can also be released by activated microglia, and the intrinsically released protein-bound and exogenously applied free polySia were equally able to attenuate proinflammatory microglia activation via the inhibitory immune receptor Siglec-E. In this study, we explore polySia as a candidate substance for promoting myelin regeneration by immunomodulation. Lysophosphatidylcholine-induced demyelination of organotypic cerebellar slice cultures was used as an experimental model to analyze the impact of polySia with different degrees of polymerization (DP) on remyelination and inflammation. In lysophosphatidylcholine-treated cerebellar slice cultures, polySia-positive cells were abundant during demyelination but largely reduced during remyelination. Based on the determination of DP24 as the minimal polySia chain length required for the inhibition of inflammatory BV2 microglia activation, pools with short and long polySia chains (DP8-14 and DP24-30) were generated and applied to slice cultures during remyelination. Unlike DP8-14, treatment with DP24-30 significantly improved remyelination, increased arginase-1-positive microglia ratios, and reduced the production of nitric oxide in wildtype, but not in Siglec-E-deficient slice cultures. In vitro differentiation of oligodendrocytes was not affected by DP24-30. Collectively, these results suggest a beneficial effect of exogenously applied polySia DP24-30 on remyelination by Siglec-E-dependent microglia regulation.

RESUMEN

Polysialylation is a process of polysialic acid (polySia) addition to neural cell adhesion molecule (NCAM), which is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. Polysialylation can be catalyzed by two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST). It has been proposed that two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs, are possible binding sites for the intermolecular interactions of polyST-NCAM and polyST-polySia, respectively, as well as the intramolecular interaction of PSTD-PBR. In this study, Chou's wenxiang diagrams of the PSTD and PBR are used to determine the key amino acids of these intermolecular and intramolecular interactions, and thus it may be helpful for the identification of the crucial amino acids in the polyST and for the understanding of the molecular mechanism of NCAM polysialylation by incorporating the wenxiang diagram and molecular modeling into NMR spectroscopy.

Asunto(s)

Moléculas de Adhesión de Célula Nerviosa , Sialiltransferasas , Animales , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Sialiltransferasas/metabolismo , Ácidos Siálicos/metabolismo , Espectroscopía de Resonancia Magnética , Aminoácidos , Mamíferos/metabolismo

RESUMEN

BACKGROUND: Polysialic acids (abbr. polySia) are found on numerous tumors, including neuroendocrine lung tumors. They have previously been shown to impact metastatic potential, as they can influence the signaling and adhesion properties of neuronal cell adhesion molecules (abbr. NCAM) and other cell adhesion molecules. Therefore, the aim of this small pilot study was to analyze whether there was a correlation between polySia-NCAM expression and specific clinical or histopathologic characteristics, and if polySia-NCAM expression had an impact on treatment response, disease progression and prognosis of lung neuroendocrine neoplasms. METHODS: This work was based on an analysis of 28 digitized patient records and corresponding patient samples. The response to therapy was radiologically determined at the time of diagnosis and at certain intervals during therapy following the current RECIST1.1 and volumetric sphere calculation. To analyze whether polySia-NCAM expression had prognostic relevance, polySia-NCAM-positive and -negative cases were compared in a Kaplan-Meier survival analysis. FINDINGS: A majority of 78.6% lung neuroendocrine neoplasms showed a strong staining signal for polySia-NCAM. There was a significant correlation between expression and histopathological grade (p = 0.0140), since carcinoids were less likely polySia-NCAM-positive compared to small cell lung carcinoma (abbr. SCLC) and large cell neuroendocrine carcinomas of the lung (abbr. LCNEC). There was no significant association between polySia-NCAM expression and clinical characteristics (age: p = 0.3405; gender: p = 0.6730; smoking history: p = 0.1145; ECOG: p = 0.1756, UICC8 stage: p = 0.1182) or radiologically determined disease progression, regardless of the criteria used to categorize response (RECIST 1.1: p = 0.0759; sphere: p = 0.0580). Furthermore, polySia-NCAM expression did not affect progression-free survival (p = 0.4198) or overall survival (p = 0.6918). INTERPRETATION: PolySia-NCAM expression was more common in high-grade compared to low-grade neuroendocrine neoplasms of the lung; however, this small pilot study failed to show an association between polySia-NCAM expression and response to therapy.

RESUMEN

Sialic acids are terminal sugars on the cell surface that are found on all cell types including immune cells like natural killer (NK) cells. The attachment of sialic acids to different glycan structures is catalyzed by sialyltransferases in the Golgi. However, the expression pattern of sialyltransferases in NK cells and their expression after activation has not yet been analyzed. Therefore, the present study determines which sialyltransferases are expressed in human NK cells and if activation with IL-2 changes the sialylation of NK cells. The expression of sialyltransferases was analyzed in the three human NK cell lines NK-92, NKL, KHYG-1 and primary NK cells. NK-92 cells were cultured in the absence or presence of IL-2, and changes in the sialyltransferase expression were measured by qPCR. Furthermore, specific sialylation was investigated by flow cytometry. In addition, polySia and NCAM were measured by Western blot analyses. IL-2 leads to a reduced expression of ST8SIA1, ST6GAL1 and ST3GAL1. α-2,3-Sialylation remained unchanged, while α-2,6-sialylation was increased after IL-2 stimulation. Moreover, an increase in the amount of NCAM and polySia was observed in IL-2-activated NK cells, whereas GD3 ganglioside was decreased. In this study, all sialyltransferases that were expressed in NK cells could be identified. IL-2 regulates the expression of some sialyltransferases and leads to changes in the sialylation of NK cells.

RESUMEN

Polysialic acid (polySia) is an unusual glycan that posttranslational modifies neural cell adhesion molecule (NCAM) proteins in mammalian cells. The up-regulated expression of polySia-NCAM is associated with tumor progression in many metastatic human cancers and in neurocognitive processes. Two members of the ST8Sia family of α2,8-polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST) both catalyze synthesis of polySia when activated cytidine monophosphate(CMP)-Sialic acid (CMP-Sia) is translocate into the lumen of the Golgi apparatus. Two key polybasic domains in the polySTs, the polybasic region (PBR) and the polysialyltransferase domain (PSTD) areessential forpolysialylation of the NCAM proteins. However, the precise molecular details to describe the interactions required for polysialylation remain unknown. In this study, we hypothesize that PSTD interacts with both CMP-Sia and polySia to catalyze polysialylation of the NCAM proteins. To test this hypothesis, we synthesized a 35-amino acid-PSTD peptide derived from the ST8Sia IV gene sequence and used it to study its interaction with CMP-Sia, and polySia. Our results showed for the PSTD-CMP-Sia interaction,the largest chemical-shift perturbations (CSP) were in amino acid residues V251 to A254 in the short H1 helix, located near the N-terminus of PSTD. However, larger CSP values for the PSTD-polySia interaction were observed in amino acid residues R259 to T270 in the long H2 helix. These differences suggest that CMP-Sia preferentially binds to the domain between the short H1 helix and the longer H2 helix. In contrast, polySia was principally bound to the long H2 helix of PSTD. For the PSTD-polySia interaction, a significant decrease in peak intensity was observed in the 20 amino acid residues located between the N-and C-termini of the long H2 helix in PSTD, suggesting a slower motion in these residues when polySia bound to PSTD. Specific features of the interactions between PSTD-CMP-Sia, and PSTD-polySia were further confirmed by comparing their 800 MHz-derived HSQC spectra with that of PSTD-Sia, PSTD-TriSia (DP 3) and PSTD-polySia. Based on the interactions between PSTD-CMP-Sia, PSTD-polySia, PBR-NCAM and PSTD-PBR, these findingsprovide a greater understanding of the molecular mechanisms underlying polySia-NCAM polysialylation, and thus provides a new perspective for translational pharmacological applications and development by targeting the two polysialyltransferases.

Asunto(s)

Ácido N-Acetilneuramínico Citidina Monofosfato/metabolismo , Imagen por Resonancia Magnética/métodos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Sialiltransferasas/química , Sialiltransferasas/metabolismo , Aparato de Golgi/metabolismo , Humanos , Modelos Moleculares , Polimerizacion , Conformación Proteica , Dominios Proteicos

RESUMEN

We identified and analyzed α2,8-sialyltransferases sequences among 71 ray-finned fish species to provide the first comprehensive view of the Teleost ST8Sia repertoire. This repertoire expanded over the course of Vertebrate evolution and was primarily shaped by the whole genome events R1 and R2, but not by the Teleost-specific R3. We showed that duplicated st8sia genes like st8sia7, st8sia8, and st8sia9 have disappeared from Tetrapods, whereas their orthologues were maintained in Teleosts. Furthermore, several fish species specific genome duplications account for the presence of multiple poly-α2,8-sialyltransferases in the Salmonidae (ST8Sia II-r1 and ST8Sia II-r2) and in Cyprinus carpio (ST8Sia IV-r1 and ST8Sia IV-r2). Paralogy and synteny analyses provided more relevant and solid information that enabled us to reconstruct the evolutionary history of st8sia genes in fish genomes. Our data also indicated that, while the mammalian ST8Sia family is comprised of six subfamilies forming di-, oligo-, or polymers of α2,8-linked sialic acids, the fish ST8Sia family, amounting to a total of 10 genes in fish, appears to be much more diverse and shows a patchy distribution among fish species. A focus on Salmonidae showed that (i) the two copies of st8sia2 genes have overall contrasted tissue-specific expressions, with noticeable changes when compared with human co-orthologue, and that (ii) st8sia4 is weakly expressed. Multiple sequence alignments enabled us to detect changes in the conserved polysialyltransferase domain (PSTD) of the fish sequences that could account for variable enzymatic activities. These data provide the bases for further functional studies using recombinant enzymes.

Asunto(s)

Sialiltransferasas/genética , Vertebrados/genética , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Biología Computacional/métodos , Evolución Molecular , Peces/genética , Peces/metabolismo , Expresión Génica , Sitios Genéticos , Modelos Moleculares , Familia de Multigenes , Filogenia , Conformación Proteica , Sialiltransferasas/química , Sialiltransferasas/metabolismo , Relación Estructura-Actividad , Vertebrados/metabolismo

RESUMEN

ST8Sia II (STX) is a highly homologous mammalian polysialyltransferase (polyST), which is a validated tumor-target in the treatment of cancer metastasis reliant on tumor cell polysialylation. PolyST catalyzes the synthesis of α2,8-polysialic acid (polySia) glycans by carrying out the activated CMP-Neu5Ac (Sia) to N- and O-linked oligosaccharide chains on acceptor glycoproteins. In this review article, we summarized the recent studies about intrinsic correlation of two polybasic domains, Polysialyltransferase domain (PSTD) and Polybasic region (PBR) within ST8Sia II molecule, and suggested that the critical amino acid residues within the PSTD and PBR motifs of ST8Sia II for polysialylation of Neural cell adhesion molecules (NCAM) are related to ST8Sia II activity. In addition, the conformational changes of the PSTD domain due to point mutations in the PBR or PSTD domain verified an intramolecular interaction between the PBR and the PSTD. These findings have been incorporated into Zhou's NCAM polysialylation/cell migration model, which will provide new perspectives on drug research and development related to the tumor-target ST8Sia II.

Asunto(s)

Inhibidores Enzimáticos/farmacología , Sialiltransferasas/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/química , Humanos , Mutación Puntual , Dominios Proteicos , Sialiltransferasas/genética , Sialiltransferasas/metabolismo

RESUMEN

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. It has been known that two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research results about the intermolecular interactions between the PBR and NCAM, the PSTD and cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms, which may be helpful to design and develop new polysialyltransferase inhibitors.

Asunto(s)

Movimiento Celular , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Animales , Humanos , Moléculas de Adhesión de Célula Nerviosa/química , Ácidos Siálicos/química

RESUMEN

Formulas derived from theoretical physics provide important insights about the nematocyst discharge process of Cnidaria (Hydra, jellyfishes, box-jellyfishes and sea-anemones). Our model description of the fastest process in living nature raises and answers questions related to the material properties of the cell- and tubule-walls of nematocysts including their polysialic acid (polySia) dependent target function. Since a number of tumor-cells, especially brain-tumor cells such as neuroblastoma tissues carry the polysaccharide chain polySia in similar concentration as fish eggs or fish skin, it makes sense to use these findings for new diagnostic and therapeutic approaches in the field of nanomedicine. Therefore, the nematocyst discharge process can be considered as a bionic blue-print for future nanomedical devices in cancer diagnostics and therapies. This approach is promising because the physical background of this process can be described in a sufficient way with formulas presented here. Additionally, we discuss biophysical and biochemical experiments which will allow us to define proper boundary conditions in order to support our theoretical model approach. PolySia glycans occur in a similar density on malignant tumor cells than on the cell surfaces of Cnidarian predators and preys. The knowledge of the polySia-dependent initiation of the nematocyst discharge process in an intact nematocyte is an essential prerequisite regarding the further development of target-directed nanomedical devices for diagnostic and therapeutic purposes. The theoretical description as well as the computationally and experimentally derived results about the biophysical and biochemical parameters can contribute to a proper design of anti-tumor drug ejecting vessels which use a stylet-tubule system. Especially, the role of nematogalectins is of interest because these bridging proteins contribute as well as special collagen fibers to the elastic band properties. The basic concepts of the nematocyst discharge process inside the tubule cell walls of nematocysts were studied in jellyfishes and in Hydra which are ideal model organisms. Hydra has already been chosen by Alan Turing in order to figure out how the chemical basis of morphogenesis can be described in a fundamental way. This encouraged us to discuss the action of nematocysts in relation to morphological aspects and material requirements. Using these insights, it is now possible to discuss natural and artificial nematocyst-like vessels with optimized properties for a diagnostic and therapeutic use, e.g., in neurooncology. We show here that crucial physical parameters such as pressure thresholds and elasticity properties during the nematocyst discharge process can be described in a consistent and satisfactory way with an impact on the construction of new nanomedical devices.

Asunto(s)

Cnidarios/química , Ácido N-Acetilneuramínico/química , Nematocisto/química , Animales , Pared Celular/química , Cubomedusas/química , Elasticidad/efectos de los fármacos , Humanos , Hydra/química , Morfogénesis/efectos de los fármacos , Nanomedicina/métodos

RESUMEN

Polysialic acid (polySia) is widely investigated in various biopharmaceutical applications (e.g. treatment of inflammatory neurodegenerative diseases), whereby a certain polySia chain length with an average degree of polymerization 20 (polySia avDP20) shows most promising effects. In this study, a rapid analytical method using a HPLC and charged aerosol detector (CAD) for the direct chain length characterization of biopharmaceutically relevant polySia was developed. It was evaluated as a fast alternative to the commonly used 1,2-diamino-4,5-methylenedioxybenzene (DMB) HPLC application. In contrast to HPLC-FLD, the CAD-application provides the actual chain length of polySia within ∼3 h. The reliability of the HPLC-CAD was evaluated with a commercial reference sample of known chain length and biotechnologically produced LC polySia (long chain polySia with a DP ∼130). Moreover, HPLC-CAD was successfully applied in the direct detection of oligo- and polySia until DP ∼65 and can be used to monitor the thermal hydrolysis and subsequent chromatographic isolation of polySia avDP20 (average degree of polymerization 20) without DMB sample derivatization. In addition, CAD was successfully applied for polySia quantification using a modified elution gradient. It was tested as a fast alternative to commonly used thiobarbituric acid (TBA) assay. A differentiation between LC polySia and smaller, hydrolysed polySia chains was intended and possible. For LC polySia and polySia avDP20, a quadratic relation between polySia mass-concentration and CAD signal was observed. In case of LC polySia, a quadratic dependency with a determination coefficient of R2 = 0.99 in a broad concentration range between 0.025 and 15 mg mL-1 was determined. Quantification of polySia avDP20 was found to have quadratic dependency with a determination coefficient of R2 = 0.99 in a concentration range between 0.02 and 0.25 mg mL-1. The HPLC-CAD was tested for quantification with polySia references of known concentration and showed high accordance with a concentration deviation ≤6.7%. The CAD quantification method was also applied in the polySia avDP20 production process and was compared to the TBA assay. Results of a correlation plot showed a high determination coefficient of R2 = 0.98. Overall, HPLC-CAD analysis was successfully tested as a suitable characterization and quantification application in the biopharmaceutical production of polySia.

Asunto(s)

Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión , Escherichia coli/química , Ácidos Siálicos/análisis , Aerosoles/química , Hidrólisis , Polimerizacion , Reproducibilidad de los Resultados

RESUMEN

Polysialic acid (polySia) is a complex sugar that in the nervous system appears mainly as a posttranslational modification of the neural cell adhesion molecule (NCAM). PolySia plays important roles during brain development, but also in its plasticity during adulthood. Two polysialyltransferases (polyST), ST8SIA2 and ST8SIA4, are involved in the synthesis and attachment of polySia. Both polyST are relevant for developmental migration of cortical interneurons and their establishment in the prefrontal cortex (PFC). In contrast, only ST8SIA4 appears to be important for the structural plasticity of a subpopulation of cortical interneurons in the adult. Interestingly, ST8SIA2 and NCAM are candidate genes for schizophrenia, a disorder in which interneuronal circuits are altered. However, there is still no data on the effects of polyST depletion on the dendritic structure or the connectivity of cortical interneurons. Here, we studied the contribution of each polyST on these parameters in the medial PFC (mPFC) of polyST knock-out mice with GAD67-GFP-labeled interneurons. Genetic depletion of ST8SIA4, but not ST8SIA2, resulted in a decrease in the complexity of the dendritic arbor of interneurons. In contrast, ablation of either of the two polyST induced a decrease in the density of parvalbumin (PV) expressing perisomatic puncta on pyramidal neurons. Thus, the depletion of each polyST results in similar impairments of not only developmental migration but also efferent synaptic connectivity of interneurons. In contrast, the loss of ST8SIA4 has a unique effect on dendritic structure, hence on afferent connectivity, suggesting differential and independent contributions of each polyST to neuritogenesis and synaptogenesis.

RESUMEN

Polysialic acid (polySia) and polySia glycomimetic molecules support nerve cell regeneration, differentiation, and neuronal plasticity. With a combination of biophysical and biochemical methods, as well as data mining and molecular modeling techniques, it is possible to correlate specific ligand-receptor interactions with biochemical processes and in vivo studies that focus on the potential therapeutic impact of polySia, polySia glycomimetics, and sulfated polysaccharides in neuronal diseases. With this strategy, the receptor interactions of polySia and polySia mimetics can be understood on a submolecular level. As the HNK-1 glycan also enhances neuronal functions, we tested whether similar sulfated oligo- and polysaccharides from seaweed could be suitable, in addition to polySia, for finding potential new routes into patient care focusing on an improved cure for various neuronal diseases. The knowledge obtained here on the structural interplay between polySia or sulfated polysaccharides and their receptors can be exploited to develop new drugs and application routes for the treatment of neurological diseases and dysfunctions.

Asunto(s)

Polisacáridos/metabolismo , Ácidos Siálicos/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Resonancia Magnética Nuclear Biomolecular , Polisacáridos/química , Polisacáridos/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Ácidos Siálicos/química , Ácidos Siálicos/farmacología

RESUMEN

The neural cell adhesion molecule (NCAM) and its functionally linked polysialyltransferases, ST8SIA2 and ST8SIA4, are crucial for synaptic plasticity. Variations in encoding genes have been associated with mental illness. Since cannabinoids can alter NCAM polysialylation, we hypothesized that delta-9-tetrahydrocannabinol (Δ9-THC) might act as environmental 'second hit' regarding cognition of St8sia2(-/-) mice. These mice show per se minor behavioral abnormalities, consisting of reduced anxiety and mild cognitive deficits. Chronic Δ9-THC treatment of juvenile male wildtype mice (St8sia2(+/+)) (7mg/kg every other day over 3 weeks) did not appreciably affect cognition. St8sia2(-/-) mice, however, displayed a synergistic negative consequence of Δ9-THC on learning/memory, accompanied by polysialic acid-free NCAM-180 reduction in hippocampus and polysialic acid increase in dentate outer molecular layer. These synergistic effects became obvious only months after the last Δ9-THC. We conclude that juvenile cannabis exposure may cause delayed but lasting damage on cognition in subjects genetically predisposed to altered NCAM polysialylation.

Asunto(s)

Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/genética , Dronabinol/toxicidad , Psicotrópicos/toxicidad , Sialiltransferasas/deficiencia , Factores de Edad , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Sialiltransferasas/genética