scholarly journals Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: roles of chromatin remodelling and Bcl-2 induction

2013 ◽  
Vol 16 (3) ◽  
pp. 607-620 ◽  
Author(s):  
Yan Leng ◽  
Emily Bame Fessler ◽  
De-Maw Chuang
Keyword(s):  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Mood Stabilizer ◽  
B Cell Lymphoma ◽  
Mood Stabilizers ◽  
Glutamate Excitotoxicity ◽  
Neuroprotective Effects ◽  
Histone Deacetylase Inhibition ◽  
Protein Levels ◽  
Underlying Mechanisms

Abstract Lamotrigine (LTG), a phenyltriazine derivative and anti-epileptic drug, has emerged as an effective first-line treatment for bipolar mood disorder. Like the other mood stabilizers lithium and valproate, LTG also has neuroprotective properties but its exact mechanisms remain poorly defined. The present study utilized rat cerebellar granule cells (CGCs) to examine the neuroprotective effects of LTG against glutamate-induced excitotoxicity and to investigate potential underlying mechanisms. CGCs pretreated with LTG were challenged with an excitotoxic dose of glutamate. Pretreatment caused a time- and concentration-dependent inhibition of glutamate excitotoxicity with nearly full protection at higher doses (⩾100 µm), as revealed by cell viability assays and morphology. LTG treatment increased levels of acetylated histone H3 and H4 as well as dose- and time-dependently enhanced B-cell lymphoma-2 (Bcl-2) mRNA and protein levels; these changes were associated with up-regulation of the histone acetylation and activity of the Bcl-2 promoter. Importantly, lentiviral-mediated Bcl-2 silencing by shRNA reduced both LTG-induced Bcl-2 mRNA up-regulation and neuroprotection against glutamate excitotoxicity. Finally, the co-presence of a sub-effective concentration of LTG (10 µm) with lithium or valproate produced synergistic neuroprotection. Together, our results demonstrate that the neuroprotective effects of LTG against glutamate excitotoxicity likely involve histone deacetylase inhibition and downstream up-regulation of anti-apoptotic protein Bcl-2. These underlying mechanisms may contribute to the clinical efficacy of LTG in treating bipolar disorder and warrant further investigation.

Selenium compounds counteract the stimulation of ecto-nucleotidase activities in rat cultured cerebellar granule cells: Putative correlation with neuroprotective effects

2008 ◽  
Vol 1221 ◽  
pp. 134-140 ◽  
Author(s):  
Gabriele Ghisleni ◽  
Lisiane O. Porciúncula ◽  
Sabrina Mioranzza ◽  
Carina R. Boeck ◽  
João B.T. Rocha ◽  
...  
Keyword(s):  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Neuroprotective Effects ◽  
Selenium Compounds ◽  
Cerebellar Granule ◽  
Stimulation Of

scholarly journals Autophagy Regulates the Post-Translational Cleavage of BCL-2 and Promotes Neuronal Survival

2010 ◽  
Vol 10 ◽  
pp. 924-929 ◽  
Author(s):  
Laura Lossi ◽  
Graziana Gambino ◽  
Chiara Salio ◽  
Adalberto Merighi
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Calcium Release ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Apoptotic Protein ◽  
Niemann Pick

B-cell lymphoma 2 protein (BCL-2) is one of the more widely investigated anti-apoptotic protein in mammals, and its levels are critical for protecting from programmed cell death. We report here that the cellular content of BCL-2 is regulated at post-translational level along the autophagy/lysosome pathways in organotypic cultures of post-natal mouse cerebellar cortex. Specifically this mechanism appears to be effective in the cerebellar granule cells (CGCs) that are known to undergo massive programmed cell death (apoptosis) during post-natal maturation. By the use of specific agonists/antagonist of calcium channels at the endoplasmic reticulum it was possible to understand the pivotal role of calcium release from intracellular stores in CGC neuroprotection. The more general significance of these findings is supported by a very recent study Niemann-Pick transgenic mice.

scholarly journals Tissue specificity and regulation of the N-terminal diversity of reticulon 3

2004 ◽  
Vol 385 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Franck DI SCALA ◽  
Luc DUPUIS ◽  
Christian GAIDDON ◽  
Marc DE TAPIA ◽  
Natasa JOKIC ◽  
...  
Keyword(s):  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Granule Neurons ◽  
Cerebellar Granule ◽  
Preferential Expression ◽  
Protein Levels ◽  
The Central Nervous System ◽  
Cerebellum Development ◽  
Promoter Usage

Over the last few years, the widely distributed family of reticulons (RTNs) is receiving renewed interest because of the implication of RTN4/Nogo in neurite regeneration. Four genes were identified in mammals and are referred to as RTN1, 2, 3 and the neurite outgrowth inhibitor RTN4/Nogo. In the present paper, we describe the existence of five new isoforms of RTN3 that differ in their N-termini, and analysed their tissue distribution and expression in neurons. We redefined the structure of human and murine rtn3 genes, and identified two supplementary exons that may generate up to seven putative isoforms arising by alternative splicing or differential promoter usage. We confirmed the presence of five of these isoforms at the mRNA and protein levels, and showed their preferential expression in the central nervous system. We analysed rtn3 expression in the cerebellum further, and observed increased levels of several of the RTN3 isoforms during cerebellum development and during in vitro maturation of cerebellar granule cells. This pattern of expression paralleled that shown by RTN4/Nogo isoforms. Specifically, RTN3A1 expression was down-regulated upon cell death of cerebellar granule neurons triggered by potassium deprivation. Altogether, our results demonstrate that the rtn3 gene generates multiple isoforms varying in their N-termini, and that their expression is tightly regulated in neurons. These findings suggest that RTN3 isoforms may contribute, by as yet unknown mechanisms, to neuronal survival and plasticity.

scholarly journals Serine 1283 in extracellular matrix glycoprotein Reelin is crucial for Reelin′s function in brain development

2022 ◽  
Author(s):  
Ralf Kleene ◽  
Gabriele Loers ◽  
Ahmed Sharaf ◽  
Shaobo Wang ◽  
Hardeep Kataria ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Adhesion Molecules ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Phosphorylation Site ◽  
Proteolytic Processing ◽  
Brain Anatomy ◽  
Wild Type ◽  
Protein Levels

Deficiency in the extracellular matrix glycoprotein Reelin severely affects migration of neurons during development. The function of serine at position 1283 in Reelin has remained uncertain. To explore its relevance we generated rlnA/A mice that carry alanine instead of serine at position 1283, thereby disrupting the putative casein kinase 2 (CK2) phosphorylation site S1283DGD. Mutated mice displayed reeler-like locomotor behavior, abnormal brain anatomy and decrease of Reelin RNA and protein levels during development and in adulthood. Since serine 1283 was previously proposed to mediate proteolysis of adhesion molecules, we investigated proteolysis of cell adhesion molecule L1 and found it normal in rlnA/A mice. Neuronal migration in the embryonic rlnA/A cerebral cortex was impaired, but rescued by in utero electroporation of the Reelin fragment N-R6 containing the putative CK2 phosphorylation site. In rlnA/A mice migration of cerebellar granule cells in vitro was promoted by application of wild-type but not by mutated Reelin. In cerebellar neuron cultures, Reelin expression was decreased upon inhibition of ecto-phosphorylation by CK2. Biochemically purified wild-type, but not mutated Reelin was found phosphorylated. Altogether, the results indicate that ecto-phosphorylation at serine 1283 rather than proteolytic processing of adhesion molecules by Reelin plays an important role in Reelin functions.

scholarly journals The neurotrophic and neuroprotective effects of psychotropic agents

2009 ◽  
Vol 11 (3) ◽  
pp. 333-348 ◽  
Keyword(s):  
Neurodegenerative Diseases ◽  
Animal Studies ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Brain Regions ◽  
Mood Stabilizers ◽  
Mitogen Activated Protein Kinase ◽  
Neuroprotective Effects ◽  
Psychotropic Agents

Accumulating evidence suggests that psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics realize their neurotrophic/neuroprotective effects by activating the mitogen activated protein kinase/extracellular signal-related kinase, PI3-kinase, and wingless/glycogen synthase kinase (GSK) 3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as brain-derived neurotrophic factor, nerve growth factor, B-cell lymphoma 2, serine-threonine kinase, and Bcl-2 associated athanogene 1, and inactivate proapoptotic molecules such as GSK-3. They also promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Most if not all, of this evidence was collected from animal studies that used clinically relevant treatment regimens. Furthermore, human imaging studies have found that these agents increase the volume and density of brain tissue, as well as levels of N-acetyl aspartate and glutamate in selected brain regions. Taken together, these data suggest that the neurotrophic/neuroprotective effects of these agents have broad therapeutic potential in the treatment; not only of mood disorders and schizophrenia, but also neurodegenerative diseases and ischemia.

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