Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity

Hashimoto, Ryota; Takei, Nobuyuki; Shimazu, Kazuhiro; Christ, Lori; Lu, Bai; Chuang, De‐Maw

doi:10.1016/s0028-3908(02)00217-4

Cited by 232 publications

(139 citation statements)

References 46 publications

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“…In a model of glutamate excitotoxicity, BDNF-TrkB blockade partially inhibited the protective effect of lithium. 38 Neuroprotection provided by PBI-05204, a plant extract from Nerium oleander, is blocked by BDNF-TrkB inhibition with K252a in ischemic brain slices. 39 Furthermore, neurogenic effects of HDAC inhibitors were attenuated upon BDNF blockade with BDNF antibodies in neurons 40 as well as with K252a in a rodent model of ischemia: sodium butyrate-induced neurogenesis in various brain regions 41 as well as oligodendrogenesis and reduction of white-matter injury were demonstrated to depend on BDNF-TrkB signaling.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

Schweizer

Harms

Lerch

et al. 2015

J Cereb Blood Flow Metab

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Cerebral ischemia induces a complex transcriptional response with global changes in gene expression. It is essentially regulated by transcription factors as well as epigenetic players. While it is well known that the inhibition of transcriptionally repressive histone deacetylases leads to neuroprotection, the role of histone methyltransferases in the postischemic transcriptional response remains elusive. We investigated the effects of inhibition of the repressive H3K9 histone methyltransferases SUV39H1 and G9a on neuronal survival, H3K9 promoter signatures and gene expression. Their inhibition either with the specific blocker chaetocin or by use of RNA interference promoted neuronal survival in oxygen glucose deprivation (OGD). Brain-derived neurotrophic factor (BDNF) was upregulated and BDNF promoter regions showed an increase in histone marks characteristic for active transcription. The BDNF blockade with K252a abrogated the protective effect of chaetocin treatment. In conclusion, inhibition of histone methyltransferases SUV39H1 and G9a confers neuroprotection in a model of hypoxic metabolic stress, which is at least in part mediated by BDNF.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

Schweizer

Harms

Lerch

et al. 2015

J Cereb Blood Flow Metab

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“…These include lithium's ability to inhibit N-methyl-D-aspartate receptors (4,29), upregulate cytoprotective Bcl-2 (6,7,30), down-regulate proapoptotic p53 and Bax (7), inhibit glutamate-induced mitogenactivated protein kinase activation (31), facilitate glutamate uptake into presynaptic nerve endings (32), induce the expression of brain-derived neurotrophic factor in discrete brain areas (33,34), and enhance neurogenesis in the hippocampus (35). These actions require long-term treatment and could be more likely involved in the ''delayed'' phase of the neuroprotective effects of this drug.…”

Section: Discussionmentioning

confidence: 99%

Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model

Ren

Senatorov

Chen

et al. 2003

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

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191

165

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Lithium has long been a primary drug used to treat bipolar mood disorder, even though the drug's therapeutic mechanisms remain obscure. Recent studies demonstrate that lithium has neuroprotective effects against glutamate-induced excitotoxicity in cultured neurons and in vivo. The present study was undertaken to examine whether postinsult treatment with lithium reduces brain damage induced by cerebral ischemia. We found that s.c. injection of lithium dose dependently (0.5-3 mEq͞kg) reduced infarct volume in the rat model of middle cerebral artery occlusion͞reperfusion. Infarct volume was reduced at a therapeutic dose of 1 mEq͞kg even when administered up to 3 h after the onset of ischemia. Neurological deficits induced by ischemia were also reduced by daily administration of lithium over 1 week. Moreover, lithium treatment decreased the number of neurons showing DNA damage in the ischemic brain. These neuroprotective effects were associated with an up-regulation of cytoprotective heat shock protein 70 (HSP70) in the ischemic brain hemisphere as determined by immunohistochemistry and Western blotting analysis. Lithium-induced HSP70 up-regulation in the ischemic hemisphere was preceded by an increase in the DNA binding activity of heat shock factor 1, which regulates the transcription of HSP70. Physical variables and cerebral blood flow were unchanged by lithium treatment. Our results suggest that postinsult lithium treatment reduces both ischemia-induced brain damage and associated neurological deficits. Moreover, the heat shock response is likely to be involved in lithium's neuroprotective actions. Additionally, our studies indicate that lithium may have clinical utility for the treatment of patients with acute stroke. cerebral ischemia ͉ heat shock factor 1 ͉ heat shock protein ͉ neuroprotection ͉ DNA damage L ithium has been extensively used in the treatment of bipolar mood disorder, although the mechanisms underlying the drug's therapeutic action remain unclear. There is growing evidence that lithium is neuroprotective against a variety of insults, such as glutamate-induced excitotoxicity, in cultured cells and animal models of diseases (1-3). The mechanisms underlying lithium-induced neuroprotection are complex and may include inactivation of N-methyl-D-aspartate receptors (4), activation of the phosphatidylinositol 3-kinase͞Akt cell survival pathway (5), enhanced expression of cytoprotective Bcl-2 (6, 7), and inhibition of glycogen synthase kinase-3␤ (8).The brain is extremely sensitive to ischemic insult, and the resulting brain damage is related to excitotoxicity. Development of neuroprotective agents against ischemia-induced brain damage has been a therapeutic strategy to reduce the mortality and morbidity associated with stroke. Animal models of brain focal ischemia primarily involve middle cerebral artery occlusion (MCAO). We previously found that lithium pretreatment decreased the infarct volume and neurological deficits in a permanent MCAO model of rats (9). The present study was undertaken to explor...

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“…18 It has also been reported that BDNF protein levels are increased in the brain of rats chronically treated with lithium or VPA, [18][19][20] and in cultured rat cortical neurons exposed to lithium or VPA. 21,22 In the case of lithium-induced protection against glutamate-elicited neurotoxicity in cortical neurons, induction of BDNF is an obligatory event, as BDNF knockout or its receptor blockade prevents the neuroprotective effects of lithium. 21 Recent studies demonstrate that glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase consisting of two isoforms and regulating an array of transcription factors, is a direct target of lithium, 23,24 while VPA inhibits histone deacetylase (HDAC), which has a prominent role in the regulation of gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…21,22 In the case of lithium-induced protection against glutamate-elicited neurotoxicity in cortical neurons, induction of BDNF is an obligatory event, as BDNF knockout or its receptor blockade prevents the neuroprotective effects of lithium. 21 Recent studies demonstrate that glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase consisting of two isoforms and regulating an array of transcription factors, is a direct target of lithium, 23,24 while VPA inhibits histone deacetylase (HDAC), which has a prominent role in the regulation of gene expression. 25,26 Emerging evidence suggests that inhibition of GSK-3 and HDAC are responsible, at least in part, for the neuroprotective effects of lithium and VPA, respectively.…”

Section: Introductionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity

Cited by 232 publications

References 46 publications

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

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