Seizure activity induces PIM-1 expression in brain

Feldman, Jonathan D.; Vician, Linda; Crispino, Marianna; Tocco, Georges; Baudry, Michel; Herschman, Harvey R.

doi:10.1002/(sici)1097-4547(19980815)53:4<502::aid-jnr13>3.0.co;2-3

Cited by 24 publications

(35 citation statements)

References 28 publications

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“…However, relatively little is known about the regulation and function of Pim kinases in the CNS. Pim-1 expression has been shown to increase in the dentate gyrus of the hippocampus after systemic kainic acid administration in rats (Feldman et al, 1998) and has also been reported to be induced by plasticity-producing stimulation in the brain (Konietzko et al, 1999). The present study demonstrates that G-CSF treatment significantly increased nuclear Pim-1 expression in the injured cortex after focal cerebral ischemia.…”

Section: Discussionsupporting

confidence: 65%

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

et al. 2006

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We investigated the molecular mechanisms of the anti-apoptotic properties of Granulocyte-Colony Stimulating Factor (G-CSF) on neurons and whether G-CSF affects glial cell survival following focal cerebral ischemia in rats. Sprague-Dawley rats were subjected to a transient 90min middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Rats were treated with either a single dose of G-CSF (50 μg/kg, subcutaneously) at the onset of reperfusion or G-CSF (50 μg/kg body weight, subcutaneously) was administered starting at the onset of reperfusion and followed by the administration of the same dose per day for an additional 2 days. Brains were harvested either 24hrs, 72hrs or 2 weeks after reperfusion for assays of infarct volume, immunohistological studies and Western Blot analysis for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Pim-1, bcl-2, Bax, cytochrome c, cellular inhibitor of apoptosis protein 2 (cIAP2), and cleaved caspase-3 levels. G-CSF significantly reduced infarct volume and ameliorated the early neurological outcome. G-CSF treatment significantly up-regulated pSTAT3, Pim-1, bcl-2 expression, and down-regulated cytochrome c release to the cytosol, Bax translocation to the mitochondria, and cleaved caspase-3 levels in neurons. The activation of the STAT3 pathway was accompanied by increased cIAP2 expression in glial cells. After MCAO, G-CSF treatment increased both neuronal and glial survival by effecting different anti-apoptotic pathways which reflects the multifactorial actions of this drug. These changes were associated with remarkable improvement in tissue preservation and behavioral outcome. KeywordsApoptosis; Bcl-2; Glia; Pim-1; STAT; Stroke Granulocyte-Colony Stimulating Factor (G-CSF) is a member of the hematopoietic growth factor family, which orchestrates the proliferation, differentiation, and survival of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Demetri and Griffin, 1991). It has been widely used in clinical practice for the treatment of such conditions as neutropenia, associated with cytotoxic therapy. NIH Public AccessHowever, growing evidence has suggested that G-CSF also has important non-hematopoietic functions in other tissues including the central nervous system (CNS). Recent studies have shown the presence of the G-CSF-receptor (G-CSFR) in a wide variety of cells in the brain, including neurons and glial cells (Schneider et al., 2005). G-CSF and its receptor are coexpressed in neurons and are upregulated in response to neural injury, suggesting an autrocrine protective signalin...

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Section: Discussionsupporting

confidence: 65%

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

et al. 2006

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“…STAT3 can bind directly to the Pim-1 promoter sequence and upregulate pim-1 gene expression. Reports have noted that Pim-1 is elevated after seizure (Feldman et al, 1998). We found an upregulation of Pim-1 after hypoxia-ischemia, and that this was enhanced by G-CSF treatment ( Figure 7A).…”

Section: Discussionsupporting

confidence: 63%

Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia–ischemia in rats

et al. 2007

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Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo, and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 μg/kg, subcutaneous) was administered 1 hour after HI, and given on four subsequent days (five total injections). Animals were euthanized 24 hours, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase 3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury, and that this may occur in part by an inhibition of apoptotic cell death.

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“…The inhibitory profiles of the three active compounds DMAT, DRB, and emodin also support other potential candidates. DMAT inhibits Dyrk1A (35), which binds and phosphorylates ␣-syn (30), and PIM-1, which is induced in the brain upon seizures and long term potentiation (59,60). DRB inhibits cyclin-dependent kinase 7 (36), which is increased in brain during aging and in Alzheimer disease (61).…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein Aggregation and Ser-129 Phosphorylation-dependent Cell Death in Oligodendroglial Cells

Kragh

Lund

Febbraro

et al. 2009

Journal of Biological Chemistry

130

163

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Multiple system atrophy is a neurodegenerative disorder characterized by accumulation of aggregated Ser-129-phosphorylated ␣-synuclein in oligodendrocytes. p25␣ is an oligodendroglial protein that potently stimulates ␣-synuclein aggregation in vitro. To model multiple system atrophy, we coexpressed human p25␣ and ␣-synuclein in the rat oligodendroglial cell line OLN-93 and observed a cellular response characterized by a fast retraction of microtubules from the cellular processes to the perinuclear region followed by a protracted development of apoptosis. This response was dependent on phosphorylation at Ser-129 in ␣-synuclein as demonstrated by site-directed mutagenesis. Treatment of the cells with the kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole that targets kinases like casein kinase 2, and polo-like kinases abrogated the toxicity. The polo-like kinase inhibitor BI 2536 caused apoptosis in the model. Ser-129 phosphorylation was linked to the formation of phosphorylated oligomers detectable by immunoblotting, and their formation was inhibited by 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole. The process of microtubule retraction was also dependent on aggregation as demonstrated by the protective effect of treating the cells with the specific peptide inhibitor of ␣-synuclein aggregation ASI1D and the non-selective inhibitors Congo Red and baicalein. The fast microtubule retraction was followed by the development of the apoptotic markers: activated caspase-3, phosphatidylserine externalization, nuclear condensation, and fragmentation. These markers could all be blocked by the inhibitors of phosphorylation, aggregation, and caspase-3. Hence, the model predicts that both Ser-129 phosphorylation and aggregation control the toxic ␣-syn pathway in oligodendroglial cells and may represent therapeutic intervention points in multiple system atrophy.2 is a soluble protein localized in presynaptic terminals (1). It accumulates as insoluble aggregates in cytoplasmic inclusions in ␣-synucleinopathies, among which Parkinson disease (PD) and dementia with Lewy bodies are the predominant members (2-4). Mutations in the ␣-syn gene leading to amino acid substitutions (A30P, A53T, and E46K) (5-7), and multiplications of the ␣-syn gene (8, 9) are associated with rare familial forms of PD and Lewy bodies.Multiple system atrophy (MSA) represents a special case among the ␣-synucleinopathies. The histological hallmark of MSA is the presence of ␣-syn-containing inclusions in oligodendrocytes, referred to as glial cytoplasmic inclusions (10, 11). Clinically, MSA presents with parkinsonism, ataxia, and autonomic failure, which signify the wide distribution of the degenerative processes (12). The degeneration of oligodendrocytes has been studied using transgenic mice expressing human ␣-syn under the control of oligodendroglial promoters (13-15). These models have demonstrated that expression of ␣-syn in oligodendrocytes results in formation of ␣-syn-containing glial cytoplasmic inclusions, myelin damage, and c...

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Seizure activity induces PIM-1 expression in brain

Cited by 24 publications

References 28 publications

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat

Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia–ischemia in rats

α-Synuclein Aggregation and Ser-129 Phosphorylation-dependent Cell Death in Oligodendroglial Cells

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