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Protection by D609 Through Cell-Cycle Regulation After Stroke

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Abstract

Expressions of cell-cycle regulating proteins are altered after stroke. Cell-cycle inhibition has shown dramatic reduction in infarction after stroke. Ceramide can induce cell-cycle arrest by up-regulation of cyclin-dependent kinase (Cdk) inhibitors p21 and p27 through activation of protein phosphatase 2A (PP2A). Tricyclodecan-9-yl-xanthogenate (D609)-increased ceramide levels after transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR) probably by inhibiting sphingomyelin synthase (SMS). D609 significantly reduced cerebral infarction and up-regulated Cdk inhibitor p21 and down-regulated phospho-retinoblastoma (pRb) expression after tMCAO in rat. Others have suggested bFGF-induced astrocyte proliferation is attenuated by D609 due to an increase in ceramide by SMS inhibition. D609 also reduced the formation of oxidized phosphatidylcholine (OxPC) protein adducts. D609 may attenuate generation of reactive oxygen species and formation of OxPC by inhibiting microglia/macrophage proliferation after tMCAO (please also see note added in proof: D609 may prevent mature neurons from entering the cell cycle at the early reperfusion, however may not interfere with later proliferation of microglia/ macrophages that are the source of brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) in offering protection). It has been proposed that D609 provides benefit after tMCAO by attenuating hypoxia-inducible factor-1α and Bcl2/adenovirus E1B 19 kDa interacting protein 3 expressions. Our data suggest that D609 provides benefit after stoke through inhibition of SMS, increased ceramide levels, and induction of cell-cycle arrest by up-regulating p21 and causing hypophosphorylation of Rb (through increased protein phosphatase activity and/or Cdk inhibition).

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Abbreviations

ARE:

Antioxidant response element

ARNT:

Aryl hydrocarbon receptor nuclear translocator

ASMase:

Acid sphingomyelinase

BDNF:

Brain derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

BNIP3:

Bcl2/adenovirus E1B 19kDa interacting protein 3

CC:

Contralateral cortex

CCT:

Cytidine triphosphate (CTP):phosphocholine cytidylyltransferase

Cdk:

Cyclin dependent kinase

CDP-choline:

Cytidine 5′-diphosphocholine

CPT:

CDP-choline:DAG phosphocholine transferase

CTP:

Cytidine triphosphate

D609:

Tricyclodecan-9-yl-xanthogenate

DAG:

1,2-diacylglycerol

EPO:

Erythropoietin

GLUT-1:

Glucose transporter-1

HIF:

Hypoxia-inducible factor

IC:

Ischemic cortex core

IGF-1:

Insulin-like growth factor

IL-1ß:

Interleukin 1ß

IL-6:

Interleukin 6

IP3 :

Inositol 1,4,5-trisphosphate

LPA:

Lyso-phosphatidic acid

OxPC:

Oxidized phosphatidylcholine

PA:

Phosphatidic acid

PC:

Phosphatidylcholine

PC-PLC:

PC-phospholipase C

Penum:

Penumbra

PIP2 :

Phosphatidylinositol 4,5-bisphosphate

PKC:

Protein kinase C

PLA2 :

Phospholipase A2

PLD:

Phospholipase D

PP:

Protein Phosphatase

pRb:

phospho-Retinoblastoma

Rb:

Retinoblastoma

ROS:

Reactive oxygen species

SM:

Sphingomyelin

Smase:

Sphingomyelinase

SMS:

Sphingomyelin synthase

SPT:

Serine palmitoyltransferase

TNF-α:

Tumor necrosis factor-α

TPA:

12-O-tetradecanoylphorbol-13-acetate

VEGF:

Vascular endothelial growth factor

VHL:

von-Hippel Lindau protein

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Acknowledgements

We would like to thank Drs. H. Kalluri, M. Kunnimalaiyaan for helpful discussions, University of Wisconsin Graduate School and School of Medicine and Public Health for supporting this research.

Note added in proof

Recent studies indicate that ablation of proliferating microglia exacerbates ischemic injury in mice after 1 hr tMCAO and reperfusion [80]. This could also suggest that D609 (one dose given at the onset of reperfusion) may prevent mature neurons from entering the cell cycle at the early reperfusion, however may not interfere with later (2-3 day) proliferation of microglia/macrophages that are the source of trophic factors such as brain derived neurotrophic factor (BDNF) [81] and insulin-like growth factor (IGF-1) in offering protection. Interestingly ablation of proliferating microglia resulted in an increase in the number of cells expressing cytokines TNF-1α, IL-1ß and IL-6. However the identity of these cells was not determined. It will be interesting to resolve whether microglia/macrophages are the primary source of pro-inflammatory cytokines [74] or other cells in the absence of activated microglia/macrophages will still provide the pro-inflammatory cytokines [80]. Defining the role of microglia/macrophages in CNS injury is a challenge since they are the source for both pro-inflammatory as well as neurotrophic factors [81–83].

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  1. Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, H4-330, Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792-3232, USA

    Rao Muralikrishna Adibhatla & James F. Hatcher

  2. Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Rao Muralikrishna Adibhatla

  3. Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Rao Muralikrishna Adibhatla

  4. William S. Middleton Veterans Affairs Hospital, Madison, WI, USA

    Rao Muralikrishna Adibhatla

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  1. Rao Muralikrishna Adibhatla
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  2. James F. Hatcher
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Correspondence to Rao Muralikrishna Adibhatla.

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Adibhatla, R.M., Hatcher, J.F. Protection by D609 Through Cell-Cycle Regulation After Stroke. Mol Neurobiol 41, 206–217 (2010). https://doi.org/10.1007/s12035-010-8100-1

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