Characterization of cyclin D1 expression in a rat global model of cerebral ischemia

Small, Daniel L.; Monette, Robert; Fournier, Marie-Christine; Zurakowski, Bogdan; Fiander, H.; Morley, Paul

doi:10.1016/s0006-8993(01)02102-3

Cited by 26 publications

(18 citation statements)

References 33 publications

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“…Depletion of cyclin D1 appears to lead to the loss of CDK activity (Carlson et al, 1999;Kim et al, 2000) and this showed that Schwann cells fail to proliferate in cyclin D1-null mice during Wallerian degeneration. Cyclin D1 has also been implicated in numerous in vivo models of neuronal death and degeneration, such as cerebral ischemia (Li et al, 1997;Small et al, 2001), Alzheimer's disease (Raina et al, 2000), and epilepsy (Timsit et al, 1999). In the present study, cyclin D1 gene knockout effectively inhibited activation and proliferation of astrocytes and neuronal apoptosis after local cerebral ischemia.…”

Section: Discussionsupporting

confidence: 55%

Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo

Zhu

Zhang

et al. 2007

Glia

111

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Astrogliosis occurs in a variety of neuropathological disorders and injuries, and excessive astrogliosis can be devastating to the recovery of neuronal function. In this study, we asked whether reactive astrogliosis can be suppressed in the lesion area by cell cycle inhibition and thus have therapeutic benefits. Reactive astrogliosis induced in either cultured astrocytes by hypoxia or scratch injury, or in a middle cerebral artery occlusion (MCAO) ischemia model were combined to address this issue. In the cultured astrocytes, hypoxia induced a cell cycle activation that was associated with upregulation of the proliferating cell nuclear marker (PCNA). Significantly, the cell cycle inhibitor, olomoucine, inhibited hypoxia-induced cell cycle activation by arresting the cells at G1/S and G2/M in a dose-dependent manner and also reversed hypoxia-induced upregulation of PCNA. Also in the cultured astrocytes, scratch injury induced reactive astrogliosis, such as hypertrophy and an increase in BrdU(+) astrocytes, both of which were ameliorated by olomoucine. In the MCAO ischemia mouse model, dense reactive glial fibrillary acidic protein and PCNA immunoreactivity were evident at the boundary zone of focal cerebral ischemia at days 7 and 30 after MCAO. We found that intraperitoneal olomoucine administration significantly inhibited these astrogliosis-associated changes. To demonstrate further that cell cycle regulation impacts on astrogliosis, cyclin D1 gene knockout mice (cyclin D1(-/-)) were subjected to ischemia, and we found that the percentage of Ki67-positive astrocytes in these mice was markedly reduced in the boundary zone. The number of apoptotic neurons and the lesion volume in cyclin D1(-/-) mice also decreased as compared to cyclin D1(+/+) and cyclin D1(+/-) mice at days 3, 7, and 30 after local cerebral ischemia. Together, these in vitro and in vivo results strongly suggest that astrogliosis can be significantly affected by cell cycle inhibition, which therefore emerges as a promising intervention to attenuate reactive glia-related damage to neuronal function in brain pathology.

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Section: Discussionsupporting

confidence: 55%

Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo

Zhu

Zhang

et al. 2007

Glia

111

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“…In non-injured cortex, cyclin D1 is co-expressed in MAP2 positive cells, demonstrating its presence in neurons [6,61]. Expression of the CDKIs, such as p27, is high in the normal cortex [58].…”

Section: Cell Cycle Proteins In Vivomentioning

confidence: 96%

“…Cyclin D1 and CDK4 are both expressed in association with apoptosis after transient spinal cord ischemia [78]. However, after global brain ischemia cyclin D1 and CDK4 are not increased above normal values [4,61,76]. However, elevated levels of CDK5 were found after ischemia [76].…”

Section: Traumatic Brain and Spinal Cord Injurymentioning

confidence: 99%

Role of Cell Cycle Proteins in CNS Injury

Byrnes

Faden

2007

Neurochem Res

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Following trauma or ischemia to the central nervous system (CNS), there is a marked increase in the expression of cell cycle-related proteins. This up-regulation is associated with apoptosis of post-mitotic cells, including neurons and oligodendrocytes, both in vitro and in vivo. Cell cycle activation also induces proliferation of astrocytes and microglia, contributing to the glial scar and microglial activation with release of inflammatory factors. Treatment with cell cycle inhibitors in CNS injury models inhibits glial scar formation and neuronal cell death, resulting in substantially decreased lesion volumes and improved behavioral recovery. Here we critically review the role of cell cycle pathways in the pathophysiology of experimental stroke, traumatic brain injury and spinal cord injury, and discuss the potential of cell cycle inhibitors as neuroprotective agents.

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“…In this activated state, microglia express many of the same markers that are seen in macrophages. Expression of cyclin D1 has also been reported in microglia; however, this is usually attributed to proliferation in response to injury (Ino and Chiba, 2001;Small et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage

et al. 2003

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The interactions of glia and neurons during injury and subsequent neurodegeneration are a subject of interest both in disease and chemical-induced brain injury. One such model is the prototypical hippocampal toxicant trimethyltin (TMT). An acute injection of TMT (2.0 mg/kg, i.p.) to postnatal day 21 CD-1 male mice produced neuronal necrosis and loss of dentate granule cells, astrocyte hypertrophy, and microglia activation in the hippocampus within 24 hrs. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-alpha, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-alpha mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h. Immunohistochemistry suggested a cellular localization of cyclin A to microglia in the region of neuronal necrosis in the dentate, cyclin B in glial cells in juxtaposition to neurons in the hilus of the hippocampus and cyclin D1 to non-glial cells in the dentate. mRNA levels for cyclin D1 were elevated approximately 1.5-fold by 72 h as determined by RNase protection assay. No changes were seen in mRNA levels for cyclins E, F, G1, G2, H or I nor cyclin dependent kinases. These elevations are not associated with proliferation of microglia as determined by BrdU incorporation and Ki-67 immunohistochemistry. Upregulation of cell cycle genes was associated with cellular processes other than proliferation and may contribute to the differentiation of microglia to a phagocytic phenotype. These data suggest an integrated role for cell cycle regulation of neural cells in the manifestation of hippocampal pathophysiology.

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Characterization of cyclin D1 expression in a rat global model of cerebral ischemia

Cited by 26 publications

References 33 publications

Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo

Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo

Role of Cell Cycle Proteins in CNS Injury

Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage

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