. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8333-8. PubMed.

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  1. Di Giovanni and colleagues provide convincing evidence that
    traumatic brain injury causes upregulation of cell cycle proteins in rat
    brains, and that prevention of cell cycle entry attenuates the neuronal
    cell death and glial proliferation resulting from such injury. First, the investigators
    carried out expression profiling to detect genes in which expression was
    altered by traumatic brain injury. They found significantly increased
    expression of a number of DNA damage-related and cell cycle genes. They also found that expression of cell cycle inhibitor genes was unchanged or decreased in
    brains subjected to this injury. In vitro studies were then carried out to
    demonstrate that treatment of rat primary neuronal cultures with the
    DNA-damaging agent etoposide caused some of the same gene changes,
    including increased expression of cyclin D1 and PCNA, and decreased
    expression of the cyclin dependent kinase (CDK) inhibitor p27. Etoposide
    also caused apoptosis of the primary cortical neurons. Treatment of the
    cultures with the selective CDK inhibitor flavopiridol, which inhibits the
    G1 to S transition, 1 hour before etoposide administration caused reversal
    of both the gene expression changes and apoptosis mediated by etoposide. In a
    separate experiment, flavopiridol also inhibited proliferation of primary
    cortical astrocytes.

    Having shown these effects of flavopiridol in what
    were essentially in vitro models of specific aspects of traumatic brain
    injury, the authors moved back to the in vivo model. They inflicted
    traumatic brain injury on rats that were treated with flavopiridol or vehicle intraventricularly. As before, traumatic brain injury
    caused increased expression of cyclin D1 and PCNA, decreased expression of
    p27, and proliferation of astrocytes. Flavopiridol treatment after
    traumatic brain injury reduced the expression of cell cycle proteins in
    neurons and glia, decreased neuronal apoptosis, and limited astroglial
    proliferation in the region of the injury. These flavopiridol-induced
    changes were accompanied by a remarkable reduction of brain lesion volume
    and of the cognitive deficits normally mediated by traumatic brain injury.

    There are several interesting take-home lessons from this
    study. First, cell cycle inhibition not only protected neurons subjected
    to traumatic brain injury, but also reduced glial proliferation and scar
    formation. Thus, it has a two-pronged beneficial effect. Secondly, it
    provides yet another example of neurodegeneration that is accompanied by
    cell cycle alterations. Aberrations of the cell cycle have been reported
    in Alzheimer disease, tauopathies, Niemann-Pick disease type C,
    amyotrophic lateral sclerosis, and ataxia-telangiectasia, suggesting that
    these diseases have in common a loss of cell cycle control that underlies
    the neurodegeneration. Loss of cell cycle control is not necessarily a
    universal mechanism in neurodegenerative diseases, however; cell cycle
    abnormalities have not yet been detected in Parkinson disease,
    Huntington disease, or AIDS dementia, for example. These findings
    suggest that a subset of neurodegenerative disease involves loss of
    neuronal cell cycle control. The third lesson to be taken from this study
    is that a CDK inhibitor can work in vivo to prevent
    neurodegeneration. This, of course, has enormous therapeutic
    implications. The authors of the paper point out that flavopiridol has
    been tested in phase I and II clinical trials as a potential anticancer
    agent, and has not shown as much efficacy as other anticancer
    drugs. However, the trials have shown that flavopiridol is safe at doses
    needed to block induction of cell cycle proteins in animal models, holding
    out hope that cell cycle inhibitors may yet be useful in the clinic for
    neurodegenerative disorders.