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Vol. 301, Issue 2, 494-500, May 2002
Neuroinflammation Research Laboratories of the Department of
Psychiatry, the Mount Sinai School of Medicine, New York, New York
In previous studies we found that neuronal overexpression of human
cyclooxygenase (COX)-2 in transgenic mice potentiated excitotoxicity in
vivo and in vitro. To clarify the molecular mechanisms involved in
COX-2-mediated potentiation of excitotoxicity, we used cDNA microarray
to identify candidate genes the expression of which is altered in the
cerebral cortex of homozygous human hCOX-2 transgenic mice. We found
that the mRNA expression of the cell cycle kinase (CDK)
inhibitor-inhibitor kinase (INK) p18INK4, a specific
inhibitor of CDK 4,6, which controls the activation of the
retinoblastoma (Rb) tumor suppressor protein phosphorylation, was
decreased in the brain of adult hCOX-2 homozygous transgenics. Conversely, chronic treatment of the hCOX-2 transgenics with the preferential COX-2 inhibitor nimesulide reversed the hCOX-2-mediated decrease of cortical p18INK4 mRNA expression in the brain.
Further in vitro studies revealed that in primary cortico-hippocampal
neurons derived from homozygous hCOX-2 transgenic mice, COX-2
overexpression accelerates glutamate-mediated apoptotic damage that is
prevented by the CDK inhibitor flavoperidol. Moreover, treatment of
wild-type primary cortico-hippocampal neuron cultures with the COX-2
preferential inhibitor nimesulide significantly attenuated
glutamate-mediated apoptotic damage, which coincided with inhibition of
glutamate-mediated pRb phosphorylation. These data indicate that hCOX-2
overexpression causes neuronal cell cycle deregulation in the brain and
provides further rationale for targeting neuronal COX-2 in
neuroprotective therapeutic research.
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