Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation.
Cellular injury can involve the aberrant stimulation of cell cycle proteins in part through activation of phosphodiesterases (PDEs) and downstream expression of cell-cycle components such as cyclin D1. In mature non-proliferating cells activation of the cell cycle can lead to the induction of programmed cell death. In the present study, we investigated the in vitro neuroprotective efficacy and mechanism of action of vinpocetine (PDE1 inhibitor), trequinsin (PDE3 inhibitor), and rolipram (PDE4 inhibitor) in four mechanistically-distinct models of injury to primary rat cortical neurons as related to cell cycle regulation and apoptosis. Cellular injury was induced by hypoxia/hypoglycemia, veratridine (10 microM), staurosporine (1 microM), or glutamate (100 microM), resulting in average neuronal cell death rates of 43-48% as determined by MTT assay. Treatment with each PDE inhibitor (PDEI) resulted in a similar concentration-dependent neuroprotection profile with maximal effective concentrations of 5-10 microM (55-77% neuroprotection) in all four neurotoxicity models. Direct cytotoxicity due to PDE inhibition alone was not observed at concentrations below 100 microM. Further studies indicated that PDEIs can suppress the excitotoxic upregulation of cyclin D1 similar to the effects of flavopiridol, a cyclin-dependent kinase inhibitor, including suppression of pro-apoptotic caspase-3 activity. Overall, these data indicate that PDEIs are broad-spectrum neuroprotective agents acting through modulation of cell cycle elements and may offer a novel mode of therapy against acute injury to the brain.
Chen
Ren-Wu
RW
Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Williams
Anthony J
AJ
Liao
Zhilin
Z
Yao
Changping
C
Tortella
Frank C
FC
Dave
Jitendra R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010726:Phosphodiesterase Inhibitors; D019938:Cyclin D1; D010727:Phosphoric Diester Hydrolases; D053148:Caspase 3