Delayed combinatorial treatment with flavopiridol and minocycline provides longer term protection for neuronal soma but not dendrites following global ischemia.
We previously reported that delayed administration of the general cyclin-dependent kinase inhibitor flavopiridol following global ischemia provided transient neuroprotection and improved behavioral performance. However, it failed to provide longer term protection. In the present study, we investigate the ability of delayed flavopiridol in combination with delayed minocycline, another neuroprotectant to provide sustained protection following global ischemia. We report that a delayed combinatorial treatment of flavopiridol and minocycline provides synergistic protection both 2 and 10 weeks following ischemia. However, protected neurons in the hippocampal CA1 are synaptically impaired as assessed by electrophysio logical field potential recordings. This is likely because of the presence of degenerated processes in the CA1 even with combinatorial therapy. This indicates that while we have addressed one important pre-clinical parameter by dramatically improving long-term neuronal survival with delayed combinatorial therapy, the issue of synaptic preservation of protected neurons still exists. These results also highlight the important observation that protection does not always lead to proper function.
Iyirhiaro
Grace O
GO
Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ontario, Canada.
Brust
Tyson B
TB
Rashidian
Juliet
J
Galehdar
Zohreh
Z
Osman
Aweis
A
Phillips
Maryam
M
Slack
Ruth S
RS
Macvicar
Brian A
BA
Park
David S
DS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020520:Brain Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005419:Flavonoids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D005419:Flavonoids; D018696:Neuroprotective Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D008911:Minocycline