ABSTRACT
Brain ischemia leads to severe damage in the form of delayed neuronal cell death. In our study, we show that the marked neuroprotection of the new immunosuppressant FR901495 in forebrain ischemia is due not only to inhibition of calcineurin, but also to protection against mitochondrial damage caused by mitochondrial permeability transition pore formation through cyclophilin D, one of the prolyl cis/trans isomerase family members. These findings shed light on the clinical application and development of new drugs for the treatment of ischemic damage in the brain as well as in the heart and liver.
Subject(s)
Brain Injuries/drug therapy , Brain Injuries/metabolism , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Neuroprotective Agents/administration & dosage , Animals , Brain Injuries/complications , Brain Ischemia/complications , Calcineurin , Cyclophilins , Cyclosporine , Disease Models, Animal , Dose-Response Relationship, Drug , Mitochondrial Membrane Transport Proteins/drug effects , Mitochondrial Permeability Transition Pore , Prosencephalon/drug effects , Prosencephalon/injuries , Prosencephalon/metabolism , Rats , Rats, Wistar , Treatment OutcomeABSTRACT
Neuronal and glial cell death caused by axonal injury sometimes contributes to whole brain pathology after traumatic brain injury (TBI). We show that neuroprotection by 2 types of immunosuppressants, cyclosporin A (CsA) and tacrolimus (FK506), in a cryogenic brain injury model results from inhibition of calcineurin and protection from mitochondrial damage caused by formation of a mitochondrial permeability transition pore induced by cyclophilin D (CyPD), one of the prolyl cis/trans isomerase family members. We evaluated why CsA is neuroprotective by microarray analysis of gene expression in the cryogenic brain injury rat model. Analyses of expression patterns demonstrated that expression of over 14,000 genes changed between the groups with and without CsA treatment, and about 350 genes among them were extracted showing a significant difference. We learned that the differential expression of several gene targets showed specific patterns in a time-dependent manner. These results may help elucidate the mechanisms of neuronal cell death after TBI and the neuroprotective effects of CsA after TBI.
Subject(s)
Brain Injuries/drug therapy , Brain Injuries/metabolism , Cyclosporine/therapeutic use , Gene Expression Profiling/methods , Nerve Tissue Proteins/metabolism , Oligonucleotide Array Sequence Analysis/methods , Tacrolimus/therapeutic use , Animals , Biomarkers/metabolism , Brain/drug effects , Brain/metabolism , Brain Injuries/diagnosis , Gene Expression Regulation/drug effects , Genetic Markers/genetics , Male , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/genetics , Neuroprotective Agents/therapeutic use , Prognosis , Rats , Rats, Wistar , Time Factors , Treatment OutcomeABSTRACT
AIMS: The aim of the present study is to clarify the level of radioactive lymph node should be biopsied after the most radioactive SN is removed. METHODS: SNB using radionuclide was performed in our hospital for 1179 primary breast cancers between April 2000 and October 2005; most (1177/1179) were performed successfully. Our criterion for harvesting SNs is to remove tissue until no radioactive site is present. The level of radioactivity and the order of removal of each lymph node were compared with pathologic results. RESULTS: More than 2 (overall average 1.9) radioactive SNs were biopsied in 686 of 1177 breasts. Cancer positive results were recorded for 142 breasts with multiple SNs. In 142 breasts, 64 showed metastasis to the most radioactive node only, 39 showed metastasis other than the most radioactive node only, and 39 showed the most radioactive node and other radioactive nodes. Moreover, if several other criteria were applied, false-positive cases were increased significantly. CONCLUSIONS: It is necessary to harvest radioactive lymph nodes other than the most radioactive. Moreover, efforts to remove every radioactive lymph node will minimize false-negative results.
