PRIMARY OBJECTIVE: The immunosuppressant cyclosporin A (CsA) is reported to have a strong anti-ischemic effect. Although this neuroprotective effect is speculated to be related to the blockade of a mitochondrial permeability transition pore (mPTP), the underlying molecular mechanism remains to be elucidated. This study focused on the effect of CsA on transcriptional regulation in brain cells. METHODS: CsA and a control substance were injected into rat brains and purified extracted mRNA. Both mRNAs were compared using a cDNA subtraction technique. RESULTS: Nine significantly up-regulated genes and seven significantly down-regulated genes were detected following CsA administration. All of the up-regulated genes are neurotrophic or reported to have roles in regeneration of brain tissue. Among the down-regulated genes, three are known to be detrimental to neuronal cells and are also reported to facilitate the pathology of Alzheimer's disease (AD) and four genes are related to oxidative metabolism. CONCLUSIONS: Strong immunosuppression would present as a side-effect during CsA use as a neuroprotectant. The results of this study will help to discriminate between the CsA immunosuppressive effect and the neuroprotective effect at the molecular level and may lead to the development of new conceptual and pharmacological tools.
PRIMARY OBJECTIVE: The immunosuppressant cyclosporin A (CsA) is reported to have a strong anti-ischemic effect. Although this neuroprotective effect is speculated to be related to the blockade of a mitochondrial permeability transition pore (mPTP), the underlying molecular mechanism remains to be elucidated. This study focused on the effect of CsA on transcriptional regulation in brain cells. METHODS:CsA and a control substance were injected into rat brains and purified extracted mRNA. Both mRNAs were compared using a cDNA subtraction technique. RESULTS: Nine significantly up-regulated genes and seven significantly down-regulated genes were detected following CsA administration. All of the up-regulated genes are neurotrophic or reported to have roles in regeneration of brain tissue. Among the down-regulated genes, three are known to be detrimental to neuronal cells and are also reported to facilitate the pathology of Alzheimer's disease (AD) and four genes are related to oxidative metabolism. CONCLUSIONS: Strong immunosuppression would present as a side-effect during CsA use as a neuroprotectant. The results of this study will help to discriminate between the CsA immunosuppressive effect and the neuroprotective effect at the molecular level and may lead to the development of new conceptual and pharmacological tools.
Authors: Kyle D Fink; Peter Deng; Audrey Torrest; Heather Stewart; Kari Pollock; William Gruenloh; Geralyn Annett; Teresa Tempkin; Vicki Wheelock; Jan A Nolta Journal: Regen Med Date: 2015 Impact factor: 3.806