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ON THE NATURE OF CYCLOSPORIN NEUROPROTECTIVE EFFECTS: THE MITOCHONDRIA CONNECTION R. Jakob, V.P. Bindokas and R.J.
Miller
It is well established that cyclosporin A (CsA) is neuroprotective and recent data suggest that this effect does not depend on immunosuppression (calcineurin inhibition). Here we investigated the mechanism of action of CsA and its nonimmunosuppressive analogues SDZ 211811 and CsH in further detail. Immunohistochemistry and Western blot analysis were used to investigate the possible modulation of Bcl-2 and Bcl-xL protein levels and distribution in cultured hippocampal neurons as well as differentiated SH-SY5Y neuroblastoma cells. We found that pre-treatment with CsA enhanced the expression level and altered the expression pattern of Bcl-2 and Bcl-xL proteins compared to vehicle treated control cultures. These effects were mimicked by the non-immunosupressive CsA analogue SDZ 211811 as well as CsH, a derivative that does not even bind to cyclophilins. Furthermore, we observed an unexpected increase in the intensity of cytochrome oxidase staining after pre-treatment with CsA and CsH, whereas the expression of cardiolipin (determined with nonylacridine orange) remained unchanged. This suggests that mitochondria are transported from the soma into the neurites and that cytochrome oxidase levels are also upregulated by CsA and CsH. Enumeration of mitochondria in neurites showed that CsA/CsH treatment increased the number of mitochondria in the neurites. This altered distribution of mitochondria was independent of rotamase or calcineurin inhibition. These data suggest that effects of cyclosporin on Bcl protein expression as well as mitochondrial distribution and cytochrome oxidase levels may contribute to the neuroprotective effect.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
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