Effects of FK506 and cyclosporin a on calcium ionophore-induced mitochondrial depolarization and cytosolic calcium in astrocytes and neurons.

This study tested the hypothesis that sensitivity to the Ca(2+) -induced loss of mitochondrial membrane potential (ΔΨ(m)) and the sensitivity of the loss of ΔΨ to mitochondrial permeability transition pore (PTP) inhibitors are different for neurons and astrocytes. Primary cultures of rat cortical neurons and astrocytes were exposed to the Ca(2+) ionophore 4-Br-A23187, and ΔΨ(m) was monitored with the fluorescent probe tetramethylrhodamine methyl ester (TMRM). Ca(2+) ionophore caused a decline in ΔΨ(m) in both cell types that was partially inhibited by cyclosporin A (CsA) in astrocytes but not in neurons. Another PTP inhibitor, 2-aminoethoxy-diphenylborate, was ineffective at protecting against mitochondrial depolarization, but depolarization was inhibited by FK506, an immunosuppressant drug similar to CsA that does not inhibit the PTP. CsA and FK506 both significantly reduced the ionophore-induced rise in [Ca(2+) ](i) in both neurons and astrocytes. We conclude that the protective effects of CsA and FK506 against Ca(2+) ionophore-induced mitochondrial membrane depolarization in intact astrocytes is not due to PTP inhibition but possibly is a consequence of inhibiting the rise in [Ca(2+) ](i).