Abstract
Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration is effective in promoting NPC activation, tissue repair and functional recovery in a mouse model of cortical stroke. The mechanism(s) by which CsA mediates this cell survival effect remains unknown. Herein, we examined both calcineurin-dependent and calcineurin-independent pathways through which CsA might mediate NPC survival. To examine calcineurin-dependent pathways, we utilized FK506 (Tacrolimus), an immunosuppressive molecule that inhibits calcineurin, as well as drugs that inhibit cyclophilin A-mediated activation of calcineurin. To evaluate the calcineurin-independent pathway, we utilized NIM811, a non-immunosuppressive CsA analog that functions independently of calcineurin by blocking mitochondrial permeability transition pore formation. We found that only NIM811 can entirely account for the pro-survival effects of CsA on NPCs. Indeed, blocking signaling pathways downstream of calcineurin activation using nNOS mice did not inhibit CsA-mediated cell survival, which supports the proposal that the effects are calcinuerin-independent. In vivo studies revealed that NIM811 administration mimics the pro-survival effects of CsA on NPCs and promotes functional recovery in a model of cortical stroke, identical to the effects seen with CsA administration. We conclude that CsA mediates its effect on NPC survival through calcineurin-independent inhibition of mitochondrial permeability transition pore formation and suggest that this pathway has potential therapeutic benefits for developing NPC-mediated cell replacement strategies.
Highlights
Central nervous system (CNS) injury and disease often lead to severe functional deficit, with no regenerative treatment currently available
FK506 (Tacrolimus) does not have direct effects on neural precursor cell survival Neural precursor cells reside in the subependyma of the adult forebrain lining the lateral ventricles where they proliferate to generate rapidly dividing progeny that undergo cell death or migrate to the olfactory bulb where they differentiate into olfactory interneurons (Lois and Alvarez-Buylla, 1994; Morshead et al, 1994; Morshead et al, 1998)
We have established that NIM811 but not FK506 has a direct effect on adult neural precursor cells (NPCs), similar to cyclosporin A (CsA)
Summary
Central nervous system (CNS) injury and disease often lead to severe functional deficit, with no regenerative treatment currently available. Relevant molecules that modify the properties of neural stem and Received 8 October 2013; Accepted 19 May 2014 progenitor cells (termed neural precursor cells; NPCs) could well provide a foundation for regenerative strategies that aim to replace lost and damaged neural cell types in the injured CNS. Towards this end, we have previously demonstrated that cyclosporin A (CsA) has direct effects on NPCs, enhancing cell survival (Hunt et al, 2010), with no effects on cell cycle kinetics or NPC differentiation. These findings suggest that the intracellular targets of CsA could provide novel therapeutic targets for the development of NPCmediated regenerative strategies
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