Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway

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.

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Small molecule drugs clinically used for other therapeutic purposes have been found to stimulate NSPCs and promote recovery. Cyclosporine (CsA), a common immunosuppressant, is found to increase NSPC survival in vitro and in vivo, and to reduce stroke infarct volume Erlandsson et al, 2011;Sachewsky et al, 2014). Metformin, a drug for diabetes, stimulates neurogenesis in the hippocampus, improving memory in injured mice (Wang et al, 2012a); a clinical trial is underway to evaluate its potential in treating brain injury in children (NCT02040376).…”

Circumventing the blood–brain barrier: Local delivery of cyclosporin A stimulates stem cells in stroke-injured rat brain

“…Although NSPCs respond to stroke, transiently increasing proliferative activity and migrating toward the lesion [20,21], the majority undergo cell death [22,23] and have limited neurogenesis [24]. Stimulating endogenous adult forebrain NSPCs, which are located in the subependyma lining the lateral ventricles, is possible with a number of therapeutics [25], including: epidermal growth factor [26,27], human chorionic gonadotropin [28], erythropoietin [27,28], glial cell-derived neurotrophic factor [29], vascular endothelial growth factor [30] and cyclosporin A (CsA) [31,32].…”

“…CsA, a 1.2 kDa hydrophobic polypeptide, directly acts on NSPCs by promoting their survival and increasing the size of the NSPC pool in vitro and in vivo [32,33]. Indeed, systemic CsA administration for 7 to 14 days significantly increases the pool of NSPCs in both the brain and spinal cord [32,34].…”

“…Indeed, systemic CsA administration for 7 to 14 days significantly increases the pool of NSPCs in both the brain and spinal cord [32,34]. After stroke, adult mice treated with CsA show tissue regeneration and sensorimotor functional recovery [31,32].…”

“…Indeed, systemic CsA administration for 7 to 14 days significantly increases the pool of NSPCs in both the brain and spinal cord [32,34]. After stroke, adult mice treated with CsA show tissue regeneration and sensorimotor functional recovery [31,32]. Moreover, CsA has neuroprotective effects in the brain [2,35,36], with phase II clinical trials completed for stroke (NCT01527240) and traumatic brain injury (TBI) (NCT01825044).…”