Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Miriam Paulat
Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Philipp Gobrecht
Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Alexander Hilla
Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Anastasia Andreadaki
Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Rainer Guthoff
Eye Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, Germany
Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.
