Introduction: The inability of neurons to regenerate injured axons in the central nervous system (CNS) results in life-long disabilities in victims of traumatic brain injury, spinal cord injury and other CNS diseases. Like other pathways in the CNS, the optic nerve cannot regenerate if injured, resulting in lifelong losses in vision. Recent studies have achieved a moderate level of axon regeneration through the injured optic nerve by combining three treatments that synergistically activate the intrinsic growth state of retinal ganglion cells (RGCs), the projection neurons of the eye. Nonetheless, even under optimal conditions, more than 50% of RGCs die after optic nerve injury, and most of the surviving RGCs fail to regenerate axons. These observations point to the existence of additional major suppressors of RGC survival and axon regeneration.
Methods: Using autometallography (AMG) or the fluorescent Zn2+ sensor ZinPyr1, we found that levels of free Zn2+ increased in the inner plexiform layer (IPL) of the retina within an hour of optic nerve injury, whereas levels within RGCs themselves increased more slowly.
Results: The Zn2+ transporter ZnT3 is highly expressed in the IPL, suggesting that Zn2+ becomes sequestered in presynaptic vesicles after injury. Chelating Zn2+ using either TPEN or the highly selective chelator ZX1 eliminated the Zn2+ signal in the IPL and led to enduring survival of RGCs as well as considerable axon re-generation. These effects were lost when the chelators were saturated with Zn2+, suggesting that the effects of the chelators are mediated through binding of free Zn2+. Combining Zn2+ chelation with other pro-regenerative treatments enabled some RGCs to regenerate axons the full length of the optic nerve in just 2 weeks.
Conclusions: These studies indicate that Zn2+ is an endogenous suppressor of axon regeneration, and they suggest that Zn2+ chelators may be valuable in promoting recovery after various forms of traumatic CNS damage.
Patient Care: It supposed that Zn2+ chelators may be valuable in promoting recovery after various forms of traumatic or neurodegenerative CNS damages, with potential translational implications.We believe that this research project is truly groundbreaking, and that it will provide new insights into ways to repair brain circuits after injury.
Learning Objectives: By the conclusion of this session, participants should be able to understand the unique role of zinc as one of the earliest endogenous suppressor of CNS regeneration