Updates and challenges of axon regeneration in the mammalian central nervous system

Axon regeneration in the mammalian central nervous system (CNS) has been a long-standing and highly challenging issue. Successful CNS axon regeneration will benefit many human diseases involving axonal damage, such as spinal cord injury, traumatic brain injury, glaucoma, and neurodegenerative diseases. The current consensus is that the diminished intrinsic regenerative ability in mature CNS neurons and the presence of extrinsic inhibitors blocking axon regrowth are two major barriers for axon regeneration. During the past decade, studies targeting the intrinsic axon growth ability via regulation of gene transcription have produced very promising results in optic nerve and/or spinal cord regeneration. Manipulations of various signaling pathways or the nuclear transcription factors directly have been shown to sufficiently drive CNS axon regrowth. Converging evidence reveals that some pro-regenerative transcriptomic states, which are commonly accomplished by more comprehensive epigenetic regulations, exist to orchestrate the complex tasks of injury sensing and axon regeneration. Moreover, genetic reprogramming achieved via transcriptome and epigenome modifications provides novel mechanisms for enhancing axon regeneration. Recent studies also highlighted the important roles of remodeling neuronal cytoskeleton in overcoming the extrinsic inhibitory cues. However, our knowledge about the cellular and molecular mechanisms by which neurons regulate their intrinsic axon regeneration ability and response to extrinsic inhibitory cues is still fragmented. Here, we provide an update about recent research progress in axon regeneration and discuss major remaining challenges for long-distance axon regeneration and the subsequent functional recovery.

Glutamate transporters: a broad review of the most recent archaeal and human structures

Glutamate transporters play important roles in bacteria, archaea and eukaryotes. Their function in the mammalian central nervous system is essential for preventing excitotoxicity, and their dysregulation is implicated in many diseases, such as epilepsy and Alzheimer's. Elucidating their transport mechanism would further the understanding of these transporters and promote drug design as they provide compelling targets for understanding the pathophysiology of diseases and may have a direct role in the treatment of conditions involving glutamate excitotoxicity. This review outlines the insights into the transport cycle, uncoupled chloride conductance and modulation, as well as identifying areas that require further investigation.

Enhancement of neural stem cell survival, proliferation and differentiation by IGF-1 delivery in graphene oxide-incorporated PLGA electrospun nanofibrous mats

The mammalian central nervous system has a limited ability for self-repair under injury conditions.

The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel “designer” ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors.NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.