Is metabolite N, N-dimethylglycine a candidate drug for peripheral nerve injury repair?

Central nervous system (CNS) axons do not spontaneously regenerate after injury in adult mammals. In contrast, peripheral nervous system (PNS) axons readily regenerate, allowing recovery of function after peripheral nerve damage. For example, it was found that a conditioning injury to the sciatic nerve can enhance the regeneration of dorsal column axons in the mouse spinal cord. Axotomized dorsal root ganglia (DRG) neurons experienced a remote and strong cell body response, which resulted in a significant change of some regeneration-associated genes and molecules when the sciatic nerve regenerates after injury to a significant extent. As a result, the sciatic nerve injury model is typically used to identify molecular pathways and targets involved in axon regeneration. The identification of the genotype-phenotype relationship of an organism, such as responses to a disease or drug treatment or injury, is made possible by the emerging research methodology known as “metabolomics profiling,” which allows for a thorough and quantitative analysis of all metabolites in a complex biological sample present at a particular time point. In order to get new insight into the biological process of axonal regeneration, metabolomics examines end products.

Axon regeneration and metabolism are closely related. However, the general metabolic mechanisms and the metabolite landscape in peripheral nervous system neuron axon regeneration are not identified. In a new study published in The FASEB Journal Dr. Junjie Zhang, Chnuyi Jiang, Dr. Xiaohong Liu, Dr. Chen-Xiao Jiang, Dr. Qianqian Cao, Dr. Bin Yu, Dr. Yaohui Ni and Dr. Susu Mao from Nantong University used ultra-high performance liquid tandem chromatography with quadrupole time of flight mass spectrometry (UHPLC-QTOFMS) to perform comprehensive non-target screening of metabolites of DRG tissues, which contain sensory neuronal cell bodies, at various time points after sciatic nerve crush injury in rats in order to obtain the complete metabolomics profiling of DRG neurons after nerve injury.

The research team used a systems biology analysis approach of metabolite abundance alterations determined by UHPLC-qTOF-MS followed by bioinformatics studies to identify a number of metabolites and a network of metabolic pathways that are altered in injured DRGs. This indeed the first time the metabolites involved in neuronal trauma injury and axon regeneration in the peripheral nervous system have been profiled. The authors identified the histidine metabolism as the pathway in other injured groups that had the most changes in comparison to the 0 h group. Additionally, the top-ranked differential metabolic pathways in the rat DRG following sciatic nerve injury included the metabolisms of amino acids, including “Glycine serine and threonine metabolism” and “Arginine and proline metabolism.” Taurine and hypotaurine metabolism, a key metabolic route, is altered one day after sciatic nerve damage. Taurine and hypotaurine were shown to be lower in the current study’s DRG following sciatic nerve injury, but taurocholate levels rose. The new findings suggests that taurine and hypotaurine may be converted to taurocholate as a result of nerve damage.

Another important finding by the Nantong University scientists was demonstrating that only N, N-dimethylglycine (DMG) has the ability to promote the regeneration of damaged neurons both in vitro and in vivo. These findings suggest that controlling these injury-response metabolites simultaneously could be a potent means of fostering neuronal survival and axon regeneration. These findings imply that DMG may facilitate DRG neurons’ axon regeneration via the ERK-Elk1 axis. However, further research is required to determine the precise, intricate underlying mechanisms of DMG function.

In summary, the study reported several distinct metabolites and metabolic pathways after injury, making it the first ever to profile metabolites in DRGs after sciatic nerve injury. Additionally, researchers showed that DMG can help DRG neurons regenerate their axons, indicating that it may one day be used as a treatment for therapeutic interventions in neuronal survival and axon regeneration following injury. In a statement to Medicine Innovates, Dr. Susu Mao, the lead and corresponding author said the findings of their study can be valuable in advancing our knowledge on how metabolites and metabolic pathways affect the molecular controls in peripheral nerve regeneration and pave the way for new druggable targets for optimum neuronal regeneration.