Under normal physiological conditions the body has

Under normal physiological conditions, the body has sufficient oxygen supply, so glucose can produce large amounts of ATP by aerobic oxidation and oxidative phosphorylation in cells. After SCI, hypoxia ischemia can occur in local tissue, leading to decreasing of intracellular oxygen partial pressure, reduction of oxygen molecules, inhibition of glucose oxidation and oxidative phosphorylation and reduced ATP production, which cause a series of pathophysiological changes (Lee et al., 2014, Rouanet et al., 2017). In 1981, using the 2-deoxy-D-[14C] glucose technique, Rawe, et al. found that the spinal cord glucose utilization in monkeys after SCI was increased in the early 1 h in white matter at the lesion site (Rawe et al., 1981). Recently, using 18F-FDG-PET imaging technique, von Leden et al. reported that in moderate spinal cord injured rats, glucose uptake was acutely depressed followed by an increase (von Leden et al., 2016). Although, the results of different studies are not entirely consistent, the role of glucose metabolism and utilization in SCI is unquestionable. This may represent a therapeutic target for SCI. HK is the first key enzyme in glucose metabolism, so it may serve as a target for further studies. Although, there are many studies of HK related to tumors (Jang et al., 2013, Ramsay et al., 2011), very few studies are involved in central nervous system (CNS) damage. A small number of related reports are also mainly focused on AS 101 related diseases (Lundgaard et al., 2015, Shan et al., 2014, Wu et al., 2017). There are no related reports about HK in SCI. HK can catalyze the production of glucose-6-phosphate by phosphorylating glucose and effectively commits glucose to energy metabolism by preventing glucose from leaving the cells (Aleshin et al., 1998, Robey et al., 2002). While HK can help commit glucose to energy metabolism, it can still meet several fates other than glycolysis. Some studies demonstrated that shunting of glucose-6-phosphate into the pentose phosphate pathway is a major mechanism for neurons to combat oxidative stress (Chen et al., 2000, Fukushima et al., 2009, Moro et al., 2013). This suggests that elevated HK may have neuroprotective effects during CNS damage. In a recent study, we found that HK3 was significantly upregulated at mRNA level in the injured spinal cords (Shi et al., 2017). Like the other isoforms, HK3 can also protect the cell against apoptosis and promote cell survival by reducing oxidant-induced reactive oxygen species and boosting energy production (Wyatt et al., 2010). These data suggest that HK3 may play an important role in the pathological process of SCI. However, its spatio-temporal expression in the spinal cords is still unclear. The previous experiments have shown that there are no differences in pathophysiology among the sham-operated rats at all time points (Byrnes et al., 2011, Ek et al., 2010, Liang et al., 2015), Therefore, we only measured sham animals at the initial time point, and compared other time points such as 28 dpi to this original sham measurement in this study. We demonstrated that HK3 could be detected in sham-opened spinal cords. After SCI, it gradually increased, reached a peak at 7 dpi, and then gradually decreased with the time of injury, but still maintained at a high level for the longest time evaluated in this study (28 dpi). Although this study has provided new insight into the spatio-temporal expression of HK3 in the spinal cords after injury, we are still don't know whether HK3 is “good” or “bad” for repair of injured spinal cords. This is because there are both harmful and favorable cell subsets in the injured spinal cord microenvironment (Jones et al., 2005, Kigerl et al., 2009). Increased HK3 can provide energy for the two types of cells by promoting glucose metabolism. For example, based on molecular phenotypes and effector functions, macrophages can be distinguished into two major distinct subtypes: classically activated proinflammatory (M1) and alternatively activated anti-inflammatory (M2) cells (Kigerl et al., 2009). M1 cells are neurotoxic, whereas M2 cells have positive effects on neuroregeneration (Kigerl et al., 2009, Ma et al., 2015). However, the recent research showed that M1 cell response is rapidly induced and sustained, whereas M2 induction is transient after SCI (Chen et al., 2015). Recent studies have also demonstrated that neuroinflammation and ischemia can also induce two different types of reactive astrocytes, one type being harmful and the other helpful, paralleling with the nomenclature of M1 and M2 macrophage, they are termed A1 (harmful) and A2 (helpful) reactive astrocytes, respectively (Liddelow and Barres, 2017). Therefore, HKs and their related glucose metabolism pathways can be used as targets to increase the fractions of favorable cell populations and prolong their residence time in the injured local microenvironment. This might be a promising strategy for the repair of SCI.