Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death.

Traumatic brain injury (TBI) causes transitory or permanent neurological and cognitive impairments, which can intensify over time due to secondary neuronal death. However, no therapy currently exists that can effectively treat brain injury following TBI. Here, we evaluate the therapeutic potential of irradiated engineered human mesenchymal stem cells over-expressing brain-derived neurotrophic factor (BDNF), which we denote by BDNF-eMSCs, in protecting the brain against neuronal death, neurological deficits, and cognitive impairment in TBI rats. BDNF-eMSCs were administered directly into the left lateral ventricle of the brain in rats that received TBI damage. A single administration of BDNF-eMSCs reduced TBI-induced neuronal death and glial activation in the hippocampus, while repeated administration of BDNF-eMSCs reduced not only glial activation and delayed neuronal loss but also enhanced hippocampal neurogenesis in TBI rats. In addition, BDNF-eMSCs reduced the lesion area in the damaged brain of the rats. Behaviorally, BDNF-eMSC treatment improved the neurological and cognitive functions of the TBI rats. The results presented in this study demonstrate that BDNF-eMSCs can attenuate TBI-induced brain damage through the suppression of neuronal death and increased neurogenesis, thus enhancing functional recovery after TBI, indicating the significant therapeutic potential of BDNF-eMSCs in the treatment of TBI.

Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3–18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH’s antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.

Traumatic brain injury (TBI) broadly degrades the normal function of the brain after a bump, blow, or jolt to the head. TBI leads to the aggravation of pre-existing brain dysfunction and promotes neurotoxic cascades that involve processes such as oxidative stress, loss of dendritic arborization, and zinc accumulation. Acid sphingomyelinase (ASMase) is an enzyme that hydrolyzes sphingomyelin to ceramide in cells. Under normal conditions, ceramide plays an important role in various physiological functions, such as differentiation and apoptosis. However, under pathological conditions, excessive ceramide production is toxic and activates the neuronal-death pathway. Therefore, we hypothesized that the inhibition of ASMase activity by imipramine would reduce ceramide formation and thus prevent TBI-induced neuronal death. To test our hypothesis, an ASMase inhibitor, imipramine (10 mg/kg, i.p.), was administrated to rats immediately after TBI. Based on the results of this study, we confirmed that imipramine significantly reduced ceramide formation, dendritic loss, oxidative stress, and neuronal death in the TBI-imipramine group compared with the TBI-vehicle group. Additionally, we validated that imipramine prevented TBI-induced cognitive dysfunction and the modified neurological severity score. Consequently, we suggest that ASMase inhibition may be a promising therapeutic strategy to reduce hippocampal neuronal death after TBI.