Showing papers by "Sang Won Suh published in 2023"
TL;DR: In this article , the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death was explored, and the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.
Abstract: 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.
2 citations
TL;DR: In this article , the authors evaluated the therapeutic potential of irradiated engineered human mesenchymal stem cells over-expressing brain-derived neurotrophic factor (BDNF) in protecting the brain against neuronal death, neurological deficits, and cognitive impairment in TBI rats.
Abstract: 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.
1 citations
TL;DR: In this paper , the authors summarize recent experimental research findings regarding how TRP channels (mainly TRPC and TRPM) and zinc are regulated in animal brain-disease models of global cerebral ischemia, epilepsy and traumatic brain injury.
Abstract: Maintaining the correct ionic gradient from extracellular to intracellular space via several membrane-bound transporters is critical for maintaining overall cellular homeostasis. One of these transporters is the transient receptor potential (TRP) channel family that consists of six putative transmembrane segments systemically expressed in mammalian tissues. Upon the activation of TRP channels by brain disease, several cations are translocated through TRP channels. Brain disease, especially ischemic stroke, epilepsy, and traumatic brain injury, triggers the dysregulation of ionic gradients and promotes the excessive release of neuro-transmitters and zinc. The divalent metal cation zinc is highly distributed in the brain and is specifically located in the pre-synaptic vesicles as free ions, usually existing in cytoplasm bound with metallothionein. Although adequate zinc is essential for regulating diverse physiological functions, the brain-disease-induced excessive release and translocation of zinc causes cell damage, including oxidative stress, apoptotic cascades, and disturbances in energy metabolism. Therefore, the regulation of zinc homeostasis following brain disease is critical for the prevention of brain damage. In this review, we summarize recent experimental research findings regarding how TRP channels (mainly TRPC and TRPM) and zinc are regulated in animal brain-disease models of global cerebral ischemia, epilepsy, and traumatic brain injury. The blockade of zinc translocation via the inhibition of TRPC and TRPM channels using known channel antagonists, was shown to be neuroprotective in brain disease. The regulation of both zinc and TRP channels may serve as targets for treating and preventing neuronal death.
TL;DR: In this article , a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death and increased neuronal death in mice harboring a PKM 2 gene deletion.
Abstract: Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.
TL;DR: In this article , the impact of the direct molecular interaction between GAP-43 and BDNF in hippocampal neuron fate was investigated, and it was shown that GAP43 is directly associated with pathological molecules for AD (Tau and Aβ).
Abstract: Introduction Growth-associated protein 43 (GAP-43) is known as a neuronal plasticity protein because it is widely expressed at high levels in neuronal growth cones during axonal regeneration. GAP-43 expressed in mature adult neurons is functionally important for the neuronal communication of synapses in learning and memory. Brain-derived neurotrophic factor (BDNF) is closely related to neurodegeneration and synaptic plasticity during the aging process. However, the molecular mechanisms regulating neurodegeneration and synaptic plasticity underlying the pathogenesis and progression of Alzheimer's disease (AD) still remain incompletely understood. Methods Remarkably, the expressions of GAP-43 and BDNF perfectly match in various neurons in the Human Brain Atlas database. Moreover, GAP-43 and BDNF are highly expressed in a healthy adults' hippocampus brain region and are inversely correlated with the amyloid beta (Aβ), which is the pathological peptide of amyloid plaques found in the brains of patients with AD. Results These data led us to investigate the impact of the direct molecular interaction between GAP-43 and BDNF in hippocampal neuron fate. In this study, we show that GAP-43 and BDNF are inversely associated with pathological molecules for AD (Tau and Aβ). In addition, we define the three-dimensional protein structure for GAP-43 and BDNF, including the predictive direct binding sites via analysis using ClusPro 2.0, and demonstrate that the deprivation of GAP-43 and BDNF triggers hippocampal neuronal death and memory dysfunction, employing the GAP-43 or BDNF knock-down cellular models and 5XFAD mice. Conclusion These results show that GAP-43 and BDNF are direct binding partners in hippocampal neurons and that their molecular signaling might be potential therapeutic targets for AD.