Search Results (9)

Erythroid differentiation regulator 1 (Erdr1) is a cytokine known to play important roles in cell survival under stressful conditions, maintenance of cellular growth homeostasis, and activation of the immune system. However, the impact of Erdr1 on neurons remains undefined. In this study, we present novel evidence that Erdr1 plays a role in regulating glutathione (GSH) synthesis via glutamate transporter-associated protein 3-18 (GTRAP3-18), an anchor protein in the endoplasmic reticulum that holds excitatory amino acid carrier 1 (EAAC1) in neurons. Both DNA microarray and quantitative real-time PCR analyses revealed an approximately 2-fold increase in Erdr1 levels in the hippocampus of GTRAP3-18-deficient mice compared to those of wild-type mice. Knockdown of Erdr1 in vitro resulted in a decrease in GTRAP3-18 levels, leading to an increase in EAAC1 expression and intracellular GSH levels, and subsequently, cytoprotective effects against oxidative stress. Our findings shed light on the regulatory mechanisms involving Erdr1, GTRAP3-18, EAAC1, and GSH in the context of neuronal defense against oxidative stress. Understanding the intricate interplay among these molecules may pave the way for the development of promising therapeutic strategies for neurodegenerative disorders. Full article

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson’s disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A_2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases. Full article

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. Full article

Stroke is a major cause of death worldwide, leading to serious disability. Post-ischemic injury, especially in the cerebral ischemia-prone hippocampus, is a serious problem, as it contributes to vascular dementia. Many studies have shown that in the hippocampus, ischemia/reperfusion induces neuronal death through oxidative stress and neuronal zinc (Zn²⁺) dyshomeostasis. Glutathione (GSH) plays an important role in protecting neurons against oxidative stress as a major intracellular antioxidant. In addition, the thiol group of GSH can function as a principal Zn²⁺ chelator for the maintenance of Zn²⁺ homeostasis in neurons. These lines of evidence suggest that neuronal GSH levels could be a key factor in post-stroke neuronal survival. In neurons, excitatory amino acid carrier 1 (EAAC1) is involved in the influx of cysteine, and intracellular cysteine is the rate-limiting substrate for the synthesis of GSH. Recently, several studies have indicated that cysteine uptake through EAAC1 suppresses ischemia-induced neuronal death via the promotion of hippocampal GSH synthesis in ischemic animal models. In this article, we aimed to review and describe the role of GSH in hippocampal neuroprotection after ischemia/reperfusion, focusing on EAAC1. Full article

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases. Full article

Although there have been substantial advances in knowledge regarding the mechanisms of neuron death after stroke, effective therapeutic measures for stroke are still insufficient. Excitatory amino acid carrier 1 (EAAC1) is a type of neuronal glutamate transporter and considered to have an additional action involving the neuronal uptake of cysteine, which acts as a crucial substrate for glutathione synthesis. Previously, our lab demonstrated that genetic deletion of EAAC1 leads to decreased neuronal glutathione synthesis, increased oxidative stress, and subsequent cognitive impairment. Therefore, we hypothesized that reduced neuronal transport of cysteine due to deletion of the EAAC1 gene might exacerbate neuronal injury and impair adult neurogenesis in the hippocampus after transient cerebral ischemia. EAAC1 gene deletion profoundly increased ischemia-induced neuronal death by decreasing the antioxidant capacity. In addition, genetic deletion of EAAC1 also decreased the overall neurogenesis processes, such as cell proliferation, differentiation, and survival, after cerebral ischemia. These studies strongly support our hypothesis that EAAC1 is crucial for the survival of newly generated neurons, as well as mature neurons, in both physiological and pathological conditions. Here, we present a comprehensive review of the role of EAAC1 in neuronal death and neurogenesis induced by ischemic stroke, focusing on its potential cellular and molecular mechanisms. Full article

Central among the fetotoxic responses to in utero ethanol (E) exposure is redox-shift related glutathione (GSH) loss and apoptosis. Previously, we reported that despite an E-generated Nrf2 upregulation, fetal neurons still succumb. In this study, we investigate if the compromised GSH results from an impaired inward transport of cysteine (Cys), a precursor of GSH in association with dysregulated excitatory amino acid carrier1 (EAAC1), a cysteine transporter. In utero binge model involves administration of isocaloric dextrose or 20% E (3.5 g/kg)/ by gavage at 12 h intervals to pregnant Sprague Dawley (SD) rats, starting gestation day (gd) 17 with a final dose on gd19, 2 h prior to sacrifice. Primary cerebral cortical neurons (PCNs) from embryonic day 16–17 fetal SD rats were the in vitro model. E reduced both PCN and cerebral cortical GSH and Cys up to 50% and the abridged GSH could be blocked by administration of N-acetylcysteine. E reduced EAAC1 protein expression in utero and in PCNs (p < 0.05). This was accompanied by a 60–70% decrease in neuron surface expression of EAAC1 along with significant reductions of EAAC1/Slc1a1 mRNA (p < 0.05). In PCNs, EAAC1 knockdown significantly decreased GSH but not oxidized glutathione (GSSG) illustrating that while not the sole provider of Cys, EAAC1 plays an important role in neuron GSH homeostasis. These studies strongly support the concept that in both E exposed intact fetal brain and cultured PCNs a mechanism underlying E impairment of GSH homeostasis is reduction of import of external Cys which is mediated by perturbations of EAAC1 expression/function. Full article

Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system’s roles in maintaining redox homeostasis. Especially, glutathione (GSH) is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1) plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed. Full article

Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate-limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration. Full article