Abstract
Developmental seizure-induced long-term neuronal hyperexcitation is partially mediated by regenerative mossy fiber sprouting in hippocampus. Yet, there are no effective drugs available to block this pathological process. Recently, leptin has been shown to prevent the sprouting of hippocampal mossy fibers and abnormalities in the neurobehavioral parameters. However, their underlying molecular mechanisms are largely unknown. The purpose of this study was to determine the effect of glutamate on the parameters of zinc homeostasis, mitochondrial functions, and mitophagy regulating factors, as well as to investigate the protective effects of leptin against cytotoxicity of glutamate in murine HT22 hippocampal neuronal cells. Cells were assigned to one of the four groups as follows: control group, leptin alone group, glutamate injury group, and leptin pretreatment group. Our results demonstrated that glutamate induced a decrease in superoxide dismutase, GSH (glutathione), and mitochondrial membrane potential and an increase in GSSG (oxidized glutathione), mitochondrial reactive oxygen species, and supplementation of leptin blocked the toxic effect of glutamate on cell survival. The glutamate-induced cytotoxicity was associated with an increase in mitophagy and intracellular zinc ion levels. Furthermore, glutamate activated the mitophagy markers PINK1, Parkin, and the ratio of LC3-II/LC3-I, as well as increased the expression of zinc transporter 3 (ZnT3). Leptin corrected these glutamate-caused alterations. Finally, the mitophagy inhibitor, CsA, significantly reduced intracellular zinc ion content and ZnT3 expression. These results suggest that mitophagy-mediated zinc dyshomeostasis and mitochondrial activation contributed to glutamate-induced HT22 neuronal cell injury and that leptin treatment could counteract these detrimental effects, thus highlighting mitophagy-mediated zinc homeostasis via mitochondrial activation as a potential strategy to counteract neuroexcitotoxicity.
Highlights
Leptin, a 16-kDa peptide hormone produced by white adipocytes, was cloned from the ob gene in 1994 as an important milestone in reducing obesity [1]
In another study using the same neonatal seizure model, we found that chronic ketogenic diet (KD) treatment restored the upregulation of clusterin and the autophagy markers beclin-1, p62, and cathepsin-E, indicating that the abovementioned zinc/mitochondrial metabolic pathway may be involved in autophagy mechanisms [20]
HT22 cells were studied in four groups: [1] Control group (Control), [2] Leptin alone group (Leptin) (leptin (1 μg/ml) was added to cells), [3] glutamate injury group (Glutamate), and [4] leptin pretreatment group (Glutamate + Leptin)
Summary
A 16-kDa peptide hormone produced by white adipocytes, was cloned from the ob gene in 1994 as an important milestone in reducing obesity [1]. Leptin acts as a pleiotropic hormone in neuronal morphology, activity-dependent synaptic plasticity, and cognition [2, 3]. Leptin Maintained Zinc-Mitochondrial Homeostasis and neuroprotective activity, which can slow down the process of neuronal damage after acute brain injury as well as during longterm neurodegenerative processes [4]. Acute leptin application could protect neurons against cell death induced by excitotoxic and oxidative insults in hippocampus [5]. Malekizadeh et al further showed that the leptin [116–130] fragment mirrored the ability of leptin to facilitate activity-dependent hippocampal synaptic plasticity, promote the cognitive enhancing effects of leptin, and prevent hippocampal synaptic disruption and neuronal cell death [8]. Studies have shown that leptin has neuroprotective effects on the status epilepticus (SE) induced by kainic acid or pilocarpine [10, 11]
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