Abstract
The present study explored the effects of endophilin A1 (SH3GL2) against oxidative damage brought about by H2O2 in HT22 cells and ischemic damage induced upon transient forebrain ischemia in gerbils. Tat-SH3GL2 and its control protein (Control-SH3GL2) were synthesized to deliver it to the cells by penetrating the cell membrane and blood–brain barrier. Tat-SH3GL2, but not Control-SH3GL2, could be delivered into HT22 cells in a concentration- and time-dependent manner and the hippocampus 8 h after treatment in gerbils. Tat-SH3GL2 was stably present in HT22 cells and degraded with time, by 36 h post treatment. Pre-incubation with Tat-SH3GL2, but not Control-SH3GL2, significantly ameliorated H2O2-induced cell death, DNA fragmentation, and reactive oxygen species formation. SH3GL2 immunoreactivity was decreased in the gerbil hippocampal CA1 region with time after ischemia, but it was maintained in the other regions after ischemia. Tat-SH3GL2 treatment in gerbils appreciably improved ischemia-induced hyperactivity 1 day after ischemia and the percentage of NeuN-immunoreactive surviving cells increased 4 days after ischemia. In addition, Tat-SH3GL2 treatment in gerbils alleviated the increase in lipid peroxidation as assessed by the levels of malondialdehyde and 8-iso-prostaglandin F2α and in pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6; while the reduction of protein levels in markers for synaptic plasticity, such as postsynaptic density 95, synaptophysin, and synaptosome associated protein 25 after transient forebrain ischemia was also observed. These results suggest that Tat-SH3GL2 protects neurons from oxidative and ischemic damage by reducing lipid peroxidation and inflammation and improving synaptic plasticity after ischemia.
Highlights
A plethora of animal models have been used for ischemic studies; Mongolian gerbils are generally preferred because of the absence of caudal communicating arteries between the vertebral and internal carotid arteries [1]
We examined the chronological changes of SH3GL2 immunoreactivity in the gerbil hippocampus after transient forebrain ischemia and synthesized the
Protein synthesis of Tat-SH3GL2 and Control-SH3GL2 was assessed by Coomassie brilliant blue staining and Western blot analysis for polyhistidine to detect the His-Tag inserted in the vector
Summary
A plethora of animal models have been used for ischemic studies; Mongolian gerbils are generally preferred because of the absence of caudal communicating arteries between the vertebral and internal carotid arteries [1]. Simple clamping of common carotid arteries causes neuronal death in the hippocampus, thalamus, and neocortex within. 2–4 days after ischemia [2,3]. This model shows high reproducibility, success, and survival rates [4]. Transient forebrain ischemia characterized by interruption of blood supply to the brain, is a leading cause of morbidity and mortality worldwide [5]. Interruption of blood supply rapidly depletes neuronal ATP, but subsequent reperfusion of blood flow markedly increases the formation of reactive oxygen species (ROS) and intracellular transport of. Transient forebrain ischemia increases pro-inflammatory cytokine release from astrocytes and microglia to enhance neuronal damage in the hippocampus [8,9]
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