Abstract
Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 μM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.
Highlights
Traumatic brain injury (TBI) is defined as an injury of brain pathology or brain function induced by external forces, such as fall, assault, or motor vehicle crash
The levels of Malonyl dialdehyde (MDA) (Fig. 1G) and 4-HNE (Fig. 1H) were measured to determine the effect of edonerpic maleate on lipid peroxidation, and the results showed that the increased levels of these two factors after Traumatic neuronal injury (TNI) and glutamate treatment were alleviated by edonerpic maleate
Edonerpic maleate improves long-term neurological function and regulates collapsing response mediator protein 2 (CRMP2) and Arc after traumatic brain injury (TBI) in vivo Due to the negative results in locomotor function at 24 h following TBI, we further investigated the effect of edonerpic maleate (30 mg/kg) on neurological function using mNSS (Fig. 6A)
Summary
Traumatic brain injury (TBI) is defined as an injury of brain pathology or brain function induced by external forces, such as fall, assault, or motor vehicle crash. In the United States, the most recent data available from the Centers for Disease Control and Prevention (CDC) show that there were nearly 61000 TBI-related deaths in 2019, which means about 166 TBI-related deaths each day. The pathological mechanisms underlying brain damage after TBI have not been well determined, and various experimental studies and clinical trials are ongoing [2, 3]. Glutamate is the major excitatory neurotransmitter in the brain, and excessive release of glutamate has been found in many acute and chronic neurological diseases. In severe TBI patients, the microdialysis results showed that the rise in extracellular glutamate was detected from 24 h to 4 days after injury, which is directly proportional to mortality [4]. The increased extracellular glutamate levels were found at 1 h after controlled cortical impact (CCI) [5] and could be detected within mins after injury in the fluid percussion injury (FPI)
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