Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

Abstract

Background Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. Aims To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. Methods We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. Results TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. Discussion Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. Conclusion It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.

Effects of Cyfluthrin Exposure on Neurobehaviour, Hippocampal Tissue and Synaptic Plasticity in Wistar Rats

“…In this study, it was found that compared with the control group, the release of Glu in the medium- and high-dose groups showed a significant upwards trend. The release of a large amount of Glu can cause overexcitation of neurons and eventually cause damage [ 45 ]. Injury causes a large amount of Na + and Cl − to flow into the cells, causing neuronal swelling and necrosis.…”

Tracing the path of disruption: 13C isotope applications in traumatic brain injury‐induced metabolic dysfunction

“…Conversely, lactate released by astrocytes can shuttle to neurons. 61 , 62 TBI leads to neuronal and glial metabolism uncoupling, 63 which can elicit excitotoxicity. 61 , 64 Severe TBI patients also exhibit disturbances in cerebral aspartate metabolism.…”

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

“…However, excessive glutamate in the brain leads to neuronal injury or death, known as glutamate excitotoxicity, which is implicated in many acute and chronic brain diseases, including stroke, traumatic brain injury, seizures, neuropsychiatric disorders, and neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) [2][3][4][5]. Inhibition of the glutamatergic system has a neuroprotective effect when brain ischemia, traumatic brain injury, epilepsy, AD, ALS, and mental disease occur [6][7][8]. This phenomenon may be used to prevent and treat these brain diseases.…”