Delayed Modulation of Glutamate Receptors by Anti-Epileptic Drugs after Traumatic Brain Injury in Rats
Date of Degree
Biological Psychology | Medicine and Health Sciences | Neurosciences
Traumatic brain injury, AMPA receptors, glutamate, anti-epileptic drugs
Traumatic brain injury (TBI) is a significant health concern. Around 74 million people sustain a traumatic brain injury worldwide. The damage caused by TBI produces two types of injury; primary and secondary injuries. Primary injury is caused within milliseconds and is irreversible. Secondary brain injury is delayed and produced by molecular, cellular, and structural disruption after the initial injury. One of the most devastating dysfunction after TBI is glutamate neurotransmitter overactivation that could lead to neurotoxic levels of glutamate in the brain (i.e., excitotoxicity). Excitotoxicity has been linked with the development of epilepsy after TBI, also known as post-traumatic epilepsy (PTE). Several antiepileptic drugs (AEDs) have been clinically used to reduce the possibility of developing PTE and treating PTE after onset. However, some of these drugs produce harmful side effects in patients; The presence of harmful side effects has fueled the search for better pharmacological agents to treat PTE. Levetiracetam (LEV) and, to a lesser extent, brivaracetam (BREV) are AEDs that have been successful in decreasing the number of epileptic seizures produced after TBI. The mechanism of actions LEV and BREV are not fully elucidated; however, recent data suggest that they may affect glutamate transmission by engaging glutamate transporters and modulating synaptic strength through glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). Glutamate AMPAR subunit GluA1 is a calcium permeable receptor and allows the influx of calcium into the cell; on the other hand, the GluA2 AMPA receptor is the subunit that regulates the influx of calcium into the cell. Excessive calcium leads to overactivation of glutamate neurotransmission and excitotoxicity. A better understanding of the mechanism of these AEDs would help in designing a better pharmacological strategy. In this study, the controlled cortical impact (CCI) model of TBI was used to assess the effects of these two AEDs, (LEV and BREV), on glutamate AMPA receptor subunits GluA1 and GluA2. Animals were divided into four groups, Sham, CCI, and CCI animals that received either an injection of BREV or LEV. Three weeks later, brains were harvested, and the hippocampus was analyzed. The CCI model produced a traumatic brain injury on the right side of the brain. We collected and analyzed the right, injured side, and the left non-injured side of the hippocampus independently. Immunoblots showed an increased expression of the GluA1 subunit in the CCI non-injured left hippocampus group, a trend of increased protein in the CCI injured group. GluA2 expression increased in the CCI non-injured group and the LEV injured group. Additionally, the ratio of protein expression between GluA1 and GluA2 was evaluated. The findings showed an increase in the use of GluA1 over GluA2 in the CCI injured side. Overall, the findings suggest that the AED LEV and BREV modulates the levels of glutamate AMPA receptor expression after TBI, signaling a potential mechanism for preventing PTE produced by glutamate dysregulation after by TBI.
Rodriguez, Edgar, "Delayed Modulation of Glutamate Receptors by Anti-Epileptic Drugs after Traumatic Brain Injury in Rats" (2021). CUNY Academic Works.