Seite - (000289) - in Biomedical Chemistry: Current Trends and Developments

Intracranial injury, more commonly know as traumatic brain injury (TBI), occurs when a head injury results in damage to neuronal structure and integrity. There are two phases of TBI; the acute initial damage from the insult and the secondary injury that are caused by excitotoxicity. Much like the progressive neurodegenerative diseases already discussed and acute stroke, glutamate dysregulation leads to calcium influx into neurons close to the region of initial insult, which results in necrosis of neurons. TBI is complicated as there may or may not be blood flow alterations, hypoxia, swelling, and intracranial pressure. Presently, no pharmacological intervention is available to treat this secondary, excitotoxic cascade that results from TBI. Like other excitotoxic diseases, NMDA receptor antagonists showed promise in animal studies but failed to show efficacy in human clinical trials. 3.2.7 Why not Fully Block Calcium Entry via Pharmacological Agents? Could it be as simple as blocking the glutamatergic transmission so as to cut off the link between over-stimulation by extracellular glutamate and calcium-induced excitotoxicity inside of downstream neurons? Based on the studies that have been performed, it appears that is not the case. One very possible problem that is presented, though likely underappreciated, when fully antagonizing these receptors is the self- regulating mechanism that synapses use, called homeostatic plasticity. Homeostatic plasticity is the broad term used to describe all of the molecular plastic changes that a neuron uses to govern and adjust its own intrinsic excitability. One common underlying method that neurons use to make these adjustments is synaptic scaling (Thalhammer & Cingolani, 2014). That is, the neuron will adjust the properties of ion channels to meet a certain set point. This is a process that was first observed in neurons adjusting their excitatory response to glutamate release after chronic manipulations of their activity. In vitro experiments with neurons have demonstrated that chronic blockage of either NMDA receptors or AMPA receptors results in a process that looks like LTP (Lee & Chung, 2014). There have been reports of enhanced trafficking of