Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.

Traumatic brain injury (TBI) is a major cause of hospitalization and death. To mitigate these human costs, the search for effective drugs to treat TBI continues. Even mild injuries can lead to long-term deficits in memory and cognition. Predicting which patients will have long lasting memory issues following mild TBI is challenging. Our group has previously shown that in vitro models of TBI result in cell death, decreased long-term potentiation (LTP), and glial activation. In this thesis, we used chemical and electrical treatments to modulate the outcome following injury to inform future therapies. In the first aim of this thesis, we evaluated the efficacy of a novel neurosteroid, NTS-105, to reduce post-traumatic pathobiology in an in vitro model of moderate TBI that utilizes an organotypic hippocampal slice culture. Treatment with NTS-105 starting an hour after injury decreased post-traumatic cell death in a dose-dependent manner, with 10 nM NTS-105 being most effective. Post-traumatic administration of 10 nM NTS-105 also prevented deficits in LTP without adversely affecting neuronal activity in naïve cultures. Our results suggest that the pleiotropic pharmacology (affinity for the androgen, mineralocorticoid, and progesterone receptors) of NTS-105 may be a promising strategy for the effective treatment of TBI. In the second aim, we evaluated the mechanisms of NTS-105 in an in vitro model of mild blast TBI, a model in which NTS-105 is known to preserve LTP. Treatment with NTS-105 starting an hour after injury reduced a marker of microglial activation and increased expression of the GluR1 subunit of the AMPAR, which is a postsynaptic protein associated with LTP. NTS-105 is known to inhibit activation of the androgen receptor and the mineralocorticoid receptor, partially activate the progesterone B receptor and not activate the glucocorticoid receptor. NTS-105 treatment did not alter the expression of any of the oxosteroid receptors (progesterone, androgen, mineralocorticoid, and glucocorticoid). In order to demonstrate the benefits of mineralocorticoid antagonism following TBI, we administered eplerenone immediately after injury. Eplerenone treatment preserved LTP, but did increase spike magnitude at high concentrations. In the third aim, organotypic hippocampal slice cultures were biaxially stretched to model a mild TBI and serial electrophysiological recordings were collected. In this in vitro model, stretchable microelectrode arrays were embedded within the culture substrate to both deform the adhered culture and record neural signals, which are indicators of neuronal health and network connectivity. Multiple spontaneous and evoked recordings were obtained while maintaining sterility to study and modulate the electrophysiological response to injury. Bursting activity increased 2 hours after injury but returned to baseline by 24 hours. However, 24 hours after injury, both LTP and long-term depression (LTD) were impaired. In another experiment, LTP was induced multiple times, both 24 hours before and 24 hours after injury, to study how the state of the pre-injury network affected electrophysiological outcome after injury. We provide preliminary evidence that induction of LTP before injury to increase synaptic strength was detrimental to neuronal plasticity (LTP) after injury. This thesis has expanded upon the understanding of TBI injury mechanisms and hormone receptor modulators following TBI. Future studies will continue to examine NTS-105 and study the benefits of androgen receptor antagonism. Future studies will also continue to use the stretchable microelectrode arrays and our induction paradigm to test if induction of LTD, a weakening of synaptic strength, could increase resiliency to injury.