Extensive evidence suggests that glucose has both positive and negative effects on memory and these effects likely involve an influence on the brain. For instance, direct infusions of glucose into the septum (MS) or hippocampus can enhance or impair memory. The present set of experiments attempted to determine the different conditions that dissociate the memory-enhancing and -impairing effects of glucose in rats. Specifically, these experiments examined the effects of glucose in spontaneous alternation, a measure of spatial working memory and shock avoidance, an index of emontional long-term memory. The results showed that the memory-impairing effects of MS infusions of glucose are not concentration-dependent. These data also indicated that the memory-impairing effects of MS glucose elevations are specific to gamma-aminobutyric acid GABA receptor activation but do not depend on increases in MS GABA synthesis or release. Importantly, we showed that the memory-impairing interaction between MS glucose and GABA agonists does not generalize to the hippocampus, suggesting the memory-modulating effects of glucose are brain region-dependent. We showed further that these brain region-dependent effects of glucose are not due to difference in basal extracellular glucose levels. Moreover, these findings showed that the memory-enhancing effects of hippocampus glucose override the memory-impairing interaction between MS glucose and GABA. These findings are important because they are the first to show that the memory-modulating effects of glucose are both neurotransmitter- and brain region-dependent. Furthermore, these findings provide preliminary evidence suggesting that the memory-impairing effects of MS glucose may involve compromised hippocampal function. These data also suggest the memory-impairing effects of MS co-infusions of glucose with GABA agonists likely involve an influence on the GABAergic SH projection. Finally, these findings demonstrate the mnemonic and neurochemical consequences of glucose in the MS and hippocampus, two brain regions affected by normal aging, Alzheimer’s disease, and diabetes.

Traumatic brain injury (TBI) is an injury of the brain most often caused by blunt force trauma to the head and typically characterized by an increase in reactive oxygen species (ROS), inflammation, and hemorrhaging. Heme oxygenase (HO) catalyzes the breakdown of heme into carbon monoxide (CO), biliverdin which is further reduced to bilirubin, and ferrous iron. There are two active isoforms: HO-1 which is inducible and found predominantly in liver and spleen tissue; and HO-2 which is constitutive and found predominantly in the brain and testis. The metabolites of heme possess cytoprotective properties that can limit damage resulting from TBI. Our laboratory has found a selective HO-2 activator known as menadione (MD) that has been found to increase HO-2 activity by 4-fold while not affecting HO-1 in vitro. Given the higher amounts of HO-2 found in the brain and the cytoprotective properties of heme metabolites, we postulate that activation of HO-2 using menadione would mitigate further damage after TBI. The rat controlled cortical impact (CCI) model was used to simulate TBI with spontaneous locomotor activity (SLA), spontaneous alternation behaviour (SAB), and beam balance (BB) as the behavioural tasks to assess cognitive and motor function. A dose-response study (25, 50, 100, 200 μmol/kg) was performed to ascertain the effect of MD treatment on injured animals comparing to uninjured controls and injured animals treated with the vehicle (saline). We found that BB performance improved to control levels after MD treatment at 25 μmol/kg and 50 μmol/kg whereas animals treated with saline did not improve. SLA and SAB performance did not improve after treatment with MD. The findings suggest that HO-2 activation may be a viable method in mitigating further injury after TBI. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2014-06-27 19:33:45.645