| dc.contributor.author | Gilby, Krista Lynn. | en_US |
| dc.date.accessioned | 2014-10-21T12:35:07Z | |
| dc.date.available | 2000 | |
| dc.date.issued | 2000 | en_US |
| dc.identifier.other | AAINQ57363 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55713 | |
| dc.description | Recent studies have shown that Clomethiazole (CMZ) may be neuroprotective in both global and focal animal models of ischemia. The primary objective of this thesis was to determine whether a single dose of CMZ could provide neuroprotection when administered following severe global ischemia. We used the Rice-Vannucci model of hypoxia-ischemia (H-I) to produce a large unilateral global ischemic injury in young (PND25) male rats. After testing several doses and timepoints of administration for CMZ, we were able to determine that doses of 100, 150 and 200 mg/kg administered at 1, 2 or 3 hours post-hypoxia provided significant neuroprotection in all brain regions normally susceptible to H-I injury. The ability of CMZ to potentiate GABAergic neurotransmission has generally been credited for its neuroprotective effects in animal models of ischemia. In order to determine whether the neuroprotective efficacy of CMZ was due to its GABAA-potentiating properties, we examined the neuroprotective efficacy of known GABAA-potentiating agents in the H-I model. Regardless of dosage, the highly specific GABAA-agonist, muscimol, did not provide neuroprotection in any cell layer of H-I animals when administered at 3 hours post-hypoxia. However, high doses of the benzodiazepine, midazolam (l50 and 200 mg/kg), provided significant neuroprotection in all cell layers of H-I animals when administered 3 hours post-hypoxia. Importantly, the neuroprotective efficacy of midazolam was substantially less than that of CMZ in this model. We, therefore, investigated whether an additive or alternate mechanism of action may be responsible for the profound neuroprotection provided by CMZ in the H-I model. | en_US |
| dc.description | The effects of CMZ administration on normal patterns of gene expression following H-I were investigated using a number of molecular biological tools including RT-PCR. in situ hybridization, differential display and DNA sequencing. Results of these experiments demonstrated that CMZ administration altered the normal patterns of expression for several mRNAs following H-I including hsh70, hsp25, hsp40, calmodulin. c-fox , and c-jun and several proteins including Hsp70, Hsp25 and c-Fos. The effect of CMZ administration on subsequent gene expression in the H-I model was diverse but may indicate that a molecular mechanism of action exists for this compound. | en_US |
| dc.description | In a parallel series of experiments, we investigated whether the apparent morphological neuroprotection provided by CMZ translated into functional sparing of neurons susceptible to H-I injury. Specifically, we wanted to determine whether the neuronal circuitry originating from cell regions normally susceptible to H-I was fully functional in CMZ-treated animals. Both vehicle-injected and CMZ-injected (200 mg/kg and 100 mg/kg) H-I animals were kindled approximately two months following H-I treatment in order to compare seizure susceptibility and seizure propagation characteristics in the ipsilateral hippocampus of animals from both treatment groups. CMZ-treated H-I animals exhibited a decreased susceptibility to seizures and a stronger resistance to initial seizure propagation than vehicle-injected H-I animals. Moreover, the seizure susceptibility of CMZ-treated H-I animals was decreased even when compared to naive control animals. These results indicate that despite the apparent complete morphological neuroprotection observed following CMZ administration, permanent changes in neuronal circuitry may occur in CMZ treated H-I animals. It is unclear whether this alteration in neuronal circuitry would have clinical implications in stroke patients. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2000. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Biology, Neuroscience. | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.title | An investigation into the mechanism responsible for clomethiazole-induced neuroprotection in a rat model of severe global ischemia. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
