Characterization, Mechanism, and Treatment of Postictal Hypoperfusion/Hypoxia

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atmire.migration.oldid5904
dc.contributor.advisorTeskey, G. Campbell
dc.contributor.authorFarrell, Jordan
dc.date.accessioned2017-08-31T15:21:24Z
dc.date.available2017-08-31T15:21:24Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractFollowing seizure cessation, specific behavioural impairments emerge that reflect the networks involved in ictal activity and extend for tens of minutes to hours. Postictal behavioural dysfunction is epitomized by Todd’s Paresis: limb weakness or paralysis following seizures that begin within or spread to motor cortex. This observation was described over a century ago, yet still lacks physiological explanation and therapies. The similarities shared between postictal behavioural dysfunction and neurological deficits following stroke suggest a potential common mechanism. I hypothesized that seizures result in a period of severe hypoperfusion/hypoxia that is responsible for behavioural impairment and not the seizure per se. Systematic characterization of local blood flow and tissue oxygen levels following focal seizures revealed a period of severe hypoperfusion/hypoxia (~50% reduction in blood flow, pO2 < 10mmHg) that often lasted over an hour in several rodent seizure models and persons with epilepsy. Cyclooxygenase-2 and L-type calcium channels were identified as key molecular targets that mediate local vasoconstriction. Further interrogation of the mechanism determined that the canonical cyclooxygenase-2 signalling cascade, involving oxygenation of arachidonic acid to prostaglandins, was not responsible for this phenomenon. Instead, oxygenation of the endocannabinoid, 2- arachidonoylglyerol, which yields novel prostaglandin glycerol esters, was identified as the primary pathway mediating severe postictal hypoperfusion/hypoxia. Thus, disrupting cyclooxygenase-2 function or L-type calcium channel activity prevented the expression of this pathological event. Inhibition of either target, which blocked hypoxia but not seizures, revealed that severe postictal hypoperfusion/hypoxia is responsible for postictal memory deficits and Todd’s paresis. These findings may extend to several negative features of epilepsy including other acute behavioural impairments, sudden unexpected death in epilepsy, anatomical abnormalities, epileptogenesis, and interictal comorbidities. This research identifies a novel, testable theory for epilepsy which places severe postictal hypoperfusion/hypoxia as a causal mechanism behind epilepsy pathology and behavioural dysfunction. Most importantly, the molecular targets identified herein may ultimately lead to new therapies for untreated aspects of epilepsy and improve quality of life.en_US
dc.identifier.citationFarrell, J. (2017). Characterization, Mechanism, and Treatment of Postictal Hypoperfusion/Hypoxia (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25265en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/25265
dc.identifier.urihttp://hdl.handle.net/11023/4054
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectNeuroscience
dc.subject.otherSeizure
dc.subject.otherEpilepsy
dc.subject.otherHypoxia
dc.subject.otherCOX-2
dc.subject.otherEndocannabinoids
dc.titleCharacterization, Mechanism, and Treatment of Postictal Hypoperfusion/Hypoxia
dc.typedoctoral thesis
thesis.degree.disciplineNeuroscience
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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