Stroke is a devastating neurological disease with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic injury. The work reported in this thesis was undertaken to investigate the hypothesis that fenamate NSAIDs have neuroprotective properties against ischemic stroke and to explore the underlying mechanisms for any efficacy. Fenamates are non-selective inhibitors of cyclooxygenases. In addition, fenamates are antagonists of non-selective cation channels, subtype-selective modulators of GABA A receptors, weak inhibitors of glutamate receptors and activators of some potassium channels, all potentially important in the pathogenesis of ischemic stroke. Mefenamic acid, a prototype fenamate, administered by intracerebroventricular (ICV) infusion, reduced the ischemic brain damage and edema volume in the middle cerebral artery occlusion model in male rats. Consistent with these results, systemic administration of mefenamic acid, by multiple intravenous injections, also reduced the ischemic damage and edema volume measured by morphometric analysis and as a function of brain water content. These are the first set of experiments to demonstrate a significant neuroprotective effect of a fenamate against an in vivo model of ischemic stroke. In vitro , mefenamic acid was also shown to reduce glutamate-evoked cell death ( excitotoxicity ) in a concentration-dependent manner in cultured embryonic rat hippocampal neurons. Similarly, selected other fenamates also reduced excitotoxicity in the rank order (from highest): mefenamic acid > flufenamic acid ≥ meclofenamic acid > niflumic acid supporting the idea that this is a drug class action. Three pharmacological properties of fenamates, cyclooxygenase inhibition, GABA A receptor modulation and potassium channel activation were investigated as the potential mechanism(s) for the neuroprotective effects of mefenamic acid against excitotoxicity. The experimental results suggest that these are not the primary mechanisms for neuroprotective effects of mefenamic acid against glutamate-evoked cell death. Collectively, these data support the hypothesis that fenamate NSAIDs are neuroprotective against experimental models of cerebral ischemia and suggest they should be further investigated as potential pharmacological treatments for stroke.

Yes / Endothelial dysfunction and damage underlie cerebrovascular disease and ischemic stroke. We undertook corneal confocal microscopy (CCM) to quantify corneal endothelial cell and nerve morphology in 146 patients with an acute ischemic stroke and 18 age-matched healthy control participants. Corneal endothelial cell density was lower (P<0.001) and endothelial cell area (P<0.001) and perimeter (P<0.001) were higher, whilst corneal nerve fbre density (P<0.001), corneal nerve branch density (P<0.001) and corneal nerve fbre length (P=0.001) were lower in patients with acute ischemic stroke compared to controls. Corneal endothelial cell density, cell area and cell perimeter correlated with corneal nerve fber density (P=0.033, P=0.014, P=0.011) and length (P=0.017, P=0.013, P=0.008), respectively. Multiple linear regression analysis showed a signifcant independent association between corneal endothelial cell density, area and perimeter with acute ischemic stroke and triglycerides. CCM is a rapid non-invasive ophthalmic imaging technique, which could be used to identify patients at risk of acute ischemic stroke. / Qatar National Research Fund Grant BMRP20038654

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Layer 3 (L3) pyramidal neurons are involved in intrinsic and extrinsic corticocortical communications that are integral to area specific cortical functions. The functional and morphological properties of these neurons are altered in the lateral prefrontal cortex (LPFC) of aged rhesus monkeys, changes which parallel the decline of working memory (WM) function. What is not yet understood is the time course of these neuronal alternations during the aging process, or the impact of neuronal changes on the function of local networks that underlie WM. By comparing the properties of L3 pyramidal neurons from the LPFC of behaviorally characterized rhesus monkeys over the adult lifespan using whole cell patch clamp recordings and neuronal reconstructions, the present dissertation demonstrates that WM impairment, neuronal hyperexcitabilty and spine loss begin in middle age. We use bump attractor models to predict how empirically observed changes affect performance on the Delayed Response Task and Delayed Recognition Span Task (spatial). The performance of both models is affected much more by neuronal hyperexcitability than by synapse loss. In a separate study, we examine pathological changes of L3 pyramidal neurons in the perilesional ventral premotor cortex following acute ischemic injury to the primary motor cortex. Neurons from lesioned monkeys exhibit hyperexcitability and changes the excitatory:inhibitory synaptic balance in favor of inhibition. As oxidative stress and inflammation are known to exacerbate both age-related and injury-induced neuronal pathology, we characterize neuronal properties in both conditions after administering therapeutic interventions which target inflammatory pathways and which have previously been shown to ameliorate behavioral deficits. Chronic dietary curcumin treatment dampens neuronal hyperexcitability in middle-aged subjects, but the neuronal changes are not correlated with WM improvements. Treatment with mesenchymal-derived extracellular vesicles lowers firing rates and restores excitatory:inhibitory synaptic balance, and importantly, these changes correlate significantly with motor function.

Paroxysmal Atrial fibrillation (AF) is often clinically silent and may be missed by the usual diagnostic workup after ischemic stroke. We aimed to determine whether shape characteristics of ischemic stroke lesions can be used to predict AF in stroke patients without known AF at baseline. Lesion shape quantification on brain MRI was performed in selected patients from the intervention arm of the Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS) study, which included patients with ischemic stroke or TIA without prior AF. Multiple morphologic parameters were calculated based on lesion segmentation in acute brain MRI data. Multivariate logistic models were used to test the association of lesion morphology, clinical parameters, and AF. A stepwise elimination regression was conducted to identify the most important variables. A total of 755 patients were included. Patients with AF detected within 2 years after stroke (n=86) had a larger overall oriented bounding box (OBB) volume (p=0.003) and a higher number of brain lesion components (p=0.008) than patients without AF. In the multivariate model, OBB volume (OR 1.72, 95%CI 1.29–2.35, p<0.001), age (OR 2.13, 95%CI 1.52–3.06, p<0.001), and female sex (OR 2.45, 95%CI 1.41–4.31, p=0.002) were independently associated with detected AF. Ischemic lesions in patients with detected AF after stroke presented with a more dispersed infarct pattern and a higher number of lesion components. Together with clinical characteristics, these lesion shape characteristics may help in guiding prolonged cardiac monitoring after stroke.

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