Year: 2014
Type: dissertation
Abstract: Ischemic stroke, characterized by sudden reduction in blood flow into one or more of the cerebral arteries, often affects the elderly population accompanied by co-morbid conditions such as atherosclerosis, infections and diabetes.Novel therapeutic compounds with neuroprotective properties in preclinical models have failed in human clinical trials.The reason for the failure may be partly explained by the use of the homogenous cohorts of young healthy animals in preclinical studies bearing little relevance to heterogenic conditions of human stroke.Especially, the interaction between aging and inflammation in patients predisposed to co-morbid conditions is poorly understood.In this study, we aimed to elucidate the impact of co-morbid conditions on ischemic inflammation in experimental settings and develop clinically more relevant rodent models that bear resemblance to human stroke.We investigated the role of ApoE4 on aged mice fed with a high-fat diet and assessed the inflammatory and behavioral outcome following permanent middle cerebral artery occlusion (pMCAo).We show that aged transgenic mice expressing human ApoE4 isoforms fed with a high fat diet were more susceptible to sensorimotor deficits.These deficits were accompanied by increased astrogliosis, impaired neurogenesis, increased cyclooxygenase-2 immunoreactivity and increased peripheral IL-6 levels in plasma.Next, we carried out a study where we assessed the effect of aging and predisposing peripheral infection on the outcome of cerebral ischemia in mice.Induction of chronic Th-1 polarized systemic infection by administration of gut parasite T. muris induced significant brain damage specifically in aged mice, and this damage correlated with pre-stroke plasma level of RANTES.In addition, significant infiltration of neutrophils in the infarct core and increased plasma levels of interleukin-17α and tumor necrosis factor-α were evident in aged infected mice when compared to their young counterparts.Finally, we applied therapeutic intervention to inhibit proinflammatory receptor, cluster of differentiation 36 (CD36), in order to halt the brain damage following ischemia.We tested the therapeutic potential of a well-known inhibitor of CD36, sulfosuccinimidyl oleate sodium (SSO) against ischemic brain damage.Orally administered SSO reduced the infarct size of the animals that underwent surgery with the concomitant decrease in COX-2 immunoreactivity and microgliosis in the peri-ischemic area.SSO reduced the phagocytotic activity of BV2 microglial cells following LPS stimulation.The results of this thesis show that 1) chronic peripheral infection and a high fat diet in combination with ApoE4 isoform in aged mice renders the brain more vulnerable to ischemic insults by altering the brain inflammatory status and 2) therapeutic intervention targeting the proinflammatory receptors like CD36 may be a suitable approach for designing treatment strategies.Our results show that co-morbid conditions alter the ischemia induced inflammatory status especially in aged mice pointing out the need to consider heterogeneity in preclinical modeling of stroke.
Author: Hiramani Dhungana
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3175754253