Date of Award
Doctor of Philosophy
Field of Study
Graduate School of Biomedical Sciences
Although less appreciated, recent findings introduced critical contributions of astrocytes to numerous CNS functions, like neurogenesis, synaptogenesis, ion homeostasis, neurotransmission, and blood brain barrier formation. Their active participation in the progression of specific CNS pathologies has garnered major attention and culminated in thorough investigation of astrocyte function in brain. Reactive astrogliosis, characterized by increases in glial fibrillary acidic protein (GFAP) and cellular hypertrophy, describes the extensive structural and functional changes that astrocytes undergo in response to tissue injury. Despite of extensive investigation, the molecular mechanism of reactive astrogliosis in ischemic stroke still remains elusive. p38 MAPK is a well studied signal transducing pathway known to be involved in modulating cell type specific responses to ischemic injury. The first study presented in the dissertation delineates the involvement p38 MAPK signaling pathway in reactive astrogliosis after ischemic stroke. Results showed that astrocyte specific deletion of p38 MAPK attenuated oxygen-glucose deprivation (OGD)-induced increase in GFAP expression in primary astrocytes in vitro. Additionally, inhibition of p38 MAPK (SB239063/genetic deletion) slowed astrocyte migration without affecting astrocyte proliferation. In vivo deletion of p38 MAPK from astrocytes attenuated reactive astrogliosis after permanent middle cerebral artery occlusion in mice. These findings strongly indicated that p38 MAPK plays a critical role in reactive astrogliosis after ischemic stroke. During ischemic stroke, astrocyte dysfunction causes extensive cell death through excitotoxicity, disruption of ion and water homeostasis. Restoration of astrocyte function thus may be beneficial to ischemic tissue in the long term. Methylene blue (MB), a metabolic enhancer, has been well studied and known to improve cellular respiration, glucose metabolism and attenuate superoxide production by efficient electron transport in mitochondria. In the second part of this dissertation we determined the effect of MB in astrocytes under oxygen glucose deprivation (OGD) and reoxygenation stress and the underlying protective mechanisms. Our studies demonstrated that MB improved astrocyte bioenergetics and promoted astrocyte survival following OGD and reoxygenation. In conclusion both the studies presented, provide a unique perspective of the importance of astroglial response in ischemic injury and how its modulation can benefit the healing and recovery of the brain following ischemic injury.
Roy Choudhury, G.
"Astrocytes & Ischemic stroke" Fort Worth, Tx: University of North Texas Health Science Center;