Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Ücal, M.
THE ROLE OF NITRIC OXIDE IN INJURY INDUCED CEREBRAL DAMAGE
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.141.
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- Autor*innen der Med Uni Graz:
- Ücal Muammer
- Betreuer*innen:
- Öttl Karl
- Schäfer Ute
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- Abstract:
- Nitric oxide (NO) is a non-canonical intercellular messenger and a free radical. It is known to regulate a wide variety of cellular processes that include cell viability, proliferation, mitochondrial energy metabolism, cell death, and shown to mediate a broad spectrum of physiological processes regulated by the CNS, like regulation of cardiovascular responses, sympathetic and parasympathetic nerve activity, sleep and appetite. In traumatized brain, NO has frequently been associated with secondary damage after brain injury. However, average NO levels in different brain regions before and after traumatic brain injury (TBI) and its role in post-TBI mitochondrial dysfunction remain unclear. Furthermore, TBI-induced changes in NO metabolism in distant organs, such as heart and liver, have not been studied. In this study, NO changes in brain, liver and heart after TBI and possible association to its detrimental and beneficial effects were investigated. Here, we demonstrate for the first time that basal NO levels vary significantly in the healthy cortex (0.44 ±0.04 µM), hippocampus (0.26 ±0.03 µM), and cerebellum (1.24 ±0.08 µM). Within 4 h of severe lateral fluid percussion injury, NO levels almost doubled in these regions, thereby preserving regional differences in NO levels. TBI-induced NO generation was associated with inducible NO synthase (iNOS) increase in ipsilateral but not in contralateral regions. The transient NO increase resulted in a persistent tyrosine nitration adjacent to the injury site. Nitrosative stress-associated cell loss via apoptosis and receptor-interacting serine/threonine kinase 3 (RIPK3)-mediated necrosis were also observed in the ipsilateral cortex, despite high levels of NO in the contralateral cortex. NO-mediated impairment of mitochondrial state 3 respiration dependent on complex I substrates was transient and confined to the ipsilateral cortex. Decrease in glutamate-dependent state 3 respiration was more prominent as compared to pyruvate-dependent state 3 respiration, suggestive of particular vulnerability of glutamate node in the mitochondrial respiration to TBI-induced NO changes in injured brain. Our results demonstrate that NO dynamics and associated effects (detrimental or beneficial) differ in various regions of the injured brain. A potential association between the observed mitochondrial electron flow through complex I, but not complex II, and the modulation of TBI induced NO levels in different brain regions has to be prospectively analyzed in more detail. In liver and heart, a transient and but significant increase in NO levels was detected isochronous to the changes observed in brain regions. Clinical relevance of TBI-induced NO changes in distant organs has to be analysed in further research.