Browsing by Subject "neurobiology"

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  • Pospelov, Alexey (Helsingin yliopisto, 2021)
    Treatment of birth asphyxia (BA) is a challenging problem – this condition is common and often leads to severe life-long neurological dysfunction. The pathophysiology of BA is complex and not fully understood, and the existing therapeutic approaches are not effective. Animal models are the main source of knowledge about the pathophysiology of BA, but many of the existing models have little relevance to the defining features of BA – the co-occurring hypoxia and hypercapnia – making the results obtained from such models, which concentrate on hypoxia in isolation, difficult to apply in clinical practice. This Dissertation consists of three studies (Studies I–III), which address the above shortcomings and suggest alternative approaches. Study I characterizes the pH-dependent vasomotor responses in a novel, physiologically-validated model of BA. The key advantage of this model is that it reproduces not only the hypoxic but also the hypercapnic component of asphyxia. The importance of the co-occurrence of these two components is directly demonstrated in experiments showing that in the absence of hypercapnia, shifts in brain pH and in partial pressure of oxygen (Po2) during and after hypoxia are qualitatively different from those during asphyxia proper. The respiratory acidosis, associated with the latter, triggers protective mechanisms that have emerged during mammalian evolution to ameliorate brain damage during asphyxia. In Study II, we investigated the therapeutic potential of carbon dioxide (CO2) supplemented in ambient air for the treatment of BA-seizures. Seizures are a common acute consequence of BA and they exacerbate the brain damage caused by asphyxia itself. We found that supplementing the inhaled air with 5% CO2 immediately after the asphyxia period prevents seizures, presumably by slowing down the brain pH recovery from acidosis caused by asphyxia. Study III focuses on carbonic anhydrase inhibitors (CAIs), drugs that cause respiratory acidosis by retention of metabolically-generated CO2. These drugs produced brain pH and Po2 responses similar to the responses to CO2 supplementation and similarly suppressed seizures triggered by BA. As first shown in this study, the most widely used CAI, acetazolamide (AZA) is therefore a candidate drug for the treatment of BA seizures. In sum, this doctoral thesis work developed and characterized a novel rodent model of BA and used this model for testing a novel treatment strategy for BA and post-asphyxia seizures.