Abstract
Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activities of HO and BVR in the brain regions Hc, mC, striatum and cerebellum of rats subjected to ventricular fibrillation CA (6 min or 8 min) after 2 weeks following resuscitation, or sham operation. From all investigated regions, only Hc and mC showed significantly decreased HO activities, while BVR activity was not affected. In order to find an explanation for the changed HO activity, we analyzed protein abundance and mRNA expression levels of HO-1, the inducible, and HO-2, the constitutively expressed isoform, in the affected regions. In both regions we found a tendency for a decreased immunoreactivity of HO-2 using immunoblots and immunohistochemistry. Additionally, we investigated the histological appearance and the expression of markers indicative for activation of microglia [tumor necrosis factor receptor type I (TNFR1) mRNA and immunoreactivity for ionized calcium-binding adapter molecule 1 (Iba1])], and activation of astrocytes [immunoreactivity for glial fibrillary acidic protein (GFAP)] in Hc and mC. Morphological changes were detected only in Hc displaying loss of neurons in the cornu ammonis 1 (CA1) region, which was most pronounced in the 8 min CA group. In this region also markers indicating inflammation and activation of pro-death pathways (expression of HO-1 and TNFR1 mRNA, as well as Iba1 and GFAP immunoreactivity) were upregulated. Since HO products are relevant for maintaining neuronal function, our data suggest that neurodegenerative processes following CA may be associated with a decreased capacity to convert heme into HO products in particularly vulnerable brain regions.
Highlights
Neurologic outcome in patients resuscitated from cardiac arrest (CA) remains poor, despite improvements in advanced life support and post-resuscitation care
Our data suggest that reduced protein levels of Heme oxygenase (HO)-2 may contribute to the decreased tissue capacity to produce HO reaction products
In the cornu ammonis 1 (CA1) region of Hc, a region typically affected in cerebral ischemia, the decrease in HO activity went in parallel with neuronal loss in CA1 and an increase in levels of markers indicating ongoing gliosis
Summary
Neurologic outcome in patients resuscitated from cardiac arrest (CA) remains poor, despite improvements in advanced life support and post-resuscitation care. Brain injury starts during the initial CA (no-flow time), continues during resuscitation (lowflow time) and culminates after re-oxygenation with the return of spontaneous circulation (ROSC). These pathophysiological events prepare the base of the post-cardiac arrest syndrome [1, 2] and lead to neurologic and motor deficits [3], which were shown to persist for a long time [4, 5]. An experimental study using rats revealed that cognitive deficits in response to global ischemia continue to develop and were most severe after 6 months when rats are in their middle age [10]. The same group showed that cognitive deficits produced by ischemia are severe in middle aged rats, suggesting that repair mechanisms decline with age [11]
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