Experimental paperRegional TNFα mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats☆
Introduction
Overall mortality after cardiac arrest (CA) remains high, despite improvements in resuscitation and critical care.1 Neurocognitive disabilities are frequently observed in survivors from CA. Histological damage including neuronal cell loss was characterized in multiple experimental global ischemia–reperfusion insults. Several selectively vulnerable regions have been identified, namely hippocampus, cerebellar Purkinje neurons, lamina IV cortical layer and striatum.2, 3 Both the systemic inflammatory response to CA and the local central nervous system (CNS) specific response may contribute to the ultimate histological damage.
CA and resuscitation result in a systemic inflammatory response that has been compared to sepsis.4 Cytokines produced by multiple cells including resident CNS cells are considered a hallmark of inflammatory reaction to an insult. Systemic and CNS levels of various cytokines including tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-8, IL-10, and others are increased after CA.4, 5, 6, 7
We have recently established a rat model of ventricular fibrillation (VF) CA and characterized extensive neuronal death with characteristic regional pattern.8 We hypothesized that neuroinflammation after CA might also show a regional pattern and be related to the duration of the insult. Thus, we used ELISA and Luminex methods to explore regional brain tissue levels of multiple cytokines after 6, 8 and 10 min of VF CA in cortex, hippocampus, striatum and cerebellum at 3 and 6 h after restoration of spontaneous circulation (ROSC) to study the early inflammatory response to ischemia and reperfusion. We furthermore assessed TNFα levels in rats that survived for 2 weeks. We have used immunocytochemistry to identify the cell sources of TNFα.
Section snippets
Methods
The study protocol was approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh. A total of 45 adult male Sprague–Dawley rats (350–400 g; Hilltop Lab Animals, Scottdale, PA) were used as described in detail previously. In brief, isoflurane-anesthetized rats were intubated and mechanically ventilated, while maintaining normothermia. After cannulations, rats were subjected to 6 min (CA6), 8 min (CA8) or 10 min (CA10) of untreated VF CA or sham, and 3 or 6 h of
Results
There were no significant group differences at baseline. As expected, CA resulted in significant duration-dependent derangements in multiple biochemical parameters (Table 1 – Supplemental File).
Rats in the CA10 group could not be weaned from the ventilator. Therefore, the cytokine profiles could only be studied at 3 h timepoint.
Cytokine levels after 3 h and 6 h of observation time are presented in Fig. 1, Fig. 2, Fig. 3. Significant differences between groups were detected for TNFα and IL-1β and
Discussion
This study was designed to explore the regional pattern of brain tissue cytokines early after VF CA to identify possible therapeutic targets. We used our established VF CA model characterized by neurologic impairment and extensive histological damage in multiple brain regions, including hippocampus and striatum.8
We found that brain tissue levels of TNFα are increased as early as 3 h after CA, being the most prominent in the striatum. This early TNFα response in the striatum was more pronounced
Conclusions
To our knowledge, this is a first exploratory study evaluating early regional cytokine profile in a clinically relevant VF CA model. CA induced cerebral cytokine production with a distinct spatial and temporal pattern and suggested neurons as an important early source of TNFα. Early after CA, the striatum showed marked increase in TNFα levels with highest levels after prolonged CA. 14 d after CA, brain tissue levels of TNFα remained increased over shams, but without regional differences. Our
Conflict of interest statement
All other authors report no conflict of interest.
Acknowledgements
Dr. Janata was supported by a Peter Safar Research Fellowship and Grant-in-Aid from the Laerdal Foundation for Acute Medicine, and by the Erwin Schroedinger Stipend. Dr. Uray was supported by the Max Kade Fellowship. Dr. Kochanek was supported by NS30318. Dr. Drabek was supported by the AHA #09BGIA2310196, the Laerdal Foundation and Anesthesia Seed Grant.
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.01.033.