Targeting TNFα-mediated cytotoxicity using thalidomide after experimental cardiac arrest in rats: An exploratory study

Abstract

Cardiac arrest (CA) results in a central and systemic cytokine and inflammatory response. Thalidomide has been reported to be neuroprotective by selectively decreasing TNFα synthesis. We hypothesized that thalidomide would decrease the systemic and organ-specific TNFα/cytokine response and biomarkers of injury in rats subjected to 10 min CA. Naïves, CA treated with vehicle (CA) and CA treated with thalidomide (50 mg/kg; CA+T) were studied (n=6 per group). TNFα and key cytokines were assessed at 3 h after resuscitation in the cortex, hippocampus, striatum, cerebellum, plasma, heart and lung. Neuron specific enolase (NSE), S100b, cardiac troponin T (cTnT) and intestinal fatty acid binding protein (IFABP) were used to assess neuronal, glial, cardiac and intestinal damage, respectively. CA increased TNFα and multiple pro-inflammatory cytokines in plasma and selected tissues with no differences between the CA and CA+T groups in any region. NSE, S100b, cTnT and IFABP were increased after CA or CA+T vs. in the naïve group (all P<0.05) without significant differences between the CA and CA+T groups. In conclusion, CA resulted in a TNFα and cytokine response, with increased biomarkers of organ injury. Notably, thalidomide at a dose reported to improve the outcome in in vivo models of brain ischemia did not decrease TNFα or cytokine levels in plasma, brain or extracerebral organs, or biomarkers of injury. Although CA at 3 h post resuscitation produces a robust TNFα response, it cannot be ruled out that an alternative dosing regimen or assessment at other time-points might yield different results. The marked systemic and regional cytokine response to CA remains a potential therapeutic target.

Keywords: brain ischemia; cardiopulmonary resuscitation; heart arrest/pathology; microglia/drug effects; neurons/drug effects; post-cardiac arrest syndrome; thalidomide/pharmacology; tumor necrosis factor-α.

Figure 1

TNFα levels in plasma at 3 h after prolonged ventricular fibrillation CA in rats. Boxes represent the 25-75% interquartile range, the line across the box represents the median, and the whiskers are min-max values. The thick horizontal line signifies P<0.05 between groups (one-way ANOVA with post hoc Tukey's test). CA, cardiac arrest (control group); CA+T, cardiac arrest plus thalidomide (treatment group).

Figure 2

TNFα levels in selected brain regions and extracerebral organs at 3 h after prolonged ventricular fibrillation CA in rats. Boxes represent the 25-75% interquartile range, the line across the box represents the median, and the whiskers are min-max values. The thick horizontal line signifies P<0.05 between groups (Kruskal-Wallis test followed by Dunn-Bonferroni post-hoc test). The round marker and the asterisk represent outliers (‘out’ and ‘far out’ values). CA, cardiac arrest (control group); CA+T, cardiac arrest plus thalidomide (treatment group); CB, cerebellum; CTX, cortex; HIP, hippocampus; STRI, striatum.