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.

Analysis of cerebral Interleukin-6 and tumor necrosis factor alpha patterns following different ventilation strategies during cardiac arrest in pigs

“…Recent scientific findings suggest that activation of the immune system and release of pro-inflammatory cytokines after cardiac arrest can lead to secondary brain injury, exacerbating the initial injury caused by ischemia and reperfusion ( Sandroni, Cronberg & Sekhon, 2021 ; Björklund et al, 2014 ; Rocha-Ferreira et al, 2017 ; Graber, Costine & Hickey, 2015 ). IL-6 and TNFα expression have been found to be involved in inflammation due to tissue hypoxia after cardiac arrest ( Bro-Jeppesen et al, 2015 ; Tanaka & Kishimoto, 2018 ; Meyer et al, 2020 ; Niemann et al, 2013 ; Palmer et al, 2022 ). Apart from numerous studies conducted by our own research group, there have been relatively few investigations examining the specific distribution of proinflammatory cytokines in different brain regions in the porcine model following resuscitation ( Ruemmler et al, 2020 ).…”

“…This observation is consistent with our findings, showing that IL-6 mRNA-levels were overall significantly higher than TNFα mRNA-levels. However, it must be kept in mind that while significantly higher levels of IL-6 have been found, concentrations of TNFα in the picogram range can have powerful effects ( Palmer et al, 2022 ; Niemann et al, 2013 ). Further studies will have to show, if our TNFα mRNA-levels, although they are significantly lower than the IL-6 mRNA-levels, have an impact on PCABI in swine.…”

“…, tissue hypoxia after cardiac arrest and has been shown to be independently associated with poor outcomes in unconscious out-of-hospital cardiac-arrest patients ( Bro-Jeppesen et al, 2015 ; Tanaka & Kishimoto, 2018 ; Meyer et al, 2020 ). Due to cardiac arrest and cerebral ischemia also the expression of TNFα gets up-regulated ( Niemann et al, 2013 ; Palmer et al, 2022 ).…”