Regional TNFα mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats

Abstract

Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6 min (CA6), 8 min (CA8) or 10 min (CA10) of VF CA, or sham group. Cortex, striatum, hippocampus and cerebellum were evaluated for TNFα and interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 and interferon gamma at 3 h, 6 h or 14 d after CA by ELISA and Luminex. Immunohistochemistry was used to determine the cell source of TNFα. CA resulted in a selective TNFα response with significant regional and temporal differences. At 3 h after CA, TNFα-levels increased in all regions depending on the duration of the insult. The most pronounced increase was observed in striatum that showed 20-fold increase in CA10 vs. sham, and 3-fold increase vs. CA6 or CA8 group, respectively (p < 0.01). TNFα levels in striatum decreased between 3 h and 6 h, but increased in other regions between 3 h and 14 d. TNFα levels remained twofold higher in CA6 vs. shams across brain regions at 14 d (p < 0.01). In contrast to pronounced TNFα response, other cytokines showed only a minimal increase in CA6 and CA8 groups vs. sham in all brain regions with the exception that IL-1β increased twofold in cerebellum and striatum (p < 0.01). TNFα colocalized with neurons. In conclusion, CA produced a duration-dependent acute TNFα response, with dramatic increase in the striatum where TNFα colocalized with neurons. Increased TNFα levels persist for at least two weeks. This TNFα surge contrasts the lack of an acute increase in other cytokines in brain after CA. Given that striatum is a selectively vulnerable brain region, our data suggest possible role of neuronal TNFα in striatum after CA and identify therapeutic targets for future experiments.

Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation

“…Intranasal ORXA administration inhibited the concerted activation of IL1β, TNFα, and iNOS markers in a number of brain structures, including the hippocampus and hypothalamus. Previously, cytokine activation including such key components as TNFα and IL1β have been shown in different models of CA [ 16 , 17 , 57 ] although the involvement of other cytokines is likely to be affected by type of the model, duration of CA and other procedure-related factors [ 16 , 17 ].…”

“…CA has been shown to result in cell- and brain-region-specific cytokine production. For example, CA-induced TNFα has being co-localized with neurons and IL1β with astrocytes in striatum [ 16 , 17 ].…”

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

“…In addition, IL-12 levels in plasma and brain tissue are significantly increased in an animal model of cardiac arrest after ventricular fibrillation. (Janata et al, 2014;Heo et al, 2017). In a mouse model of heart transplantation, administration of an anti-IL-12p40 antibody significantly reduced invasion by gdT cells, reduced the expression of various inflammatory factors, and greatly improved the survival of mice .…”

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

“…16 Adrenalin (2 μg/100 g) and 0.1 mL sodium bicarbonate (8.4%) were immediately administered to the rats at the beginning of CPR and repeated at 3-minute intervals as needed. 12,[17][18][19][20] The administration of intravenous fluid during CPR was limited to <2 mL. Three minutes after chest compressions were started, defibrillation was performed with direct-current single-phase waves of 2 J when the ECG displayed VF.…”