Abstract | BACKGROUND: METHODS: Adult male Sprague-Dawley rats resuscitated from 10 min of asphyxia- induced cardiac arrest were randomized to four separate experiments including time-course, short-term outcomes, long-term outcomes and mechanism studies. The effect of mast cell tryptase inhibition on asphyxial cardiac arrest outcomes was examined after intranasal administration of selective mast cell tryptase inhibitor (APC366; 50 μg/rat or 150 μg/rat). AC55541 (selective PAR-2 activator; 30 μg/rat) and SB203580 (selective p38 inhibitor; 300 μg/rat) were used for intervention. Short-term neurocognitive functions were evaluated using the neurological deficit score, number of seizures, adhesive tape removal test, and T-maze test, while long-term cognitive functions were evaluated using the Morris water maze test. Hippocampal neuronal degeneration was evaluated by Fluoro-Jade C staining. RESULTS:
Mast cell tryptase and PAR-2 were dramatically increased in the brain following asphyxia- induced cardiac arrest. The inhibition of mast cell tryptase by APC366 improved both short- and long-term neurological outcomes in resuscitated rats. Such behavioral benefits were associated with reduced expressions of PAR-2, p-p38, NFκB, TNF-α, and IL-6 in the brain as well as less hippocampal neuronal degeneration. The anti-neuroinflammatory effect of APC366 was abolished by AC55541, which when used alone, indeed further exacerbated neuroinflammation, hippocampal neuronal degeneration, and neurologic deficits following cardiac arrest. The deleterious effects aggregated by AC55541 were minimized by p38 inhibitor. CONCLUSIONS:
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Authors | Umut Ocak, Pinar Eser Ocak, Lei Huang, Weilin Xu, Yuchun Zuo, Peng Li, Marcin Gamdzyk, Gang Zuo, Jun Mo, Guangyu Zhang, John H Zhang |
Journal | Journal of neuroinflammation
(J Neuroinflammation)
Vol. 17
Issue 1
Pg. 144
(May 04 2020)
ISSN: 1742-2094 [Electronic] England |
PMID | 32366312
(Publication Type: Journal Article)
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Chemical References |
- NF-kappa B
- Receptor, PAR-2
- Tryptases
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Topics |
- Animals
- Asphyxia
(complications)
- Brain
(metabolism, pathology)
- Heart Arrest
(complications)
- Hypoxia-Ischemia, Brain
(etiology, metabolism, pathology)
- Inflammation
(etiology, metabolism)
- MAP Kinase Signaling System
(physiology)
- Male
- NF-kappa B
(metabolism)
- Rats
- Rats, Sprague-Dawley
- Receptor, PAR-2
(metabolism)
- Signal Transduction
(physiology)
- Tryptases
(antagonists & inhibitors)
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