Abstract
BackgroundThe NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL-1β and IL-18. Fluoxetine has been shown to have the anti-inflammatory properties in many disease models. However, the effects and mechanisms of these effects of fluoxetine in early brain injury after subarachnoid hemorrhage (SAH) have not been defined.MethodsThe SAH model was induced by an endovascular perforation in adult male Sprague-Dawley (SD) rats weighing 300–320 g. N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (AC-YVAD-CMK) was injected intraperitoneally (5 mg/kg) 1 h after SAH. Fluoxetine was administered via intravenous route 6 h after SAH. 3-Methyladenine (3-MA) was intracerebroventricularly injected 20 min before SAH. SAH grade, neurological function, brain water content, propidium iodide (PI) staining, western blot, double immunostaining, and transmission electron microscopy were performed.ResultsExpression of caspase-1 increased and peaked at 24 h after SAH. Caspase activation was along with the increased necrotic cells, which occurred mainly in neurons. Necrotic cell death of microglia and astrocyte were also found. Administration of AC-YVAD-CMK, a caspase-1 inhibitor, reduced the expression of IL-1β and IL-18 and the number of PI-positive cells, attenuated brain edema, and improved neurological function, which was also observed in fluoxetine-treated rats. Furthermore, fluoxetine treatment significantly decreased the expression of NLRP3 and cleaved caspase-1 and upregulated the expression of beclin-1, a marker for autophagy. Finally, the effects of fluoxetine in NLRP3 inflammasome activation were reversed by additional 3-MA administration.ConclusionsTogether, our present study indicated that NLRP3 inflammasome and caspase-1 activation play a deleterious role in early brain injury and fluoxetine mitigates NLRP3 inflammasome and caspase-1 activation through autophagy activation after SAH, providing a potential therapeutic agent for SAH treatment.
Highlights
The NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL-1β and IL-18
Our findings indicated that caspase-1 activation was induced at the early stages of subarachnoid hemorrhage (SAH) and promoted necrotic cell death and expression of inflammatory cytokines (IL-1β and IL-18) in early brain injury after SAH
In experiment 3, the SAH + vehicle group exhibited 33.3% (9 of 27 rats) mortality, whereas 21.7% (5 of 23 rats) mortality occurred in SAH + fluoxetine group
Summary
The NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL-1β and IL-18. The effects and mechanisms of these effects of fluoxetine in early brain injury after subarachnoid hemorrhage (SAH) have not been defined. The significant mortality and morbidity may result from both the early brain injury and delayed cerebral ischemia [1]. A ruptured aneurysm leads to many physiological derangements such as elevated intracranial pressure (ICP), decreased cerebral blood flow (CBF), and decreased cerebral perfusion pressure (CCP). These events initiate various cascades of injuries such as inflammation, oxidative stress, blood brain barrier dysfunction, brain edema, and apoptosis [5, 6]
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