5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

Abstract

Early brain injury (EBI) is a major contributor to the high mortality and morbidity after subarachnoid hemorrhage (SAH). Inflammatory responses and neuronal apoptosis are important causes of EBI. Because 5- lipoxygenase (5-LOX) is known to be involved various central nervous system diseases, we investigated the effects of 5-LOX inhibition during EBI after SAH. Zileuton and LY294002 were used to inhibit expression of 5-LOX and Akt, respectively. We found that 5-LOX expression was significantly increased in the cytoplasm of cortical neurons after SAH and was accompanied by upregulated expression of the inflammatory factors LTB4, TNF-α, IL-1β and IL-6; upregulation of the pro-apoptotic factor Bax; downregulation of the anti-apoptotic factor Bcl-2; and an increased apoptosis rate. Gastric Zileuton administration significantly suppressed all of those effects and improved neurological function. Zileuton also upregulated activated (phosphorylated) AKT levels, and these beneficial effects of Zileuton were abolished by intracerebroventricular infusion of the PI3K inhibitor LY294002. Taken together, these findings indicate that 5-LOX mediates pro-inflammatory and pro-apoptotic effects that contribute to EBI after SAH and that those effects are suppressed by activation of PI3K/Akt signaling. This suggests targeting 5-LOX may be an effective approach to treating EBI after SAH.

Protective mechanism of FoxO1 against early brain injury after subarachnoid hemorrhage by regulating autophagy

“…Many experiments have shown that apoptosis may play an important role in EBI (Liu L. et al., 2021 ). During cerebral ischemia, the concentration of free radicals exceeds the local antioxidant capacity, causing brain damage and vascular membrane destruction, leading to cell apoptosis (Li X., Liu W. et al., 2020 ).…”

Role of Inflammatory Processes in Hemorrhagic Stroke

“…149 Another study reported increased neuronal expression of 5-LOX‚ with 5-LOX inhibition reducing neuroinflammation and neuronal cell death after experimental SAH. 150 The cytochrome P450 pathway converts arachidonic acid into epoxyeicosatrienoates and hydroxyeicosatetraenoates, which play opposing roles in cerebrovascular function and in pathological processes underlying neural injury, including ischemic and hemorrhagic stroke. Epoxyeicosatrienoates are protective in ischemic stroke due to their vasodilator property, but they have also been shown to have anti-inflammatory properties, [151][152][153] in part mediated via peroxisome proliferator-activated receptor α.…”

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

“…Recently, Liu et al. reported that increased 5-lipoxygenase in cytoplasm of cortical neurons along with expression of upregulated inflammatory factors LTB4, TNF-α, IL-1β, and IL-6 contributed to EBI after SAH ( 142 ). In this process, activation of PI3K/Akt signaling significantly suppressed the 5-lipoxygenase-induced SAH pathologic manifestation ( 142 ).…”

“…reported that increased 5-lipoxygenase in cytoplasm of cortical neurons along with expression of upregulated inflammatory factors LTB4, TNF-α, IL-1β, and IL-6 contributed to EBI after SAH ( 142 ). In this process, activation of PI3K/Akt signaling significantly suppressed the 5-lipoxygenase-induced SAH pathologic manifestation ( 142 ). Taken together, the activation of the PI3K/Akt signaling pathway potentially improves the immune inflammatory response, eventually resulting in protection against the damage following SAH.…”