EFFECTS AND UNDERLYING MECHANISM OF 5-LIPOXYGENASE INHIBITOR (ZILEUTON) ON MICE DEPRESSIVE-LIKE BEHAVIOR

SAPTARSHI PANIGRAHI; SOMNATH SURAI; HAO HONG

doi:10.22159/ajpcr.2020.v13i3.37106

Authors

SAPTARSHI PANIGRAHI Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China.
SOMNATH SURAI Department of Pharmaceutics, Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
HAO HONG Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China.

DOI:

https://doi.org/10.22159/ajpcr.2020.v13i3.37106

Keywords:

Depression, Zileuton, 5-Lipoxygenase, Neuroinflammation, Apoptosis

Abstract

Objective: Treatment experiment was conducted to investigate the effectiveness and mechanism of the action of zileuton in corticosteroid-induced depressive mice model through neuroinflammation.

Methods: The mice were randomly separated into four groups: (Veh+Veh), (Corticosteroid+Veh), (Corticosteroid+ZIL50), and (Corticosteroid+ZIL100). Intraperitoneal injection of corticosterone (CORT) (20 mg/kg for 6 weeks) was used in the mice to induce depression and neuroinflammation diverse from the Veh+Veh group, which was injected only physiological saline. The drug-treated groups (Corticosteroid+ZIL50 and Corticosteroid+ZIL100) were orally administered with the mentioned doses of zileuton. After confirming the effectiveness of zileuton through the behavioral tests, the mechanism of the action of the drug was explored through a set of biochemical assays.

Results: Zileuton (50/100 mg/kg) administration improved the performance of the mice in the behavioral experiments (p<0.05 or 0.01). Immunohistochemistry detection of Iba1+ revealed over activation of microglial cells in the corticosteroid-treated mice which was suppressed by the zileuton (50 or 100 mg/kg [p<0.05 or 0.01]). Through Western blotting tests, it had been found that CORT (i.p.) administration led to the increment of the protein 5-Lipoxygenase in the mouse hippocampus associated with neuroinflammation, which was decreased significantly by zileuton (p<0.05 or 0.01). Level of tumor necrosis factor-alpha, interleukin-1 beta, nuclear factor kappa B p65 protein (for neuroinflammation), Bax, and cleaved caspase-3 and TUNEL assay increased, and Bcl-2 expression decreased in the CORT-induced depressive mice. These were significantly reversed by zileuton (50 or 100 mg/kg [p<0.05 or 0.01]).

Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor zileuton can efficiently inhibit the depressive-like behavior/activity in CORT-induced depressive mouse model. Moreover, the underlying mechanism may be the inhibition of hippocampal neuroinflammation and apoptosis.

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