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

  • 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.

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.

Keywords: Depression, Zileuton, 5-Lipoxygenase, Neuroinflammation, Apoptosis

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PANIGRAHI, S., S. SURAI, and H. HONG. “EFFECTS AND UNDERLYING MECHANISM OF 5-LIPOXYGENASE INHIBITOR (ZILEUTON) ON MICE DEPRESSIVE-LIKE BEHAVIOR”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 13, no. 3, Feb. 2020, pp. 180-6, doi:10.22159/ajpcr.2020.v13i3.37106.
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