Dapsone Protects Against Lithium-Pilocarpine-Induced Status Epilepticus in Rats through Targeting Tumor Necrosis Factor-α and Nitrergic Pathway

Amirhossein Koohfar; Faezeh Eslami; Maryam Shayan; Nastaran Rahimi; Farid Moradi; Hasti Tashak Golroudbari; Mehdi Ghasemi; Ahmad Reza Dehpour

doi:10.14581/jer.22008

Dapsone Protects Against Lithium-Pilocarpine-Induced Status Epilepticus in Rats through Targeting Tumor Necrosis Factor-α and Nitrergic Pathway

J Epilepsy Res. 2022 Dec 30;12(2):39-47. doi: 10.14581/jer.22008. eCollection 2022 Dec.

Authors

Amirhossein Koohfar^#^{1

2}, Faezeh Eslami^#^{1

2

3}, Maryam Shayan^{1

2}, Nastaran Rahimi^{1

2}, Farid Moradi^{1

2}, Hasti Tashak Golroudbari^{1

2}, Mehdi Ghasemi⁴, Ahmad Reza Dehpour^{1

2}

Affiliations

¹ Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
² Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
³ Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, USA.
⁴ Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, USA.

^# Contributed equally.

Abstract

Background and purpose: Status epilepticus (SE) results in permanent neuronal brain damage in the central nervous system. One of the complex etiologies underlying SE pathogenesis is neuroinflammation. Dapsone has been recently considered as a potential neuroprotective agent in neuroinflammatory conditions. Therefore, the present study aims to investigate effects of dapsone on lithium-pilocarpine-induced SE in rats and assess whether tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) pathway participate in this effect.

Methods: SE was established by injecting lithium chloride (127 mg/kg, intraperitoneally [i.p.]) and pilocarpine (60 mg/kg, i.p.). The animals received pre-treatment dapsone (2, 5, 10, and 20 mg/kg, oral gavage) and post-treatment dapsone (10 mg/kg). Subsequently, seizure score and mortality rate were documented. To assess the underlying signaling pathway, L-Nω-Nitro-L-arginine methyl ester hydrochloride (a non-specific NO synthase [NOS] inhibitor), 7-nitroindazole (a specific neuronal NOS inhibitor), and aminoguanidine (a specific inducible NOS inhibitor) were administered 15 minutes before dapsone (10 mg/kg) pre- or post-treatment. Hippocampal tissue TNF-α and NO concentrations were quantified using the enzyme-linked immunosorbent assay method.

Results: Dapsone (10 mg/kg) pre-and post-treatment significantly attenuated the increased seizure score and mortality rate due to lithium-pilocarpine-induced SE. The development of SE in animals was associated with higher TNF-α and NO metabolites levels, which notably decreased in the dapsone-treated rats. Moreover, co-administration of NOS inhibitors with dapsone markedly reversed the anti-epileptic effects of dapsone and caused an escalation in TNF-α level but a significant reduction in NO concentration level.

Conclusions: It seems that dapsone may exert an anti-epileptic effect on lithium-pilocarpine-induced SE through TNF-α inhibition and modulation of the nitrergic pathway.

Keywords: Dapsone; Nitric oxide; Status epilepticus; Tumor necrosis factor-alpha.