Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway

Arvin Haj-Mirzaian, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Kiana Ramezanzadeh, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Armin Tafazolimoghadam, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Kiarash Kazemi, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Rajan Nikbakhsh, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Rambod Nikbakhsh, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran.
Hossein Amini-Khoei, Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Khashayar Afshari, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Nazgol-Sadat Haddadi, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Saeed Shakiba, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Fahimeh Azimirad, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Seyyed Elahe Mousavi, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Ahmad Reza Dehpour, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpoura@sina.tums.ac.ir.

Document Type

Article

Publication Title

European journal of pharmacology

Abstract

Lipopolysaccharide (LPS) increases inflammatory cytokines of the brain and deregulates the mitochondrial function, thus could increase the seizure susceptibility. Studies have shown that minocycline has neuroprotective and antioxidant properties. In this study, we aimed to evaluate the anticonvulsant properties of minocycline in LPS-treated animals and the possible involvement of nitric oxide and mitochondrial pathways. In a PTZ model of seizure in mice, minocycline was administrated to LPS-treated mice. Then followed by co-injection of its sub-effective dose and NOS inhibitors including 7-Nitroindazole (7-NI), aminoguanidine (AG) and L-N-Nitroarginine methyl ester (L-NAME) to evaluate the changes in seizure threshold and the possible involvement of nitrergic system. Molecular assessments were used to evaluate the effects of each treatment on inflammation and mitochondrial function in the brain. LPS-treated animals had lower seizure threshold compared to intact animals; injection of minocycline (80 mg/kg) to LPS-treated mice reversed this effect. Co-injection of sub-effective doses of minocycline (40 mg/kg) and L-NAME to LPS-treated animals significantly increased seizure threshold. We observed that co-treatment of minocycline and AG dissimilar to 7-NI could increase the seizure threshold of LPS-treated animals. L-arginine reversed the anticonvulsant effect of minocycline. Also, molecular evaluations showed that LPS could increase the ATP levels, GSH levels, and reactive oxygen species formation. However, minocycline at both doses significantly reversed the effect of LPS. Minocycline counteracts the proconvulsant effects of LPS through regulating of mitochondrial function and decreasing of neuro-inflammation. Also, co-administration of minocycline and i-NOS inhibitors could intensify anticonvulsant effects of minocycline.

First Page

172446

DOI

10.1016/j.ejphar.2019.172446

Publication Date

9-5-2019

Identifier

31202800 (pubmed); 10.1016/j.ejphar.2019.172446 (doi); S0014-2999(19)30398-X (pii)

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