Low-dose ketamine improves animals' locomotor activity and decreases brain oxidative stress and inflammation in ammonia-induced neurotoxicity
Ommati, Mohammad Mehdi; Mobasheri, Ali; Niknahad, Hossein; Rezaei, Mohammad; Alidaee, Sepideh; Arjmand, Abdollah; Mazloomi, Sahra; Abdoli, Narges; Sadeghian, Issa; Sabouri, Samira; Saeed, Mohsen; Mousavi, Khadijeh; Najibi, Asma; Heidari, Reza (2023-07-26)
John Wiley & Sons
26.07.2023
M. M. Ommati, A. Mobasheri, H. Niknahad, M. Rezaei, S. Alidaee, A. Arjmand, S. Mazloomi, N. Abdoli, I. Sadeghian, S. Sabouri, M. Saeed, K. Mousavi, A. Najibi, R. Heidari, J. Low‐dose ketamine improves animals’ locomotor activity and decreases brain oxidative stress and inflammation in ammonia‐induced neurotoxicity. Biochem. Mol. Toxicol. 2023; 37:e23468. https://doi.org/10.1002/jbt.23468.
https://creativecommons.org/licenses/by-nc-nd/4.0/
© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
https://creativecommons.org/licenses/by-nc-nd/4.0/
© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
https://creativecommons.org/licenses/by-nc-nd/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202312153827
https://urn.fi/URN:NBN:fi:oulu-202312153827
Tiivistelmä
Abstract
Ammonium ion (NH4+) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4+-induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4+ metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4+ neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4+ were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1β was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.
Ammonium ion (NH4+) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4+-induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4+ metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4+ neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4+ were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1β was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.
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