Hepatic encephalopathy complications are diminished by piracetam via the interaction between mitochondrial function, oxidative stress, inflammatory response, and locomotor activity

Hossein Niknahad; Ali Mobasheri; Abdollah Arjmand; Elahe Rafiei; Sepideh Alidaee; Hadi Razavi; Sara Bagheri; Heresh Rezaei; Samira Sabouri; Asma Najibi; Forouzan Khodaei; Seyyed Mohammad Amin Kashani; Mohammad Mehdi Ommati; Reza Heidari

doi:10.1016/j.heliyon.2023.e20557

Hepatic encephalopathy complications are diminished by piracetam via the interaction between mitochondrial function, oxidative stress, inflammatory response, and locomotor activity

Heliyon. 2023 Sep 29;9(10):e20557. doi: 10.1016/j.heliyon.2023.e20557. eCollection 2023 Oct.

Authors

Hossein Niknahad^{1

2}, Ali Mobasheri^{3

4

5}, Abdollah Arjmand⁶, Elahe Rafiei¹, Sepideh Alidaee¹, Hadi Razavi^{1

2}, Sara Bagheri¹, Heresh Rezaei^{1

2}, Samira Sabouri⁷, Asma Najibi^{1

2}, Forouzan Khodaei¹, Seyyed Mohammad Amin Kashani^{1

2}, Mohammad Mehdi Ommati^{1

7

8}, Reza Heidari¹

Affiliations

¹ Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
² Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
³ Research Unit of Medical Imaging, Physics, And Technology, Faculty of Medicine, University of Oulu, FI-90014, Oulu, Finland.
⁴ University Medical Center Utrecht, Departments of Orthopedics Rheumatology and Clinical Immunology, 3508, GA, Utrecht, the Netherlands.
⁵ Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406, Vilnius, Lithuania.
⁶ Department of Toxicology and Pharmacology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁷ Shanxi Key Laboratory of Ecological, Animal Sciences, And Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China.
⁸ Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471000, Henan, China.

Abstract

Background: of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH₄⁺) levels reach critically high concentrations because of liver failure. HE could lead to a range of neurological complications from locomotor and behavioral disturbances to coma. Several tactics have been established for subsiding blood and brain NH₄⁺. However, there is no precise intervention to mitigate the direct neurological complications of NH₄⁺.

Purpose: It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH₄⁺ neurotoxicity. Piracetam is a drug used clinically in neurological complications such as stroke and head trauma. Piracetam could significantly diminish oxidative stress and improve brain mitochondrial function.

Research methods: In the current study, piracetam (100 and 500 mg/kg, oral) was used in a mice model of HE induced by thioacetamide (TA, 800 mg/kg, single dose, i.p).

Results: Significant disturbances in animals' locomotor activity, along with increased oxidative stress biomarkers, including reactive oxygen species formation, protein carbonylation, lipid peroxidation, depleted tissue glutathione, and decreased antioxidant capacity, were evident in the brain of TA-treated mice. Meanwhile, mitochondrial permeabilization, mitochondrial depolarization, suppression of dehydrogenases activity, and decreased ATP levels were found in the brain of the TA group. The level of pro-inflammatory cytokines was also significantly high in the brain of HE animals.

Conclusion: It was found that piracetam significantly enhanced mice's locomotor activity, blunted oxidative stress biomarkers, decreased inflammatory cytokines, and improved mitochondrial indices in hyperammonemic mice. These data suggest piracetam as a neuroprotective agent which could be repurposed for the management of HE.

Keywords: Brain injury; Hepatic encephalopathy; Liver failure; Locomotor disturbances; Pharmacotherapy.