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
Abstract
Background of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH 4 + ) 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 NH 4 + . However, there is no precise intervention to mitigate the direct neurological complications of NH 4 + . Purpose It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH 4 + 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.