Resveratrol Prevents Ammonia Toxicity in Astroglial Cells

Abstract

Ammonia is implicated as a neurotoxin in brain metabolic disorders associated with hyperammonemia. Acute ammonia toxicity can be mediated by an excitotoxic mechanism, oxidative stress and nitric oxide (NO) production. Astrocytes interact with neurons, providing metabolic support and protecting against oxidative stress and excitotoxicity. Astrocytes also convert excess ammonia and glutamate into glutamine via glutamine synthetase (GS). Resveratrol, a polyphenol found in grapes and red wines, exhibits antioxidant and anti-inflammatory properties and modulates glial functions, such as glutamate metabolism. We investigated the effect of resveratrol on the production of reactive oxygen species (ROS), GS activity, S100B secretion, TNF-α, IL-1β and IL-6 levels in astroglial cells exposed to ammonia. Ammonia induced oxidative stress, decreased GS activity and increased cytokines release, probably by a mechanism dependent on protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways. Resveratrol prevented ammonia toxicity by modulating oxidative stress, glial and inflammatory responses. The ERK and nuclear factor-κB (NF-κB) are involved in the protective effect of resveratrol on cytokines proinflammatory release. In contrast, other antioxidants (e.g., ascorbic acid and trolox) were not effective against hyperammonemia. Thus, resveratrol could be used to protect against ammonia-induced neurotoxicity.

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

“…Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].…”

“…However, when produced in higher amounts during neuropathology, they are known to potentiate glutamate induced cytotoxicity by inhibiting glutamate transport to the glial cells from the synaptic cleft [12,[16][17][18][19]. Even development of MHE has been described to be dependent more on enhanced inflammatory markers than the severity of CLF or HA in the CLF patients [20].…”

“…Even development of MHE has been described to be dependent more on enhanced inflammatory markers than the severity of CLF or HA in the CLF patients [20]. Moreover, some findings from in vitro studies suggest that resveratrol treatment could prevent ammonia toxicity in astroglial cells by normalizing ROS/RNS level [12,21,22]. Thus, hinting towards a significant role of resveratrol in ameliorating ammonia toxicity.…”

“…anti-aging, and anti-carcinogenic agent in vivo [12,[26][27][28]. Some reports also suggest that this natural polyphenol exerts neuroprotection during certain neurodegenerative challenges [12,[26][27][28] mainly due to its ROS scavenging properties and/or by activating some antioxidant enzymes.…”

“…Some reports also suggest that this natural polyphenol exerts neuroprotection during certain neurodegenerative challenges [12,[26][27][28] mainly due to its ROS scavenging properties and/or by activating some antioxidant enzymes. Some recent observations, mainly derived from in vitro studies, suggest that ammonia induced impaired glutamatergic communication in astroglial cells could be recovered with resveratrol treatment [29].…”