Brain ATP Depletion Induced by Acute Ammonia Intoxication in Rats Is Mediated by Activation of the NMDA Receptor and Na⁺, K⁺‐ATPase

Abstract

Injection of large doses of ammonia into rats leads to depletion of brain ATP. However, the molecular mechanism leading to ATP depletion is not clear. The aim of the present work was to assess whether ammoniuminduced depletion of ATP is mediated by activation of the NMDA receptor . It is shown that injection of MK-801, an antagonist of the NMDA receptor, prevented ammoniainduced ATP depletion but did not prevent changes in glutamine, glutamate, glycogen, glucose, and ketone bodies . Ammonia injection increased Na',K+-ATPase activity by 76%. This increase was also prevented by previous injection of MK-801 . The molecular mechanism leading to activation of the ATPase was further studied. Na+,K+-ATPase activity in samples from ammonia-injected rats was normalized by "in vitro" incubation with phorbol 12-myristate 13-acetate, an activator of protein kinase C. The results obtained suggest that ammoniainduced ATP depletion is mediated by activation of the NMDA receptor, which results in decreased protein kinase C-mediated phosphorylation of Na+,K+-ATPase and, therefore, increased activity of the ATPase and increased consumption of ATP.

Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment

“…Typically, these ammonia levels are not nearly as elevated as those that have been observed in some conditions that can cause autism, such as urea cycle disorders [66] . Ammonia requires three ATP molecules to be converted into urea and in animal studies, elevated ammonia can lead to brain ATP depletion [67] . Therefore, the increased ammonia noted in autism may be both consequentially and causally related to ATP depletion.…”

Mitochondrial Dysfunction in Early Diagnosed Autism Spectrum Disorder Children

“…So ammonia level in blood increases 9 . Increased ammonia level in autism spetrum disorder children may lead to toxicity and ATP depletion in brain 11 .…”

Brain monoamine oxidase A in hyperammonemia is regulated by NMDA receptors

“…The toxic effect of ammonia on the brain is mediated by activation of NMDA receptors [5,6]. This receptor has a calcium channel that is permeable only for extracellular Ca 2+ and K + and for intracellular Na + .…”

“…Excitotoxicity is regarded as a potential mechanism of cell death in acute and chronic neurological diseases as well as under conditions associated with hyperammonemia. It has been shown that acute intoxication with large doses of ammonia result in activation of NMDA receptors in rat brain [5,6]. The mechanisms by which overactivation of NMDA receptors lead to neuronal degeneration and death involve the increase in Ca 2+ concentration in the postsynaptic neuron [7].…”

“…However, excessive ammonia influx or production resulting from the malfunctioning enzyme utilization system can cause hyperammonemia, an abnormal increase in blood ammonia level. When introduced into animals, ammonia increases the calcium content in brain mitochondria [12], causes oxidative stress [13,14] and death [6]. Blocking NMDA receptors prevents ammonia-induced oxidative stress [14].…”