Lactic acidosis in the brain: occurrence, triggering mechanisms and pathophysiological importance

The brain's extracellular fluid provides a pH-regulated environment, which helps protect brain cells from systemic acid-base disturbances. Unlike many other cell types, brain cells are less vulnerable to systemic acidosis or alkalosis. However, cerebral intracellular acidosis is primarily endogenous, arising from lactic acid accumulation. This condition is not typically caused by systemic pH changes but rather by internal metabolic processes. Prior research has shown that brain cells maintain a stable extracellular pH, but when lactic acid builds up, it can lead to intracellular acidosis. The mechanisms behind this are not fully understood in all contexts. No prior work had resolved how different conditions trigger lactic acid accumulation. This gap motivated researchers to investigate the specific conditions and metabolic pathways involved in cerebral acidosis. Understanding these mechanisms could help clarify how acidosis contributes to brain injury.

The study aimed to explore the conditions and mechanisms that lead to lactic acid accumulation in the brain. Researchers focused on three main scenarios: hypocapnia, epileptic seizures, and hypoxia plus ischaemia. These conditions are known to influence brain pH and glycolytic activity. The goal was to determine how each condition affects the brain's metabolic state and acid-base balance. The researchers also wanted to assess the role of phosphofructokinase activation in these scenarios. By comparing these three conditions, the study sought to identify patterns in lactic acid production and its consequences. This approach allowed the team to differentiate between compensatory and pathological acidosis. The ultimate aim was to clarify how lactic acid accumulation contributes to irreversible cell damage in specific brain states.

The study examined three primary conditions associated with cerebral lactic acid accumulation: hypocapnia, seizures, and hypoxia-ischaemia. Researchers analyzed how each condition alters glycolytic rates and intracellular pH. They used biochemical markers to track lactic acid levels and phosphofructokinase activation. The team also assessed the energy state of the brain in each condition. Data collection involved measuring lactic acid concentrations in brain tissue samples. The researchers compared lactic acid levels across the three conditions to identify differences in accumulation severity. They also evaluated how pH changes correlate with metabolic enzyme activity. This approach allowed them to distinguish between compensatory and pathological acidosis mechanisms.

The study found that lactic acid accumulation occurs in three main conditions: hypocapnia, seizures, and hypoxia-ischaemia. In hypocapnia, metabolic acidosis is compensatory, but in seizures and hypoxia-ischaemia, pH decreases moderately or significantly. Phosphofructokinase activation is a common feature in all three conditions. In seizures, lactic acid levels typically reach about 10 mumol g-1. Complete ischaemia leads to only a slight increase in acidosis. However, severe incomplete ischaemia and hypoxia cause lactic acid to accumulate up to 30-50 mumol g-1. At these high levels, acidosis contributes to irreversible cell damage. These findings highlight the role of glycolytic rate in triggering lactic acid accumulation.

The authors propose that cerebral intracellular acidosis is primarily endogenous and not due to systemic pH changes. They suggest that lactic acid accumulation occurs in hypocapnia, seizures, and hypoxia-ischaemia. In these conditions, increased glycolytic rates are linked to phosphofructokinase activation. The researchers found that seizures and hypoxia-ischaemia lead to moderate or severe pH decreases. In complete ischaemia, acidosis is less pronounced than in severe incomplete ischaemia. The study suggests that lactic acid accumulation above 30-50 mumol g-1 contributes to irreversible damage. These findings support the idea that intracellular pH regulation is crucial in brain metabolism. The authors propose that understanding these mechanisms could help in managing brain injuries.