Potential involvement of intracellular pH in a mouse model of amyotrophic lateral sclerosis

Abstract

This study tested possible involvement of intracellular acidification as a secondary pathogenic factor in ALS. As one of cell death mechanisms, apoptosis is known to be involved in motor neuronal death in ALS. Cancer research has revealed that the activity of apoptosis strongly depends on intracellular pH (pHi), enhanced with low pHi and inhibited with high pHi (1). In ALS, excessive glutamate and calcium overloading are two up-stream factors for apoptosis. Other experiments have shown that neuronal pHi can be acidified by glutamate in a calcium dependent manner (2,3). We thus hypothesized that an acidified pHi may occur in the motor neurons of ALS and accelerate the disease progression. Therefore, a mild intracellular alkalinization may be beneficial to the disease. The hypothesis was tested by two chemicals, sodium bicarbonate (NaHCO3) and ammonium chloride (NH4Cl) for their major effects on adjusting pH. NaHCO3 provides base buffer for the body both extracellularly and intracellularly. NH4Cl is known to acidify extracellular pH after being largely metabolized in liver, but to alkalize pHi when dissociated ammonia diffuses into cells and combines with hydrogen proton (4). If these two chemicals with opposing effects on pHe both ameliorate symptoms in ALS mice, most likely the beneficial effects come from the common pHi alkalizing abilities.