Evidence of hydrogen sulfide involvement in amyotrophic lateral sclerosis

Abstract

Objective Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H 2 S), as a glial‐released inflammatory factor, contributes to ALS‐mediated motor neuron death. Methods H 2 S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age‐ and gender‐matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high‐performance liquid chromatography method. The effects of H 2 S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. Results We found a significantly high level of H 2 S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H 2 S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H 2 S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca 2+ increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H 2 S is mainly released by astrocytes and microglia. Interpretation This study unravels H 2 S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS. Ann Neurol 2015;77:697–709