Evidence of hydrogen sulfide involvement in amyotrophic lateral sclerosis.

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 (H₂S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death. Methods H₂S 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 H₂S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. Results We found a significantly high level of H₂S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H₂S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H₂S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca²⁺ increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H₂S is mainly released by astrocytes and microglia. Interpretation This study unravels H₂S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS. Ann Neurol 2015;77:697-709 [ABSTRACT FROM AUTHOR]