Results from amyotrophic lateral sclerosis (ALS) patients and pre-clinical studies strongly
suggest that systemic and CNS-intrinsic immune activation plays a central role in ALS pathogenesis.
Microglial cells are emerging in this context as master regulators with a bi-functional role in the
progression of the pathological response. They foster a pro-inflammatory setting through the
production of cytotoxic cytokines and chemokines (M1 phenotype), after an aborted effort to sustain
an anti-inflammatory environment for motor neurons through the release of beneficial cytokines and
growth factors (M2 phenotype). In this review, we gather information meant to propose that histamine
and ATP, which are released from mast cells, microglia and damaged neurons at sites of injury where they function as
transmitters, have to be considered as new players in the ALS neuroinflammatory arena. After all, abnormal histamine and
ATP signalling in the brain are already documented in neurodegenerative/neuroinflammatory conditions such as multiple
sclerosis, Alzheimer and Parkinson's disease and, at present, histamine- as well as ATP-related compounds are in clinical
trial for these same pathologies. Concerning ALS, while emerging data are now available about purinergic mechanisms,
the involvement of histamine is basically unexplored. The circumstantial evidence that we present here thus constitutes a
solid background for formulating novel hypotheses, stimulating a scientific debate and, most of all, inspiring future
research. We deem that a new potential role of histamine in the setting of ALS neuroinflammation might find a fertile
ground where to thrive. ALS is still a disease without a cure: why not to play with a new kid on the block?