BACKGROUND AND PURPOSE: Brain injury during stroke results in oxidative stress 
and the release of factors that include extracellular Ca(2+), hydrogen peroxide, 
adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. 
These alterations of the extracellular milieu change the activity of transient 
receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation 
channel expressed in the central nervous system and the immune system. Our goal 
was to evaluate the contribution of TRPM2 to the tissue damage after stroke.
METHODS: In accordance with current quality guidelines, we independently 
characterized Trpm2 in a murine ischemic stroke model in 2 different 
laboratories.
RESULTS: Gene deficiency of Trpm2 resulted in significantly improved 
neurological outcome and decreased infarct size. Besides an already known 
moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain 
invasion by neutrophils and macrophages was particularly reduced in 
Trpm2-deficient mice. Bone marrow chimeric mice revealed that Trpm2 deficiency 
in the peripheral immune system is responsible for the protective phenotype. 
Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 
is essential for the migration of neutrophils and, to a lesser extent, also of 
macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 
inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the 
stroke model.
CONCLUSIONS: Although a neuroprotective effect of TRPM2 in vitro is well known, 
we can show for the first time that the detrimental role of TRPM2 in stroke 
primarily depends on its role in activating peripheral immune cells. Targeting 
TRPM2 systemically represents a promising therapeutic approach for ischemic 
stroke.