Genetic deficiency of β2-containing nicotinic receptors attenuates brain injury in ischemic stroke

- Genetic deficiency of β2-nAChRs attenuates brain infarction and neurological deficit in ischemic stroke.
- Pharmacological inhibition of β2-nAChRs attenuates brain infarction and neurological deficit in ischemic stroke.
- Neuroprotection of β2-nAChRs ablation involves the reduction of glutamate-mediated excitotoxicity.
- Inhibition of β2-nAChR in stroke could provide beneficial effects against ischemic brain injury.

One of the major consequences of stroke is brain injury caused by glutamate-mediated excitotoxicity. Glutamate-mediated excitatory activities are partially driven by β2-containing nicotinic acetylcholine receptors (β2-nAChRs). In examining the role of β2-nAChRs in cerebral ischemic injury, excitotoxicity and stroke outcome, we found that deficiency of β2-nAChRs attenuated brain infarction and neurological deficit at 24 and 72 h after transient middle cerebral artery occlusion (MCAO). Genetic deletion of β2-nAChRs associated with reduced terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL+) and cleaved caspase-3+ cells after MCAO, together with a reduction of extracellular glutamate and oxygen-glucose deprivation-induced increase of excitatory inputs in cortical neurons. Pharmacologic pretreatment with a selective β2-nAChRs antagonist reduced brain infarction, neurological deficit, and MCAO-induced glutamate release. These findings suggest that deficiency of β2-nAChRs, also achievable by pharmacological blockade, can decrease brain infarction and improve the neurological status in ischemic stroke. The improved outcome is associated with reduced extracellular glutamate level and lower excitatory inputs into ischemic neurons, suggesting a reduction of glutamate-mediated excitotoxicity in the mechanisms of neuroprotection.