The only food and drug administration (FDA)-approved drug currently available for the treatment of
acute ischemic stroke is
tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear.
Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce
ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since
melatonin could regulate the expression of α7nAchR and
melatonin's
neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that
melatonin reduces
ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h
ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist
PNU282987;
Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of
Evan's blue and
IgG. Our results showed that I/R significantly increased BBB permeability accompanied by
occludin degradation, microglia activation, and high mobility group box 1 (
HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression.
Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that
melatonin provides a protective effect on
ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.