title: Activation of STAT3 is involved in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptors in rats.
abstract: Pretreatment with electroacupuncture (EA) attenuates cerebral ischemic injury through the endocannabinoid system, although the molecular mechanisms mediate this neuroprotection are unknown. It is well-known that signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell survival and proliferation. Therefore, we investigated whether STAT3 is involved in EA pretreatment-induced neuroprotection via cannabinoid CB1 receptors (CB1R) after transient focal cerebral ischemia in rats. Two hours after EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MACO) for 120 min. The expression of pSTAT3(Ser727), which is necessary for STAT3 activation, was examined in the ipsilateral ischemic penumbra. Infarct volumes and neurological scores were evaluated at 72 h after MACO in the presence or absence of the STAT3 inhibitor peptide (PpYLKTK). Neuronal apoptosis and the Bax/Bcl-2 ratio were also evaluated 24h after reperfusion. Our results showed that EA pretreatment significantly enhanced neuronal expression of pSTAT3(Ser727) in the ischemic penumbra 6h after reperfusion. Moreover, EA pretreatment reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis and decreased the Bax/Bcl-2 ratio following reperfusion. The beneficial effects of EA were attenuated by PpYLKTK administered 30 min before MACO, and PpYLKTK effectively reversed the increase in pSTAT3(Ser727) expression. Furthermore, CB1R antagonist or CB1R knockdown with siRNA blocked the elevation of pSTAT3(Ser727) expression by EA pretreatment, whereas the two CB1R agonists increased STAT3 activation. In conclusion, EA pretreatment enhances STAT3 activation via CB1R to protect against cerebral ischemia, suggesting that STAT3 activation may be a novel target for stroke intervention.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Forth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Haidong
authors.initials: H
authors.lastname: Wei
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Guo
authors.forename: Zijun
authors.initials: Z
authors.lastname: Gao
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015671:Electroacupuncture / Q000379:methods*; D007839:Functional Laterality; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents; D010455:Peptides / Q000633:toxicity; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; D043884:Receptor, Cannabinoid, CB1; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D012694:Serine; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase
keywords: 2,3,5-triphenyltetrazolium chloride; 2-AG; 2-arachidonylglycerol; AEA; Behavioral; EA; ERK1/2; Ischemic tolerance; MCAO; Middle cerebral artery occlusion; N-arach-idonoylethanolamine-anandamide; Neuroprotection; PKCε; STAT3; Signal transducers and activators of transcription 3; Stroke; TTC; TUNEL; deoxyuridine triphosphate nick-end labeling.; electroacupuncture; extracellular signal-regulated kinases1/2; middle cerebral artery occlusion; protein kinase C epsilon