Experimental stroke protection induced by 4-hydroxybenzyl alcohol is cancelled by bacitracin.
Induction of protein disulfide isomerase (PDI) is validated as a main mechanism by which 4-hydroxybenzyl alcohol (4-HBA), an active principle of Gastrodia elata Blume, reduces cerebral infarct volumes in a murine model of focal brain ischemia/reperfusion. In contrast to its position isomers, i.e. 3-hydroxybenzyl alcohol (3-HBA) and 2-hydroxybenzyl alcohol (2-HBA), and to aliphatic diols (1,4-butanediol and 1,5-pentanediol), 4-HBA administered intravenously at 25 mg/kg protected mice, significantly reducing total, cortical and sub-cortical infarct volumes by 42, 28 and 55%, respectively. All compounds, 4-HBA included, were devoid of antioedematous properties. Only the stroke protective 4-HBA, but neither 3-HBA nor 2-HBA, was capable of significantly inducing PDI in intact mouse brains. Stroke protection was fully prevented by bacitracin (500 mg/kg), a known inhibitor of PDI, which, without affecting basal brain PDI levels, altered the ability of 4-HBA to induce significantly PDI in intact brains. Taken as a whole, our data indicate that stroke protection induced by 4-HBA involves PDI as a key player, making this protein a valuable target to control brain injury disorders. The fact that 4-HBA, at doses up to 200mg/kg, was devoid of neurotoxicity in the rotarod test is also a decisive element to promote the neuroprotective use of this plant compound.
Descamps
Elodie
E
EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, 59045 Lille Cedex, France.
Petrault-Laprais
Maud
M
Maurois
Pierre
P
Pages
Nicole
N
Bac
Pierre
P
Bordet
Régis
R
Vamecq
Joseph
J
D000818:Animals; D001414:Bacitracin / Q000494:pharmacology*; D001592:Benzyl Alcohols / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D007536:Isomerism; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use* / Q000633:toxicity; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D001592:Benzyl Alcohols; D018696:Neuroprotective Agents; D001414:Bacitracin; C018966:4-hydroxybenzyl alcohol; D019704:Protein Disulfide-Isomerases