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.
EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, 59045 Lille Cedex, France.
Elodie
E
Descamps
Maud
M
Petrault-Laprais
Pierre
P
Maurois
Nicole
N
Pages
Pierre
P
Bac
Régis
R
Bordet
Joseph
J
Vamecq
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