Experimental stroke protection induced by 4-hydroxybenzyl alcohol is cancelled by bacitracin

• Published in: Neuroscience research 2009-06, Vol.64 (2), p.137-142
• Main Authors: Descamps, Elodie, Petrault-Laprais, Maud, Maurois, Pierre, Pages, Nicole, Bac, Pierre, Bordet, Régis, Vamecq, Joseph
• Format: Article
• Language: English
• Subjects: 4-Hydroxybenzyl alcohol; Animals; Bacitracin; Bacitracin - pharmacology; Benzyl Alcohols - chemistry; Benzyl Alcohols - therapeutic use; Benzyl Alcohols - toxicity; Brain - drug effects; Brain - enzymology; Brain - pathology; Gastrodia elata; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - etiology; Infarction, Middle Cerebral Artery - pathology; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - etiology; Ischemic Attack, Transient - pathology; Ischemic stroke; Isomerism; Mice; Mice, Inbred C57BL; Middle cerebral artery occlusion; Neuroprotection; Neuroprotective Agents - therapeutic use; Neuroprotective Agents - toxicity; Protein disulfide isomerase; Protein Disulfide-Isomerases - antagonists & inhibitors; Protein Disulfide-Isomerases - biosynthesis; Structure-Activity Relationship
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2009.02.005

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 200 mg/kg, was devoid of neurotoxicity in the rotarod test is also a decisive element to promote the neuroprotective use of this plant compound.