Modulation of the endocannabinoid system by focal brain ischemia in the rat is involved in neuroprotection afforded by 17β-estradiol

Diana Amantea, Paola Spagnuolo, Monica Bari, Filomena Fezza, Cinzia Mazzei, Cristina Tassorelli, Luigi A. Morrone, Maria T. Corasaniti, Mauro Maccarrone, Giacinto Bagetta

Research output: Contribution to journalArticlepeer-review


Endogenous levels of the endocannabinoid anandamide, and the activities of the synthesizing and hydrolyzing enzymes, i.e. N-acylphosphatidylethanolamine- hydrolyzing phospholipase D and fatty acid amide hydrolase, respectively, were determined in the cortex and the striatum of rats subjected to transient middle cerebral artery occlusion. Anandamide content was markedly increased (∼ 3-fold over controls; P <0.01) in the ischemic striatum after 2 h of middle cerebral artery occlusion, but not in the cortex, and this elevation was paralleled by increased activity of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (∼ 1.7-fold; P <0.01), and reduced activity (∼ 0.6-fold; P <0.01) and expression (∼ 0.7-fold; P <0.05) of fatty acid amide hydrolase. These effects of middle cerebral artery occlusion were further potentiated by 1 h of reperfusion, whereas anandamide binding to type 1 cannabinoid and type 1 vanilloid receptors was not affected significantly by the ischemic insult. Additionally, the cannabinoid type 1 receptor antagonist SR141716, but not the receptor agonist R-(+)-WIN55,212-2, significantly reduced (33%; P <0.05) cerebral infarct volume detected 22 h after the beginning of reperfusion. A neuroprotective intraperitoneal dose of 17β-estradiol (0.20 mg·kg-1) that reduced infarct size by 43% also minimized the effect of brain ischemia on the endocannabinoid system, in an estrogen receptor-dependent manner. In conclusion, we show that the endocannabinoid system is implicated in the pathophysiology of transient middle cerebral artery occlusion-induced brain damage, and that neuroprotection afforded by estrogen is coincident with a re-establishment of anandamide levels in the ischemic striatum through a mechanism that needs to be investigated further.

Original languageEnglish
Pages (from-to)4464-4475
Number of pages12
JournalFEBS Journal
Issue number17
Publication statusPublished - Sep 2007


  • Endocannabinoids
  • Estrogen
  • Middle cerebral artery occlusion
  • Stroke

ASJC Scopus subject areas

  • Biochemistry


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