The potential protective effects of cannabinoid receptor agonist WIN55,212-2 on cognitive dysfunction is associated with the suppression of autophagy and inflammation in an experimental model of vascular dementia

Psychiatry Res. 2018 Sep:267:281-288. doi: 10.1016/j.psychres.2018.06.012. Epub 2018 Jun 14.


Vascular dementia (VaD) is characteristic of chronic brain ischemia and progressive memory decline, which has a high incidence in the elderly. However, there are no effective treatments for VaD, and the underlying mechanism of its pathogenesis remains unclear. This study investigated the effects of a synthetic cannabinoid receptor agonist WIN55,212-2 (WIN) on VaD, and molecular mechanisms of the effects. VaD model was induced by 2-vessel occlusion (2VO). Spatial reference learning was evaluated by the Morris water maze, and recognition memory was assessed using the novel object recognition test. Autophagy-related proteins [microtubule-associated protein 1 light chain 3 (LC-3) and Beclin-1] were examined by immunohistochemistry and Western blot. Caspase-3 was detected by Western blot. Inflammatory factors, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), were estimated by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. VaD increased the levels of LC-3, Beclin-1, and inflammatory factors, which were reversed by chronic treatment with WIN. WIN decreased the expression of Capase-3, and improved the learning and memory impairment of VaD rats. These data indicate that WIN exerts a neuroprotective effect on the cognitive deficits of VaD rats, which may be associated with the suppression of excessive autophagy and inflammation.

Keywords: Autophagy; Cannabinoid receptor; Cognition; Inflammation; Vascular dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy / physiology
  • Benzoxazines / pharmacology
  • Benzoxazines / therapeutic use*
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Agonists / therapeutic use*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / psychology
  • Dementia, Vascular / drug therapy*
  • Dementia, Vascular / pathology
  • Dementia, Vascular / psychology
  • Disease Models, Animal
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Inflammation / psychology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Morpholines / pharmacology
  • Morpholines / therapeutic use*
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley


  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Morpholines
  • Naphthalenes
  • Neuroprotective Agents
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone