Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats

PLoS One. 2022 Mar 29;17(3):e0265961. doi: 10.1371/journal.pone.0265961. eCollection 2022.


Alzheimer's disease (AD) is characterized by an active inflammatory response induced by the brain's deposition and accumulation of amyloid-beta (Aβ). Cannabinoid receptor type 2 (CB2R) is expressed in specific brain areas, modulating functions, and pathophysiologies in CNS. Herein, we aimed to evaluate whether activation of CB2R can improve the cognitive impairment in the experimental AD-like model and determine the involved intracellular signaling pathway. Injection of D-galactose (150 mg/kg, i.p.) was performed to urge AD-like features in bilaterally ovariectomized female rats (OVC/D-gal rats) for 8-weeks. Then, AM1241, a CB2R-agonist (3 and 6 mg/kg), was injected intraperitoneally starting from the 6th week. Treatment with AM1241, significantly down-regulated; Toll-like receptor4 (TLR4), Myd88 (TLR4-adaptor protein) genes expression, and the pro-inflammatory cytokines (NFκB p65, TNF-α, IL-6, and IL-12). In contrast, it enhanced BDNF (the brain-derived neurotrophic factor) and CREB (the cyclic AMP response element-binding protein) as well as the immune-modulatory cytokines (IL-4 and IL-10) levels. Moreover, AM1241 lessened the immune-expression of GFAP, CD68, caspase-3, and NFκB p65 markers and mended the histopathological damage observed in OVC/D-gal rats by decreasing the deposition of amyloid plaques and degenerative neuronal lesions, as well as improving their recognition and learning memory in both novel object recognition and Morris water maze tests. In conclusion, activating CB2R by the selective agonist AM1241 can overrun cognitive deficits in OVC/D-gal rats through modulation of TLR4/ NFκB p65 signaling, mediated by modulating CREB/BDNF pathway, thereby can be applied as a potential therapeutic strategy in AD treatment.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Brain-Derived Neurotrophic Factor / therapeutic use
  • Cognition
  • Cognitive Dysfunction* / drug therapy
  • Cytokines / adverse effects
  • Female
  • Galactose / metabolism
  • Microglia / metabolism
  • Rats
  • Receptors, Cannabinoid
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism


  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • Receptors, Cannabinoid
  • Toll-Like Receptor 4
  • Galactose

Grants and funding

The author(s) received no specific funding for this work.