Glutamate transporter activator LDN-212320 prevents chronic pain-induced cognitive impairment and anxiety-like behaviors in a mouse model

Abstract

The astroglial glutamate transporter in the hippocampus and anterior cingulate cortex (ACC) is critically involved in chronic pain-induced cognitive and psychiatric abnormalities. We have previously reported that LDN-212320, a glutamate transporter-1 (GLT-1) activator, attenuates complete Freund’s adjuvant (CFA)-induced acute and chronic nociceptive pain. However, the cellular and molecular mechanisms underlying GLT-1 modulation in the hippocampus and ACC during chronic pain-induced cognitive deficit-like and anxiety-like behaviors remain unknown. Here, we have investigated the effects of LDN-212320 on CFA-induced chronic pain associated with cognitive deficit-like and anxiety-like behaviors in mice. We have evaluated the effects of LDN-212320 on CFA-induced impaired spatial, working, and recognition memory using Y-maze and object-place recognition tests. In addition, we have determined the effects of LDN-21230 on chronic pain-induced anxiety-like behaviors using elevated plus maze and marble burying test. We have also examined the effects of LDN-212320 on cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BDNF), protein kinase A (PKA), and Ca^2 +/calmodulin-dependent protein kinase II (CaMKII) expression in the hippocampus and ACC during CFA-induced cognitive deficit-like and anxiety-like behaviors using the Western blot analysis and immunofluorescence assay. Pretreatment with LDN-212320 (20 mg/kg) significantly attenuated CFA-induced impaired spatial, working, and recognition memory. Furthermore, LDN-212320 (20 mg/kg) significantly reduced CFA-induced anxiety-like behaviors. Additionally, LDN-212320 (20 mg/kg) significantly reversed CFA-induced decreased pCREB, BDNF, PKA and CaMKII expression in the hippocampus and ACC. Overall, these results suggest that the LDN-212320 prevents CFA-induced cognitive deficit-like and anxiety-like behaviors by activating CaMKII/CREB/BDNF signaling pathway in the hippocampus and ACC. Therefore, LDN-212320 could be a potential treatment for chronic pain associated with cognitive impairment and anxiety-like behaviors.