LDN‐212320 improves neuroprotection and synaptic plasticity in the hippocampus in an inflammatory pain model

Abstract

The astroglial glutamate transporter‐1 (GLT‐1) in the hippocampus is critically involved in acute and chronic nociceptive pain. We have previously shown that 3‐[[(2‐Methylphenyl) methyl] thio]‐6‐(2‐pyridinyl)‐pyridazine (LDN‐212320), a GLT‐1 activator, in the hippocampus attenuates acute and chronic nociceptive pain. However, the molecular mechanisms of GLT‐1 modulation in the hippocampus in chronic pain‐induced cognitive deficits and anxiety‐like behaviors remain unknown. Therefore, we have examined the effects of LDN‐212320, a GLT‐1 activator, in complete Freund’s adjuvant (CFA)‐induced cognitive deficits and anxiety‐like behaviors in mice. Furthermore, we have evaluated CFA‐induced impairment of spatial, working, and recognition memory using Y‐maze and object‐place recognition test. In addition, we have measured chronic pain‐induced anxiety‐like behaviors using elevated plus maze and marble burying test. We have also determined the effects of LDN‐212320 on cAMP response element‐binding protein (pCREB) and brain‐derived neurotrophic factor (BDNF) expressions in the hippocampus during CFA‐induced cognitive deficits and anxiety‐like behaviors using Western blot analysis and immunofluorescence assay. Pretreatment of LDN‐212320 (20 mg/kg) significantly attenuated CFA‐induced impairment of 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 and BDNF expressions in the hippocampus. Overall, these results suggest that GLT‐1 activator improves neuroprotection and synaptic plasticity by restoring pCREB and BDNF expressions in the hippocampus. Therefore, LDN‐212320 may have clinical potential for the prevention and treatment of chronic pain‐associated with cognitive deficits and anxiety‐like behaviors.