Alotaibi Ghallab, Khan Amna, Rahman Shafiqur
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Behav Brain Res. 2025 Mar 28;482:115440. doi: 10.1016/j.bbr.2025.115440. Epub 2025 Jan 22.
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/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.
海马体和前扣带回皮质（ACC）中的星形胶质细胞谷氨酸转运体在慢性疼痛引起的认知和精神异常中起关键作用。我们之前报道过，谷氨酸转运体-1（GLT-1）激活剂LDN-212320可减轻完全弗氏佐剂（CFA）诱导的急性和慢性伤害性疼痛。然而，在慢性疼痛诱导的认知缺陷样和焦虑样行为期间，海马体和ACC中GLT-1调节的细胞和分子机制仍不清楚。在此，我们研究了LDN-212320对CFA诱导的与小鼠认知缺陷样和焦虑样行为相关的慢性疼痛的影响。我们使用Y迷宫和物体位置识别测试评估了LDN-212320对CFA诱导的空间、工作和识别记忆受损的影响。此外，我们使用高架十字迷宫和大理石埋藏测试确定了LDN-21230对慢性疼痛诱导的焦虑样行为的影响。我们还使用蛋白质免疫印迹分析和免疫荧光测定法，研究了LDN-212320在CFA诱导的认知缺陷样和焦虑样行为期间对海马体和ACC中cAMP反应元件结合蛋白（pCREB）、脑源性神经营养因子（BDNF）、蛋白激酶A（PKA）和钙/钙调蛋白依赖性蛋白激酶II（CaMKII）表达的影响。用LDN-212320（20mg/kg）预处理可显著减轻CFA诱导的空间、工作和识别记忆受损。此外，LDN-212320（20mg/kg）可显著降低CFA诱导的焦虑样行为。此外，LDN-212320（20mg/kg）可显著逆转CFA诱导的海马体和ACC中pCREB、BDNF、PKA和CaMKII表达的降低。总体而言，这些结果表明，LDN-212320通过激活海马体和ACC中的CaMKII/CREB/BDNF信号通路，预防CFA诱导的认知缺陷样和焦虑样行为。因此，LDN-212320可能是治疗与认知障碍和焦虑样行为相关的慢性疼痛的潜在药物。
