Tehran University of Medical Sciences Acta Medica Iranica 0044-6025 60 9 2022 11 08 583 593 Ali Rismanbaf Department of Pharmacology and Toxicology, School of Pharmacy, Tehran Azad University of Medical Sciences, Tehran, Iran Khashayar Afshari Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran .AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Nazgol-Sadat Haddadi Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Ahmad Reza Dehpour Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Hamed Shafaroodi Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2022 01 12 2022 05 16 Macrophages and glial activation contribute to the pathophysiology of spinal cord injury (SCI). Some preclinical studies have shown the anti-inflammatory effects of aripiprazole (ARP). In the current study, we evaluated the anti-inflammatory effects of ARP in a rat SCI model. Forty male Wistar rats underwent either T9 vertebra laminectomy or were used as a sham-operated group without laminectomy. There were four major groups in this study: a sham-operated, three treatments (normal saline [vehicle] control versus ARP 10 and 20 mg/kg/day for three days after surgery, first dose 30 minutes post-surgery) SCI groups. We evaluated locomotor scaling and neuropathic pain behavioral tests over 28 days. On Day 28, tissue samples were investigated for neuroinflammatory and histopathology changes through flow cytometry and ELISA. ARP (10 and 20 mg/kg/day, 3 days) treatment significantly reduced locomotors disability (P<0.01) and mechanical (P<0.01) and thermal allodynia (P<0.001) scores. Additionally, Levels of tumor necrosis factor (TNF)-α level and interleukin (IL)-10 were significantly altered in ARP-treated spinal cord tissues 28 days after SCI (P<0.01). Moreover, spinal cord tissue expression of M1 and M2 macrophages, as well as M1/M2 ratio, were reduced in ARP-treated SCI animals, concurrent with decreased M1 and increased M2 and M1/M2 in dorsal root ganglion (P<0.001). Our study indicates that ARP has therapeutic effects on SCI via the reduction of neuroinflammation and SCI sensory and locomotor abnormalities. https://acta.tums.ac.ir/index.php/acta/article/view/9921