The immunomodulatory effects of ethosuximide and sodium butyrate on experimentally induced fibromyalgia: The interaction between IL-4, synaptophysin, and TGF-β1/NF-κB signaling

•We investigated the effect of ethosuximide and sodium butyrate on experimentally induced fibromyalgia.•Ethosuximide and sodium butyrate restored the behavioral tests to the normal values.•Both drugs elevated the levels of the anti-inflammatory cytokines.•Both drugs reduced the hippocampal NF-κB and increased synaptophysin expression.•Ethosuximide reduced only spinal cord & brain glutamate while improved brain dopamine.•Sodium butyrate elevated spinal cord dopamine and serotonin without affecting glutamate.•Sodium butyrate elevated brain serotonin & reduced glutamate without affecting brain dopamine. Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients’ life. Its pathogenesis is complex, and the treatment strategies are limited by partial efficacy and potential adverse effects. So, our aim was to investigate the possible ameliorative effects of ethosuximide and sodium butyrate on fibromyalgia and compare their effects to pregabalin. In a mouse model of reserpine induced fibromyalgia, the effect of ethosuximide, sodium butyrate, and pregabalin was investigated. Evaluation of mechanical allodynia, cold hypersensitivity, anxiety, cognitive impairment, and depression was performed. Also, the brain and spinal cord tissue serotonin, dopamine and glutamate in addition to the serum levels of interleukin (IL)-4 and transforming growth factor beta 1 (TGF-β1) were assayed. Moreover, the expression of nuclear factor kappa B (NF-κB) synaptophysin was immunoassayed in the hippocampal tissues. Ethosuximide and sodium butyrate restored the behavioral tests to the normal values except for the antidepressant effect which was evident only with ethosuximide. Both drugs elevated the levels of the anti-inflammatory cytokines IL-4 and TGF-β1, reduced the hippocampal NF-κB, and increased synaptophysin expression with superiority of sodium butyrate. Ethosuximide reduced only spinal cord and brain glutamate while improved brain dopamine while sodium butyrate elevated spinal cord dopamine and serotonin with no effect on glutamate. Also, sodium butyrate elevated brain serotonin and reduced glutamate with no effect on brain dopamine. Each of sodium butyrate and ethosuximide would serve as a promising therapeutic modality for management of fibromyalgia and its comorbid conditions.