Rosmarinic Acid Reduces Microglia Senescence: A Novel Therapeutic Approach for the Management of Neuropathic Pain Symptoms

The worldwide incidence of neuropathic pain is around 7-8% and is associated with significant and disabling comorbidities (sleep disturbances, depression, anxiety). It is now known that cellular ageing of microglia contributes to neurodegenerative diseases, mood disorders, and, even if with less evidence, chronic pain. The aim of this work was to investigate in vitro and in vivo the senolytic activity of rosmarinic acid (RA) to be exploited for the management of NP symptoms. BV2 cells were stimulated with LPS 500 ng/mL for 24 h. Treatment with RA 1 mu M improved cell viability and reduced IL-1s release leading to an attenuation of neuroinflammation. We then moved on to test the efficacy of RA in reducing microglial senescence. In our model, BV2 cells were stimulated with LPS 500 ng/mL every 72 h for 4 h/day, over a period of 10 days. RA 1 mu M reduced the expression of the beta-galactosidase enzyme, reduced the release of senescence-associated secretory phenotype (SASP) factors, increased cell viability, and reduced the presence of nuclear foci of senescence (SAHF), well-known cellular senescence markers. In the Spared Nerve Injury (SNI) model, 28 days from surgery, repeated oral administration of RA 5 mg/kg reduced hyperalgesia and NP-associated symptoms, such as anxiety and depression. A reduction of senescence markers was detected on both hippocampal and spinal samples of SNI-treated mice. This study represents a starting point for investigating the role of microglial senescence as a possible pharmacological target in controlling symptoms related to the more advanced stages of peripheral neuropathy.