Dexmedetomidine and Apigenin Combination Mitigates Memory Deficits Caused by Microglial Activation and Hippocampal Neurogenesis Impairment in Methotrexate-Induced Chemo-Brain in Rats.

Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, and apigenin (Api), a naturally occurring bioflavonoid, have recently shown neuroprotective effects in experimental models of methotrexate (MTX)-induced neurotoxicity; however, the impact of their combined administration has not yet been elucidated. This study investigated the effects of Dex on microglial activation, neuroinflammation, and apoptosis, and the role of Api in hippocampal neurogenesis, along with its combined effects via the miR-15a/ROCK-1/ERK1/2/CREB/BDNF signaling cascade. Male Sprague Dawley rats were randomly assigned into: a normal control group, Dex and Api-control groups, which received Dex or Api daily for 30 days, an MTX-only group that received MTX and leucovorin (LCV), Dex or Api cotreated groups received either Dex or Api with MTX and LCV, and a Dex + Api cotreated group received both drugs with MTX and LCV. Dex improved cognitive function by attenuating microglial activation. Api mitigated hippocampal neurogenesis, as shown by decreased Ki-67 and doublecortin (DCX) expression. Compared with Dex or Api alone, the combined treatment had more favorable effects on novel object recognition (NOR), miR-15a, ROCK-1, ERK1/2, histopathological changes, and Ki-67 neurogenesis marker over Api or Dex monotherapy, and improved CREB/BDNF signaling over Dex alone. However, no additional favorable effects on microglial activation, redox balance, IL-1β, or apoptosis were observed. The combination of Dex and Api exhibits more pronounced neuroprotective effects by potentiating modulation of the miR-15a/ROCK-1/ERK1/2/CREB/BDNF signaling cascade, improving cognitive behavior, and enhancing hippocampal neurogenesis.