Neuroprotective role of mirabegron: Targeting beta-3 adrenergic receptors to alleviate ulcerative colitis-associated cognitive impairment

Abstract

While cognitive impairment has been documented in ulcerative colitic patients, the possible influence of central β3-adrenergic receptor (β3-AR) signaling on this extraintestinal manifestation remains unclear. Previously, we identified an imperative role for mirabegron (MA) as an agonist of β3-AR, in decreasing the BACE-1/beta-amyloid (Aβ) cue in the colons of UC rats. Consequently, we investigated its therapeutic potential for alleviating cognitive impairment associated with UC. To fulfil our aim, rats administered iodoacetamide were treated with the β3-AR agonist (MA) alone, with the antagonist (SR59230A) for 8 days, or kept untreated. The animals' behavior (MWM and NOR tests) and hippocampal structure were assessed. Mechanistically, necroptosis, ER stress (ERS), Aβ-amyloidosis, inflammation/oxidative burden, and gut/BBB dysfunction were analyzed. Post-administration of MA improved weight gain, colon/hippocampal structures, and memory. Additionally, it inhibited serum levels of lipopolysaccharide and Annexin-1, indicating recovered gut and BBB integrity. MA turned off the pathogenic BACE-1/Aβ axis in the hippocampus, necroptosis trajectory (TNFR-1/RIPK1/RIPK3/MLKL), and the IRE-1α/JNK signal. Moreover, MA enhanced the transcription factor PPAR-γ, decreased NF-κΒ/TNF-α inflammatory hub, and modulated the redox imbalance by decreasing malondialdehyde and increasing catalase. Notably, MA's behavioral, structural, and molecular beneficial actions were hindered by the pre-administration of SR59230A. From a novel standpoint, we recognized the β3-AR as a therapeutic target for UC-associated cognitive impairment in the hippocampus. In this context, the aptitude of MA to inhibit UC-induced hippocampal amyloidogenesis, alongside its anti-necroptotic, anti-ERS, anti-inflammatory, and antioxidant effects, contribute to these central enhancements, while also regulating permeability in both gut and BBB barriers.