2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid ?-induced Alzheimer-like mice model: Bring the ?2 adrenergic receptor back into play

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an ?2 adrenergic receptor (?2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind ?2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid ? 1-42 (sA?1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the ?2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sA? injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of ?2AR in neuropsychiatric illness and therapies.