Intranasal Artesunate Ameliorates Hippocampal LFP Abnormalities and Cellular Apoptosis in APP/PS1 Mice via a Mechanism Involving GHRH/PI3K/AKT Signaling.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and aberrant neural network activity. Artesunate (ART) has shown neuroprotective potential, but its effects on macroscopic hippocampal network dynamics and the underlying molecular mechanisms remain unclear. This study investigated the therapeutic efficacy and mechanisms of intranasal ART in APP/PS1 transgenic mice and Aβ1-42-treated HT22 hippocampal neurons, integrating behavioral assays, multi-channel local field potential (LFP) recordings, ultrastructural analyses, and transcriptomics. In vivo, ART administration ameliorated cognitive deficits and mitigated macroscopic hippocampal LFP disruptions, manifested as an attenuation of the spectral power shift toward lower frequencies, reduced aberrant theta-gamma phase-amplitude coupling (PAC), and improved sharp-wave ripple (SWR) properties during resting states. Concurrently, ART reduced the number of TUNEL-positive cells and quantitatively preserved postsynaptic density (PSD) thickness and synaptic cleft width, alongside qualitative improvements in myelin sheath and mitochondrial morphology. Mechanistically, RNA-sequencing identified the neuroactive ligand-receptor interaction pathway as a prominent ART-responsive target, with growth hormone-releasing hormone (GHRH) emerging as a key candidate. In vitro pharmacological blockade revealed that ART's anti-apoptotic effects against Aβ toxicity depend on GHRH-R and subsequent PI3K/AKT cascade activation. This was accompanied by the inhibitory phosphorylation of GSK-3β, increased NF-κB p65 nuclear translocation, Bcl-2 upregulation, and caspase-3 inhibition. Collectively, these findings demonstrate that intranasal ART exerts sustained neuroprotective effects that preserve synaptic ultrastructure and ameliorate macroscopic network dysfunction in AD models. While the precise in vivo causality requires further validation, our in vitro data suggest that these cellular benefits are strongly associated with GHRH/PI3K/AKT signaling, highlighting ART as a promising therapeutic candidate for early AD.