Targeting the protein tyrosine phosphatase 1B signaling axis in Alzheimer's disease: Emerging therapeutic potential of ivermectin.

This study attempts to repurpose ivermectin (IVM) for AD by inhibiting the PTP1B enzyme. IVM is a widely known, commercially approved antiparasitic drug. The PTP1B enzyme dephosphorylates multiple kinase substrates and is responsible for metabolic regulation by the PI3K/AKT downstream signaling cascade. A similar signaling pathway is present in the brain. We assessed binding affinity in BIOVIA Discovery Studio Visualizer version 2021 and inhibitory activity using a commercially available ELISA kit. The streptozotocin (3 mg/kg, intracerebroventricularly)- induced AD mouse model was used to study the biological effects of IVM using NOR and Y-maze behavioral assays. Multiple disease physiologies, such as oxidative stress, mitochondrial complex (I-IV) dysfunction, brain insulin resistance, neuroinflammation, Aβ aggregation, apoptosis, and autophagy signaling cascade, were studied by assessing various biomarkers to generate a proof-of-concept. The docking study demonstrated potential interactions of IVM with the catalytic pocket of PTP1B enzyme, yielding a docking score of -8.0. To validate the docking protocol, the re-docked ligand was superimposed on the crystallographic ligand, resulting in an RMSD of 0.000 Å, therefore confirming the reliability of the computational approach. The calculated IC50 value of IVM by ELISA inhibitory assay was found 4.58 μM. The in vivo study of IVM (10 mg/kg) in the mouse model showed improvement in cognitive deficits on behavioral assays and was comparable to donepezil and DPM1001. The preliminary screening investigations through in vitro enzyme inhibition and molecular-level studies showed promising improvements in multiple physiological parameters that progressed to AD. The IHC showed a reduction in the Aβ plaque load and activated microglia cell count. These preliminary data demonstrate that IVM exhibits considerable PTP1B inhibitory potential and require further exploration in a robust, statistically powered preclinical study, followed by clinical trials, to repurpose it in AD and related conditions.