Biochemical investigation and in silico analysis of the therapeutic efficacy of Ipriflavone through Tet-1 Surface-Modified-PLGA nanoparticles in Streptozotocin-Induced Alzheimer's like Disease: Reduced oxidative damage and etiological Descriptors

Abstract

Ipriflavone (IPRI), an isoflavone derivative, is clinically used to prevent postmenopausal bone loss in addition to its antioxidant and cognitive benefits. However, its poor aqueous solubility retained its bioavailability. New strategies have been developed to improve the bioavailability and solubility of neurological medications to enhance their potency and limit adverse effects. This study aimed to prepare targeted IPRI-poly-lactic-co-glycolic acid (PLGA) nanoparticles coupled with Tet-1 peptide to increase the therapeutic potency of IPRI in a rat model of Alzheimer's disease (AD). Streptozotocin (STZ) exacerbates Alzheimer-related alterations by promoting central insulin resistance resulted from defective signaling pathways related to neuroinflammation and neurotoxicity. Bilateral intracerebroventricular (icv) injection of STZ was used to introduce the AD model. Icv-STZ injection significantly affected brain insulin, oxidative stress, inflammatory, and apoptotic indicators and caused behavioral abnormalities. STZ promoted the formation of amyloid β42 (Aβ42) by increasing BACE1 and reducing ADAM10 and ADAM17 expression levels. STZ also triggered the accumulation of neurofibrillary tangles and synaptic dysfunction, which are crucial for neurological impairments. Icv-STZ injection showed evident degenerative changes in the pyramidal cell layer and significantly reduced the count of viable cells in both CA1 and prefrontal cortex, indicating increased neuronal cell death. IPRI successfully ameliorated cognitive dysfunction by improving the phosphorylated forms of cAMP-response element-binding protein (pCREB) and extracellular signal-regulated kinase 1/2 (pERK1/2) related to synaptic plasticity. Targeted IPRI nanoparticles exceeded free IPRI potential in reducing oxidative stress, acetylcholinesterase/monoamine oxidase activities, Tau phosphorylation, and Aβ42 levels revealing less degenerative changes and increased viable neuron counts. IPRI-targeted nanoparticles improved the neuroprotective potential of free IPRI, making this strategy applicable to treat many neurodegenerative diseases. Finally, the in silico study predicted its ability to cross the BBB and to bind various protein targets in the brain.

Keywords: ADMET; BDNF/ERK/CREB signaling; Cell- and BBB-penetrating nanosystems; Cognitive impairment; Ganglioside receptor GT1B; Ipriflavone and brain health; Sustained drug release.