Preparation, characterization, and pharmacological application of oral Honokiol-loaded solid lipid nanoparticles for diabetic neuropathy

Abstract

Honokiol is a phytochemical component with a variety of pharmacological properties. However, the major limitation of Honokiol is its poor solubility and low oral bioavailability. In this study, we formulated and characterized oral Honokiol-loaded solid lipid nanoparticles (SLNs) to enhance bioavailability and then evaluated their effectiveness in experimental diabetic neuropathy (DN). The finalized formulation has a spherical morphology, a particle size (PS) of 121.31 ± 9.051 nm, a polydispersity index (PDI) of 0.249 ± 0.002, a zeta potential (ZP) of -20.8 ± 2.72 mV, and an entrapment efficiency (% EE) of 88.66 ± 2.30 %. In-vitro release data shows, Honokiol-SLNs displayed a sustained release profile at pH (7.4). The oral bioavailability of Honokiol-SLNs was remarkably greater (8-fold) than Honokiol-Pure suspension. The neuroprotective property of Honokiol-SLNs was initially demonstrated against hydrogen peroxide H₂O₂-stimulated PC12 (pheochromocytoma) cells. Furthermore, results of in-vivo studies demonstrated that treatment with Honokiol-SLNs significantly (p < 0.001) suppressed oxidative stress by inhibition of nuclear factor kappa B (NF-κB) and significant (p < 0.001) upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling in the spinal cord. The expression of transient receptor potential melastatin 8(TRPM8) and transient receptor potential vanilloid 1 (TRPV1) was significantly (p < 0.001) downregulated. Honokiol-SLNs inhibited apoptosis by significant (p < 0.001) downregulation of cleaved caspase-3 expression in the spinal cord. These findings demonstrate that Honokiol-SLNs providedbetter neuroprotection in DN because of higher oral bioavailability.

Keywords: Apoptosis; Diabetic neuropathy; Honokiol-SLNs; In-vivo studies; Oral bioavailability; Oxidative stress.