Fig. 2: Hypothesis of nanomedicine-regulated CREB phosphorylation by lipid-peptide liquid crystalline nanoassemblies of cubosome type in an in vitro Parkinson’s disease (PD) model.

Lipid nanoparticles (LNPs), loaded with neuroprotective molecules, may activate CREB through Ras-Raf-MEK-ERK (MAPK), PI3K-AKT (AKT), or PLC-PKC signaling pathways. CREB transcription factor can be phosphorylated by activation of multiple kinases including ERK, AKT, or PKC upon stimulation of a cellular G-protein-coupled receptor (GPCR) or a membrane receptor tyrosine kinase (RTK). In the PD model created in vitro (through cellular SH-SY5Y differentiation by retinoic acid (RA) for 5 days, starvation for 24 h in RA-only medium, and incubation with the neurotoxin 6-OHDA for 30 min), the inhibition of ERK, AKT and PKC pathways may cause mitochondrial dysfunction and trigger cellular apoptosis upon reduced CREB activation. CREB phosphorylation, stimulated by PUFA-plasmalogen-loaded nanoparticles in association with the neurotrophic peptide PACAP, is expected to activate the CREB-BDNF pathway and promote neuroprotection and recovery from oxidative stress-induced neuronal damage. Abbreviations: CREB cyclic AMP (cAMP)-response element-binding protein, AKT Protein kinase B, ERK Extracellular regulated protein kinase, MEK Mitogen-activated protein kinase, Ras Rat sarcoma virus, Raf Rapidly accelerated fibrosarcoma, PLC Phosphoinositol-specific phospholipase C, PKC Protein kinase C, PI3K Phosphatidylinositol-3 kinase, PDK Phosphoinositol-dependent kinase, BDNF brain-derived neurotrophic factor (BDNF), 6-OHDA 6-hydroxydopamine. The signaling pathways were drawn with BioRender (BioRender.com).