Table 3.

Natural and chemical compounds that may target ONPs.

Compounds	Targeting	Mechanism	In Vitro/In Vivo Models	Comments	Refs
Incensole acetate (IA)	Oxidative stress induced by Aβ	Increased levels of the antioxidant enzyme HO-1	Human olfactory bulb neural stem cells (hOBNSCs)	The cellular model belongs to the olfactory system; therefore, we envision similar results in our proposed cellular model.	[169]
Curcumin loaded polymeric or lipid nanosuspensions	Oxidative stress	Elevation of total cellular glutathione levels and enhanced cell viability under oxidative stress	Normal and hypoxic olfactory ensheathing cells (OECs)	The use of OECs (non-myelinating glial cells that wrap olfactory neurons) in hypoxic conditions enables a roadmap to improve the delivery of antioxidants through the nose-to-brain route.	[170,171,172]
Saturated medium-chain fatty acid (MCFA) decanoic acid (10:0)	Oxidative stress	Upregulation of catalase activity and increase in mitochondrial citrate synthase	Neuroblastoma cells (SH-SY5Y cells)	MCFA decanoic acid has only been evaluated in human cell lines. These findings suggest it is worth testing them in AD patient-derived ONPs.	[173,174]
Scutellarin (SC)	Oxidative stress and apoptosis	Enhances the levels of superoxide dismutase	L-Glu-treated HT22 cells/ AD mice induced by AlCl3 and D-gal	SC has shown antioxidant and antiapoptotic properties only in induced models of AD; thus, it would be interesting to evaluate these properties in a cellular model derived from AD patients.	[175]
Curcumin and Vitamin D3	Oxidative stress	Increased SOD enzyme activity and catalase enzyme expression	Primary neuronal cortical culture from rats treated with Aβ	Antioxidant combinations show a synergistic effect that could be tested in an ONP model.	[176]
TM-10 (a ferulic acid derivative and a highly selective BuChE inhibitor)	Oxidative stress, Aβ aggregation, butyrylcholinesterase (BuChE) inhibition	Neuroprotective effect against Aβ42- mediated SH-SY5Y neurotoxicity, and autophagy induction. In mice, improves scopolamine-inducedmemory impairment	SH-SY5Y cell, U87 cell, AlCl3-induced zebrafish AD model, and mice treated with scopolamine	The search of Multi-Target-Directed-Ligands (MTDLs) has allowed fusing novel natural antioxidants derivatives and highly selective BuChE inhibitors. Thus, compounds with multiple biological activities are obtained, including ChE inhibitory activity, MAOs inhibitory potency, antioxidant activity, disaggregation effect on Aβ, and the ability to cross the blood−brain barrier. The use of AD patient-derived ONPs could be a valuable tool for validating these compounds in humans.	[177,178]