Intranasal Administration of Isoeugenol Improves Memory Deficits in APP/PS1 Old Mice—A Role Beyond Nrf2 Activation?

Abstract

ABSTRACT Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease‐modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol‐rich Keap1, and many are Michael acceptors, such as low‐molecular‐weight (LMW) skin allergens. However, LMW allergens‐induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD‐specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10‐month‐old AD double‐transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2‐dependent anti‐inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.