Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer's mice

Highlights

• Oral linalool reverses spatial memory impairment in old 3xTg-AD mice.

• Anxiolytic activity of linalool in aged 3xTg-AD mice.

• Aged 3xTg-AD linalool-treated mice reduces β-amyloidosis.

• Linalool ameliorates tau hyperphosphorylation in aged 3xTg-AD mice.

• Linalool decreases inflammatory response in old 3xTg-AD mice.

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder. Several types of treatments have been tested to block or delay the onset of the disease, but none have been completely successful. Diet, lifestyle and natural products are currently the main scientific focuses. Here, we evaluate the effects of oral administration of the monoterpene linalool (25 mg/kg), every 48 h for 3 months, on aged (21–24 months old) mice with a triple transgenic model of AD (3xTg-AD) mice. Linalool-treated 3xTg-AD mice showed improved learning and spatial memory and greater risk assessment behavior during the elevated plus maze. Hippocampi and amygdalae from linalool-treated 3xTg-AD mice exhibited a significant reduction in extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis as well as a significant reduction in the levels of the pro-inflammatory markers p38 MAPK, NOS2, COX2 and IL-1β. Together, our findings suggest that linalool reverses the histopathological hallmarks of AD and restores cognitive and emotional functions via an anti-inflammatory effect. Thus, linalool may be an AD prevention candidate for preclinical studies.

Introduction

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia. AD is responsible for a considerable human, social and economic burden around the world (Association, 2014). In Latin America, the main causes of dementia are a sedentary lifestyle, metabolic disorder, and cardiovascular and cerebrovascular diseases (Kalaria et al., 2008). In general, AD patients present with a gradual deterioration of episodic memory, a global decline in cognitive function, and behavioral changes. AD symptoms are the clinical manifestations of a progressive accumulation of intra- and extracellular β-amyloid, the formation of neurofibrillary tangles (NFTs) and the extensive oxidative stress associated with neuron and synapse loss (Ittner and Gotz, 2011, Reitz and Mayeux, 2014).

The current standard pharmacotherapy for cognitive improvement in AD patients includes acetylcholinesterase inhibitors, such as galantamine, and the N-methyl-d-aspartate (NMDA) antagonist memantine, which promote cognitive function in patients with moderate to severe AD (Kang et al., 2014). However, the approval of these drugs has not been based on their ability to slow disease progression but on their ability to improve clinical symptomatology. Hence, only symptomatic drugs with transient benefits have been approved for clinical use in AD patients by the US Food and Drug Administration (FDA) (Bassil and Grossberg, 2009). The use of alternative therapies for neuroprotection is increasing; these alternatives include natural products, such as monoterpenes (Dinda et al., 2009, Tabassum et al., 2015).

(−)Linalool, one enantiomer of the naturally occurring monoterpene, is a major volatile component of essential oils in several aromatic plant species, such as Lavandula angustifolia Mill., Melissa officinalis L., Rosmarinus officinalis L. and Cymbopogon citratus DC. Interestingly, many linalool-producing species are traditionally used in folk medicine and in aromatherapy to relieve symptoms and to cure a variety of acute and chronic ailments (Batista et al., 2010, Elisabetsky et al., 1995). Linalool is widely used in the manufacture of fragrances for shampoos, soaps and detergents and in pharmaceutical drug formulations (Letizia et al., 2003, Mitic-Culafic et al., 2009).

Linalool exhibits a variety of pharmacological effects, including antimicrobial, antileishmanial, anti-inflammatory, anti-oxidant and cardiovascular effects, in normotensive and hypertensive rats (Anjos et al., 2013, Beier et al., 2014, Celik and Ozkaya, 2002, Huo et al., 2013, Wu et al., 2014). The strong antioxidant activity of linalool inhibits LDL oxidation; this inhibition enhances cholesterol uptake via macrophage scavenger receptors. Linalool significantly reduced plasma TG, total cholesterol and HMG-CoA levels, demonstrating in vivo anti-atherogenic activity (Cho et al., 2011, Chung et al., 2008). Linalool has remarkable effects on the central nervous system (CNS), acting as a sedative, antinociceptive, anticonvulsant and anxyolitic (Batista et al., 2010, de Almeida et al., 2009, Elisabetsky et al., 1999, Linck et al., 2009). Linalool also modulates glutamatergic neurotransmission both in vitro and in vivo, possibly through NMDA receptor interactions (Elisabetsky et al., 1995, Silva Brum et al., 2001). However, nothing is known about linalool's effect on AD neuropathology and behavioral impairments, which is the goal of the present study.