Neuroprotective Effects of Limonene (+) against Aβ42-Induced Neurotoxicity in a <i>Drosophila</i> Model of Alzheimer’s Disease

Abstract

Forest bathing is suggested to have beneficial effects on various aspects of human health. Terpenes, isoprene based-phytochemicals emitted from trees, are largely responsible for these beneficial effects of forest bathing. Although the therapeutic effects of terpenes on various diseases have been revealed, their effects on neuronal health have not yet been studied in detail. Here, we screened 16 terpenes that are the main components of Korean forests using Drosophila Alzheimer's disease (AD) models to identify which terpenes have neuroprotective effects. Six out of the 16 terpenes, ρ-cymene, limonene (), limonene (), linalool, α-pinene (), and β-pinene (), partially suppressed the beta amyloid 42 (Aβ42)-induced rough eye phenotype when fed to Aβ42-expressing flies. Among them, limonene () restored the decreased survival of flies expressing Aβ42 in neurons during development. Limonene () treatment did not affect Aβ42 accumulation and aggregation, but did cause to decrease cell death, reactive oxygen species levels, extracellular signal-regulated kinase phosphorylation, and inflammation in the brains or the eye imaginal discs of Aβ42-expressing flies. This neuroprotective effect of limonene () was not associated with autophagic activity. Our results suggest that limonene () has a neuroprotective function against the neurotoxicity of Aβ42 and, thus, is a possible therapeutic reagent for AD.

Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases

“…On the other hand, several studies have shown the effects of terpenes on the production of pro-inflammatory mediators during neuroinflammation in in vivo models. For example, d-limonene decreased NO levels in Aβ42-expressing fly heads [48], and linalool reduced the levels of the pro-inflammatory markers p38 MAPK, NOS2, COX2 and IL-1β in the brain of a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) [73]. Moreover, borneol attenuated the elevation of NO, the increase in iNOS enzymatic activity and the upregulation of iNOS expression in an ischemic model of oxygen-glucose deprivation followed by reperfusion [65].…”

“…TNF-α, IL-1β and IL-6 ↓ LPS-stimulation Raw 264.7 cell line [46] NF-kB, COX-2, iNOS and Nitrite levels ↓ Doxorubicin-induced inflammation Wistar rats [47] NO levels ↓ Aβ42 expressed heads Fruit fly [48] NO and iNOS levels ↓ In vitro treatment Human chondrocytes [49] Myrcene NO and iNOS levels ↓ In vitro treatment Human chondrocytes [49] γ-Terpinene TNF-α and IL-1β ↓ Carrageenan-induced peritonitis model Swiss mice [50] IL-1β, IL-6↓ and IL-10, COX-2, PGE2 ↑ LPS-Stimulation Macrophages from mice [51] α-Phellandrene TNF-α and IL-6 ↓ Carrageenan injection in air pouch cavities Wistar rats or swiss mice [52] IL ↓ denotes decreased activity; ↑ denotes increased activity.…”

“…β-Caryophyllene inhibited neuroinflammation and showed beneficial effects in models of insulin resistance and obesity, Parkinson's disease, and multiple sclerosis [82,83,187]. Additionally, borneol attenuated brain neuronal and microglial inflammation in LPS-induced sepsis mice [97], and d-limonene reduced glial cell number and NO levels in the brain of Drosophila model of Alzheimer's disease [48].…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…D-limonene metabolites have been detected in adipose tissue and mammary glands in a high concentration, although it has low toxicity [101]. This compound shows different pharmacological properties, which include anti-inflammatory, gastro-protective, anti-nociceptive, anti-tumor, and neuroprotective [102][103][104]. A recent study has demonstrated D-limonene anti-tumor activity (i.e., tumor cells decreased in proliferation and growth) in an animal model of chronic myeloid leukemia [102].…”

“…At a different point-of-view, Smeriglio and colleagues reported the antioxidant and free radical scavenging properties of Citrus lumia oil, which is highly-concentrated in monoterpenes (e.g., 48.9% D-limonene and 18.2% linalool), suggesting an important preventive role in the genesis of oxidative stress-related pathologies [111]. In this context, a study conducted by Shin et al showed that limonene decreased cell death, ROS levels, extracellular signal-regulated kinase phosphorylation, and overall inflammation in the brains and eyes of drosophila during Aβ42-induced neurotoxicity, a model of Alzheimer's disease (AD) [104]. These and other authors have been studying limonene effects in the context of its impacts in the CNS.…”