Longifolene mitigates amyloid beta neurotoxicity in rats and cells via PI3K/AKT/NFκB pathway

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the accumulation of Amyloid-β peptide, leading to severe oxidative stress and neuroinflammation. Current therapeutic strategies often fall short in addressing the multifactorial nature of AD, highlighting an urgent need for novel interventions. Terpenes, a diverse class of natural compounds, are recognized for their potent anti-oxidant and anti-inflammatory properties. Longifolene (LNF), a prominent sesquiterpene found in pine resin, is being investigated for its potential to modulate these critical pathological drivers of AD.

Researchers evaluated Longifolene's (LNF) neuroprotective potential using both in vitro and in vivo models. For in vitro studies, SH-SY5Y neuroblastoma cells were pre-treated with LNF at 1, 10, and 100 μM before induction of neurotoxicity with Aβ1-42. Key endpoints included assessment of ROS generation, mitochondrial function, and apoptosis. For in vivo studies, Wistar rats were subjected to an Aβ1-42 induced AD model. Rats received LNF at 10, 50, and 100 mg/kg via oral gavage, with a 20-day pre-treatment followed by 30 days of post-treatment. Primary endpoints included behavioral assessments, biochemical analysis of brain tissue (AChE, TNF-α, IL-6, BDNF levels), histopathological examination of the cortex and hippocampus, and protein expression studies via western blot.

In in vitro experiments, pre-treatment with LNF at 1, 10, and 100 μM significantly protected SH-SY5Y cells from Aβ1-42 induced neurotoxicity. Specifically, 0.5 and 1 μM of LNF significantly prevented reactive oxygen species (ROS) generation, mitigated mitochondrial dysfunction, and reduced apoptosis in the cell line. Pharmacokinetic studies in rats confirmed that LNF achieved therapeutic concentrations within the brain. In the in vivo AD model, LNF pre- and post-treatment at 10, 50, and 100 mg/kg resulted in dose-dependent improvements across behavioral, biochemical, and histopathological parameters. Functional assays demonstrated that LNF significantly reduced levels of AChE, TNF-α, and IL-6, while elevating BDNF in the rat brain. Histopathological examination of the cortex and hippocampus revealed that LNF at doses of 50 and 100 mg/kg markedly attenuated neuronal swelling and cortical atrophic changes. Importantly, it also preserved the pyramidal layer thickness in the hippocampus. Protein expression studies using western blot analysis elucidated that:

LNF exerts its anti-AD activity by modulating the PI3K/AKT/NFκB pathway, a critical signaling cascade involved in cell survival and inflammation.