Exploring the Binding Pattern of Geraniol with Acetylcholinesterase through In Silico Docking, Molecular Dynamics Simulation, and In Vitro Enzyme Inhibition Kinetics Studies.

Acetylcholinesterase (AChE) inhibition is a key element in enhancing cholinergic transmission and subsequently relieving major symptoms of several neurological and neuromuscular disorders. Here, the inhibitory potential of geraniol and its mechanism of inhibition against AChE were elucidated in vitro and validated via an in silico study. Our in vitro enzyme inhibition kinetics results show that at increasing concentrations of geraniol and substrate, Vmax did not change significantly, but Km increased, which indicates that geraniol is a competitive inhibitor against AChE with an IC50 value 98.06 ± 3.92 µM. All the parameters of the ADME study revealed that geraniol is an acceptable drug candidate. A docking study showed that the binding energy of geraniol (-5.6 kcal mol-1) was lower than that of acetylcholine (-4.1 kcal mol-1) with AChE, which exhibited around a 12.58-fold higher binding affinity of geraniol. Furthermore, molecular dynamics simulation revealed that the RMSD of AChE alone or in complex with geraniol fluctuated within acceptable limits throughout the simulation. The mean RMSF value of the complex ensures that the overall conformation of the protein remains conserved. The average values of Rg, MolSA, SASA, and PSA of the complex were 3.16 Å, 204.78, 9.13, and 51.58 Å2, respectively. We found that the total SSE of AChE in the complex was 38.84% (α-helix: 26.57% and ß-sheets: 12.27%) and remained consistent throughout the simulation. These findings suggest that geraniol remained inside the binding cavity of AChE in a stable conformation. Further in vivo investigation is required to fully characterize the pharmacokinetic properties, optimization of dose administration, and efficacy of this plant-based natural compound.

(-)-linalool-Loaded Polymeric Nanocapsules Are a Potential Candidate to Fibromyalgia Treatment.

Fibromyalgia (FM) is a chronic disease that has as main characteristic generalized musculoskeletal pain, which can cause physical and emotional problems to patients. However, pharmacological therapies show side effects that hamper the adhesion to treatment. Given this, (-)-linalool (LIN), a monoterpene with several therapeutic properties already reported in scientific literature as anti-depressive, antinociceptive, anti-inflammatory, and antihyperalgesic also demonstrated therapeutic potential in the treatment of FM. Nevertheless, physicochemical limitations as high volatilization and poor water-solubility make its use difficult. In this perspective, this present research had performed the incorporation of LIN into polymeric nanocapsules (LIN-NC). Size, morphology, encapsulation efficiency, cytotoxicity, and drug release were performed. The antihyperalgesic effect of LIN-NC was evaluated by a chronic non-inflammatory muscle pain model. The results demonstrated that the polymeric nanocapsules showed particle size of 199.1 ± 0.7 nm with a PDI measurement of 0.13 ± 0.01. The drug content and encapsulation efficiency were 13.78 ± 0.05 mg/mL and 80.98 ± 0.003%, respectively. The formulation did not show cytotoxicity on J774 macrophages. The oral treatment with LIN-NC and free-LIN increased the mechanical withdrawal threshold on all days of treatment in comparison with the control group. In conclusion, LIN-NC is a promising proposal in the development of phytotherapy-based nanoformulations for future clinical applications.

Microglial-targeting induced by intranasal linalool during neurological protection postischemia.

Stroke is the second cause of death and first cause of physical disability around the world; it affects the brain parenchyma through oxygen deficiency and spreads excitotoxicity. The complexity of the disease has made it difficult to find effective therapies. It is necessary to identify new treatments that effectively act within the narrow therapeutic window but also offer long-term protection poststroke. Our previous work found that oral linalool reversed the hippocampal and peripheral pro-inflammatory phospholipidomic biomarkers in ischemic rats; based on these observations, the "proof of concept" was to demonstrate that intranasal administration of linalool has a faster delivery to the central nervous system to protect it after focal ischemia in Wistar rats. The ischemic animals treated with linalool (25 mg/kg) showed a decrease in infarct volume at 24 h and seven days, and the treated animals had better neurological and motor skills at both poststroke times. Additionally, one month after daily intranasal administration of linalool, the ischemic rats showed improved relearning performance in the Morris water maze test. They also exhibited a reduction in microgliosis and decreased COX2, IL-1Beta and Nrf2 markers in the cerebral cortex and hippocampus. In astrocyte and microglial cultures, linalool reduced pro-inflammation and had a potent effect on microglial cells, generating Nrf2 subcellular redistribution under glutamate excitotoxicity conditions. Together, our findings indicate an acute and chronic recovery after ischemia induced by a daily intranasal puff of linalool, which mainly acts on microglial populations with anti-inflammatory actions.