Neuro-protective effect of Linalool against spinal cord injury in rats and the mechanism involved / Efecto neuroprotector del Linalool contra la lesión de la médula espinal en ratas y el mecanismo involucrado

The current study was conducted to determine the neuroprotective role and mechanism of action of Linalool (LIN) in SCI. The SCI in Sprague-Dawley (SD) rats was induced by weight-drop contusion model. Results of the suggested that LIN showed improvement in the locomotor function of SCI rats in a BBB scoring analysis. It was found in agreement with histopathological analysis of spinal cord tissue where LIN improves the neuronal architecture of spinal cord tissues, and protect neurons from degeneration. It also reduces oxidative stress via modulating endogenous antioxidants (MDA, SOD, and GSH) and inhibits the generation of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6). In western blot analysis, LIN showed dose-dependent reduction of expression of toll-like receptor (TLR-4) and nuclear factor-kappa B (NF-ĸB). Our study demonstrated that administration of Linalool alleviated spinal cord injury via anti-inflammatory and antioxidant activities in spinal cord tissues possibly due to inhibition of TLR4/NF-κB activation.

El estudio actual se realizó para determinar el papel neuroprotector y el mecanismo de acción de Linalool (LIN) en SCI. La LIN en ratas Sprague-Dawley (SD) se indujo mediante el modelo de contusión de caída de peso. Los resultados sugirieron que LIN mostró una mejora en la función locomotora de ratas SCI en un análisis de puntuación BBB. De acuerdo con el análisis histopatológico del tejido de la médula espinal se encontró que LIN mejora la arquitectura neuronal de los tejidos de la médula espinal y protege a las neuronas de la degeneración. También reduce el estrés oxidativo mediante la modulación de antioxidantes endógenos (MDA, SOD y GSH) e inhibe la generación de citocinas proinflamatorias (TNF-α, IL-1ß e IL-6). En el análisis de Western blot, LIN mostró una reducción dependiente de la dosis de la expresión del receptor tipo toll (TLR-4) y el factor nuclear kappa B (NF-ĸB). Nuestro estudio demostró que la administración de Linalool alivió la lesión de la médula espinal a través de actividades antiinflamatorias y antioxidantes en los tejidos de la médula espinal, posiblemente debido a la inhibición de la activación de TLR4/NF-κB.

(-)-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.

Induction of oxidative stress as a possible mechanism by which geraniol affects the proliferation of human A549 and HepG2 tumor cells.

Geraniol (GOH), like other plant-derived natural bioactive compounds, has been found to possess antiproliferative properties that are essential to cope with malignant tumors. However, the mechanisms of molecular action of GOH are not fully elucidated. The aim of this study was to evaluate the effect of GOH on some oxidative parameters in human tumor cell lines (HepG2 and A549). Cytotoxicity evaluated in cell lines by the MTT assay, genotoxicity by the comet assay, and lipid peroxidation by the TBARS. The activities of antioxidant the enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST), were also analyzed. Additionally, intracellular reactive oxygen species (ROS), nitric oxide, and lactate production were determined in HepG2 cells. Both tumor cell lines showed a clear concentration-dependent response to GOH in several of the parameters evaluated. Lipids turned out to be more sensitive than DNA to oxidative damage induced by GOH. TBARS levels increased with respect to control (p < 0.05) by 33% and 122% in HepG2 and A549 cells, respectively treated with 200 µM GOH. However, GOH caused a statistically significant decrease in SOD and CAT activities in HepG2 cells only. GST was not affected in any cell lines. GOH induced the production of ROS but not nitric oxide in HepG2, which shows that ROS were mainly responsible for oxidative damage. Lactate release increased statistically significantly compared to control (p < 0.001), by 41% and 86% at 200 and 800 µM GOH respectively, showing that this monoterpene also affected the glycolytic pathway in HepG2 cells. These results suggest that oxidative stress could mediate the anti-proliferative effects of GOH in HepG2 and A549 cells.

Nasal administration of nanoencapsulated geraniol/ursodeoxycholic acid conjugate: Towards a new approach for the management of Parkinson's disease.

The combined use of different therapeutic agents in the treatment of neurodegenerative disorders is a promising strategy to halt the disease progression. In this context, we aimed to combine the anti-inflammatory properties of geraniol (GER) with the mitochondrial rescue effects of ursodeoxycholic acid (UDCA) in a newly-synthesized prodrug, GER-UDCA, a potential candidate against Parkinson's disease (PD). GER-UDCA was successfully synthetized and characterized in vitro for its ability to release the active compounds in physiological environments. Because of its very poor solubility, GER-UDCA was entrapped into both lipid (SLNs) and polymeric (NPs) nanoparticles in order to explore nose-to-brain pathway towards brain targeting. Both GER-UDCA nanocarriers displayed size below 200 nm, negative zeta potential and the ability to increase the aqueous dissolution rate of the prodrug. As SLNs exhibited the higher GER-UDCA dissolution rate, this formulation was selected for the in vivo GER-UDCA brain targeting experiments. The nasal administration of GER-UDCA-SLNs (1 mg/kg of GER-UDCA) allowed to detect the prodrug in rat cerebrospinal fluid (concentration range = 1.1 to 4.65 µg/mL, 30-150 min after the administration), but not in the bloodstream, thus suggesting the direct nose to brain delivery of the prodrug. Finally, histopathological evaluation demonstrated that, in contrast to the pure GER, nasal administration of GER-UDCA-SLNs did not damage the structural integrity of the nasal mucosa. In conclusion, the present data suggest that GER-UDCA-SLNs could provide an effective and non-invasive approach to boost the access of GER and UDCA to the brain with low dosages.

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.