Pharmacokinetic and Permeation Studies in Rat Brain of Natural Compounds Led to Investigate Eugenol as Direct Activator of Dopamine Release in PC12 Cells

Abstract

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson’s disease after oral administration.

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways

“…The effective dose of eugenol that can be traced from the reported studies is around 25–100 mg/kg per oral treatment in AD and PD animals (Garabadu & Sharma, 2019; Vora et al, 2022). Although the oral bioavailability of eugenol is reported to be poor, this compound is suggested to bear good BBB permeability and demonstrated as an efficient therapeutic agent with no reported toxicity (Barot & Saxena, 2021; Pavan et al, 2023; Pramod et al, 2010; Ulanowska & Olas, 2021). Eugenol is reported to exert antioxidative effects, reduce mitochondrial dysfunction, inhibit AChE activity and restore brain ACh content and improve memory functions in rat models of AD (Garabadu & Sharma, 2019; Liu, Niu, et al, 2013; Liu, Wang, et al, 2013).…”

Conjugation, Prodrug, and Co-Administration Strategies in Support of Nanotechnologies to Improve the Therapeutic Efficacy of Phytochemicals in the Central Nervous System

“…Polyphenols, or the main components of essential oil, often appear able to permeate the brain from the bloodstream and are promising agents against neurodegenerative diseases. On the other hand, their fast elimination from the body compromises their use as therapeutic agents [ 12 , 13 , 20 , 21 , 22 , 23 , 24 ]. Co-administration forms and the development of prodrugs designed as conjugates with biocompatible molecules appear promising methods to obtain innovative nanocarriers that are able to cross the BBB and to deliver phytochemicals to the brain, thus strengthening their therapeutic effects.…”

“…The antioxidant and anti-inflammatory properties of polyphenols, one of the major categories of phytochemicals, contribute to these compound beneficial effects by modulating the activation of cytokines and regulating the gene expression of pro-inflammatory molecules [ 1 ]. Essential oils are other phytochemicals characterised by antioxidant and anti-inflammatory properties [ 8 ], and are potentially beneficial at both peripheral [ 9 , 10 ] and central levels [ 11 , 12 , 13 , 14 ].…”

“…These aspects may limit the use of phytochemicals as potential drugs for acute or long-term therapies against both peripheral and central diseases. Concerning brain diseases, it is known that several phytochemicals can penetrate the CNS from the bloodstream [ 13 , 21 , 22 ], but their permanence in the brain appears low and poorly adequate for therapeutic proposals [ 23 , 24 ]. Consequently, remarkably high doses of these compounds are generally necessary to induce neuroprotective effects [ 12 ].…”

Essential Oil Molecules Can Break the Loop of Oxidative Stress in Neurodegenerative Diseases

“…Our research group recently found that eugenol administered orally or intravenously to rats is able to efficiently cross the blood-brain barrier. Moreover, in differentiated PC12 cells, an in vitro model that mimics PD because these cells synthesize and store catecholamines and dopamine, eugenol treatment increased cell survival and enhanced dopamine secretion [49]. Eugenol was also tested in a mouse model of PD based on the i.p.…”