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.
THE ability of modafinil (Modiodal®) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77 ± 0.14; St2/St1 ratio = 0.94 ± 0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40 ± 0.05; St2/St1 ratio = 0.60 ± 0.08). Modafinil (0.3–1 μM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85 ± 0.11; 0.88 ± 0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons
1. The effect of nicotine on endogenous basal GABA outflow was studied in guinea-pig cerebral cortex slices. 2. Nicotine 1.86-18.6 mumol l-1 significantly decreased the basal, tetrodotoxin-sensitive GABA efflux, whereas at higher concentrations (186-620 mumol l-1) nicotine increased it. The inhibition was prevented by mecamylamine while the facilitation was blocked by mecamylamine, (+)-tubocurarine and tetrodotoxin. 3. The effect of nicotine was due to an indirect 5-hydroxytryptaminergic action. In fact, MDL 72222 (1 mumol l-1) completely prevented the alkaloid inhibition and methysergide (1 mumol l-1) reversed the facilitation into inhibition; concomitant treatment with methysergide and MDL 72222 antagonized the effect of nicotine at 186 mumol l-1 4. Lower concentrations of 5-HT (3-10 mumol l-1) decreased, whereas higher concentrations (30-100 mumol l-1) increased, spontaneous GABA outflow. The inhibition of GABA efflux was prevented by MDL 72222 whereas the facilitation was reversed by methysergide (1 mumol l-1) into inhibition, and prevented by MDL 72222 1 mumol l-11. 5. These results suggest that, by activating nicotinic receptors present on 5-hydroxytryptaminergic terminals, nicotine releases 5-HT which, in turn, inhibits or increases the secretory activity of cortical GABA interneurones via 5-HT3 and methysergide-sensitive receptors, respectively.
Abstract In the present dual‐probe microdialysis study the effects of intrastriatal perfusion with the tridecapeptide neurotensin(1–13) [NT(1–13)] and its active fragment NT(8–13) on striatopallidal GABA and striatal dopamine release were investigated. The modulatory action of NT(1–13) on D 2 receptor‐mediated inhibition of striatal and pallidal GABA release was also studied. Both intrastriatal NT(1–13) (100 nM) and NT(8–13) (100 nM) increased striatal (139 and 149% respectively) and pallidal (130 and 164%) GABA release, and this effect was antagonized by intrastriatal perfusion with the neurotensin receptor antagonist SR48692 (100 nM). A similar increase (155%) in striatal dopamine release was observed following intrastriatal NT(1–13) (100 nM), but not NT(8–13) (100 and 500 nM). However, at the highest concentration studied (1 μM) NT(8–13) was associated with a rapid increase (130%) in striatal dopamine release. In a second study intrastriatal NT(1–13) (10 nM) counteracted the inhibition of striatal and pallidal GABA release induced by pergolide (500 and 1500 nM). The inhibitory action of the D 2 agonist was restored when SR48692 (100 nM) was added to the perfusion medium. These results suggest that in the neostriatum the neurotensin receptor located postsynaptically on the striatopallidal GABA neurons seems to differ from the neurotensin receptor located on dopaminergic terminals, as indicated by the relative lack of effect of NT(8–13) on striatal dopamine release. Furthermore, the ability of NT(1–13) to counteract the pergolide‐induced inhibition of both striatal and pallidal GABA release strengthens the evidence for antagonistic receptor‐receptor interaction between postsynaptic striatal neurotensin and D 2 receptors located on striatopallidal GABA neurons.
