Alessandra Tiziana Peana

Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils

Linalool and linalyl acetate are the principal components of many essential oils known to possess several biological activities, attributable to these monoterpene compounds. In this work, we evaluated individually the anti-inflammatory properties of (-) linalool, that is, the natural occurring enantiomer, and its racemate form, present in various amounts in distilled or extracted essential oils. Because in the linalool-containing essential oils, linalyl acetate, is frequently present, we also examined the anti-inflammatory action of this monoterpene ester. Carrageenin-induced edema in rats was used as a model of inflammation. The experimental data indicate that both the pure enantiomer and its racemate induced, after systemic administration, a reduction of edema. Moreover, the pure enantiomer, at a dose of 25 mg/kg, elicited a delayed and more prolonged effect, while the racemate form induced a significant reduction of the edema only one hour after carrageenin administration. At higher doses, no differences were observed between the (-) enantiomer and the racemate; a further increase in the dose of both forms did not result in an increased effect at any time of observation. The effects of equi-molar doses of linalyl acetate on local edema were less relevant and more delayed than that of the corresponding alcohol. These finding suggest a typical pro-drug behavior of linalyl acetate. The results obtained indicate that linalool and the corresponding acetate play a major role in the anti-inflammatory activity displayed by the essential oils containing them, and provide further evidence suggesting that linalool and linalyl acetate-producing species are potentially anti-inflammatory agents.

Linalool produces antinociception in two experimental models of pain

Linalool is a monoterpene compound commonly found as a major component of the essential oils of several aromatic plant species, many of which are used in traditional medical systems as analgesic and anti-inflammatory remedies. We previously reported that (-)-linalool, the natural occurring enantiomer, plays a major role in the anti-inflammatory activity displayed by different essential oils, suggesting that linalool-producing species are potentially anti-inflammatory agents. In this study, the antinociceptive activity of (-)-linalool was examined in two different pain models in mice: the acetic acid-induced writhing response, a model of inflammatory pain, and the hot plate test, a model of supraspinal analgesia. Moreover, the effect of (-)-linalool on spontaneous locomotor activity (25, 50, 75 and 100 mg/kg) was evaluated. The results show that this compound induced a significant reduction of the acid-induced writhing at doses ranging from 25 to 75 mg/kg. Such effect was completely reversed both by the opioid receptor antagonist naloxone and by the unselective muscarinic receptor antagonist atropine. In the hot plate test, only the dose of 100 mg/kg of (-)-linalool resulted in a significant effect. (-)-Linalool induced a dose dependent increase of motility effects, thus ruling out the confounding influence of a possible sedative effect. The more pronounced effect of (-)-linalool on the writhing test with respect to the hot plate test is consistent with the observation that (-)-linalool possesses anti-inflammatory activity. Finally, the activation of opioidergic and cholinergic systems appears to play a crucial role in (-)-linalool-induced antinociception.

Exploratory behaviour and grooming after repeated restraint and chronic mild stress: effect of desipramine.

In a previous study, we have recently shown that chronic treatment with desipramine either reduced or potentiated the locomotor response to the dopamine D(2)-like receptor agonist quinpirole, a behavioural response mediated by the mesolimbic dopamine system, depending on whether the animals were subjected, respectively, to repeated restraint or to chronic mild stress (different stressors randomly presented). In this study, we examined the interaction between prolonged exposure to either repeated restraint stress or chronic mild stress with the chronic administration of the antidepressant desipramine on two spontaneous behaviours, in which an involvement of the mesolimbic dopamine system has been suggested: novelty-induced exploratory activity and grooming. Exploratory activity in the open field was reduced by chronic mild stress regardless of the drug treatment, while it was not influenced by restraint stress. Desipramine reduced exploratory activity in rats subjected to restraint stress. Restraint stress increased grooming and desipramine reversed this effect, while increasing grooming in the chronic mild stress group. These findings suggest that antidepressants exert their effect by opposing the modifications induced by stress. The available experimental evidence is consistent with the hypothesis that an important role in the observed behavioural changes is played by the mesolimbic dopamine system.

Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system

Ethanol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered to be responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. However, acetaldehyde (ACD), the first metabolite of EtOH, has been classically considered to be aversive and useful in the pharmacological therapy of alcoholics. Here we show that EtOH‐derived ACD is necessary for EtOH‐induced place preference, a pre‐clinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH‐increased microdialysate dopamine (DA) levels in the rat nucleus accumbens and that this effect is mimicked by intra‐ventral tegmental area (VTA) ACD administration. Furthermore, in vitro, ACD enhances VTA DA neuronal firing through action on two ionic currents: reduction of the A‐type K+ current and activation of the hyperpolarization‐activated inward current. EtOH‐stimulating properties on DA neurons are prevented by pharmacological blockade of local catalase, the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in‐vivo and in‐vitro evidence for a key role of ACD in the motivational properties of EtOH and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well‐known peripherally originating aversive properties. Careful consideration of these findings could help in devising new effective pharmacological therapies aimed at reducing EtOH intake in alcoholics.

Piecing together the puzzle of acetaldehyde as a neuroactive agent.

Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehydes psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanols central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol.

Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission.

Acetaldehyde (ACD) has been postulated to mediate some of the neurobehavioral effects of ethanol (EtOH). In this study we sought to evaluate whether the stimulatory effects of EtOH on mesolimbic dopamine (DA) transmission are affected by the administration of ACD-sequestering agent D-penicillamine (Dp). To this end we studied the effect of EtOH and ACD in the rat mesoaccumbens pathway by in vivo microdialysis in the nucleus accumbens shell (NAccs), and by single cell extracellular recordings from antidromically identified mesoaccumbens DA neurons in the ventral tegmental area (VTA). Both EtOH (1g/kg) and ACD (20mg/kg) administration increased DA levels in the NAccs and increased the activity of mesoaccumbens DA neurons. Pretreatment with Dp (50mg/kg i.p. 1h before drug challenge) prevented both EtOH- and ACD-induced stimulation of the DA mesolimbic system without affecting morphine stimulatory actions. These observations add further support to the notion that EtOH-derived ACD stimulates the mesolimbic DA system and is essential in EtOH-induced stimulation of the DA mesoaccumbens system. We conclude that modulation of ACD bioavailability may influence the addictive profile of EtOH by decreasing its psychotropic effects and possibly leading the way to new pharmacological treatments of alcoholism.

Ethanol-induced extracellular signal regulated kinase: role of dopamine D1 receptors.

BACKGROUND Addictive drugs activate extracellular signal regulated kinase (ERK) in brain regions critically involved in their affective and motivational properties. The aim of this study was to demonstrate the ethanol-induced activation of ERK in the nucleus accumbens (Acb) and in the extended amygdala [bed nucleus of the stria terminalis lateralis (BSTL) and central nucleus of the amygdala (CeA)] and to highlight the role of dopamine (DA) D(1) receptors in these effects. METHODS Ethanol (0.5, 1, and 2 g/kg) was administered by gavage and ERK phosphorylation was determined in the nucleus Acb (shell and core), BSTL, and CeA by immunohistochemistry. The DA D(1) receptor antagonist, SCH 39166 (SCH) (50 microg/kg), was administered 10 minutes before ethanol (1 g/kg). RESULTS Quantitative microscopic examination showed that ethanol, dose-dependently increased phospho-ERK immunoreactivity (optical and neuronal densities) in the shell and core of nucleus Acb, BSTL, and CeA. Pretreatment with SCH fully prevented the increases elicited by ethanol (1 g/kg) in all brain regions studied. CONCLUSIONS The results of this study indicate that ethanol, similar to other addictive drugs, activates ERK in nucleus Acb and extended amygdala via a DA D(1) receptor-mediated mechanism. Overall, these results suggest that the D(1) receptors/ERK pathway may play a critical role in the motivational properties of ethanol.

Crucial role of acetaldehyde in alcohol activation of the mesolimbic dopamine system.

Ethyl alcohol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. On the other hand, acetaldehyde (ACD), EtOHs first metabolite, has been classically considered aversive and useful in the pharmacologic therapy of alcoholics. Here we show that EtOH‐derived ACD is necessary for EtOH‐induced place preference, a preclinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH‐increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by ACD administration to the intraventral tegmental area (VTA). Furthermore, in vitro, ACD enhances VTA DA neuronal firing. Coherently, EtOH‐stimulating properties on DA neurons are prevented by pharmacologic blockade of local catalase: the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in vivo and in vitro evidence for a key role of ACD in EtOH motivational properties and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well‐known peripherally originating aversive properties. These findings could help in devising new effective pharmacologic therapies in alcoholism.

A Study on Anti-Inflammatory and Peripheral Analgesic Action of Salvia sclarea Oil and Its Main Components

Abstract Activity against the acute inflammatory process induced by carrageenin and histamine in rats and the anti-nociceptive effect in mice were investigated after administration of Salvia sclarea oil and some of its constituents. The oil showed a significant anti-inflammatory effect and moderate analgesic action after subcutaneous injection at a dose of 250 mg/kg. The anti-inflammatory action was more conspicuous in the carrageenin-induced edema, where it produced the equivalent effect of a 5 mg/kg dose of indomethacin, than in the histamine-induced edema. The effect was correlated to the presence of methyl chavicol, linalool, α-terpineol and linalyl acetate. The results show that these constituents produce less anti-inflammatory action when administered separately than the oil in toto, and are also less effective than the oxygenated fractions obtained by Flash chromatography of the oil. This indicates that the action of the oil is determined by synergistic action of its constituents. The moderate peri...

Acetaldehyde-Reinforcing Effects: A Study on Oral Self-Administration Behavior

Acetaldehyde (ACD) is the first metabolite of ethanol. Although, the role of ACD in ethanol addiction has been controversial, there are data showing a relationship. The objective of the current study was to further test the hypothesis that ACD itself is reinforcing. For this reason, we carried out a study on operant oral ACD self-administration. Wistar rats were trained to self-administer tap water or ACD by nose-poking in daily 30 min sessions for 15 consecutive days. Response on active nose-poke caused delivery of ACD solution or tap water, whereas responses on inactive nose-poke had no consequences. The results show that ACD maintains oral self-administration behavior and rates of active nose-pokes significantly higher than tap water. The dose–response plot for oral ACD self-administration is a “bell-shaped” curve suggesting reinforcing properties only in a limited range of doses. Furthermore, rats self-administering ACD show a deprivation effect upon ACD removal and gradually reinstated active nose-poke response when ACD was reintroduced. Overall, this study shows that ACD is orally self-administered and further supports the hypothesis that ACD possesses reinforcing properties, which suggests that some of the pharmacological effects attributed to ethanol may result from its biotransformation into ACD, thereby supporting an active involvement of ACD in ethanol addiction.