Neuromelanin in Parkinson's Disease: from Fenton Reaction to Calcium Signaling.

Neuromelanin is supposed to play a key role in the pathogenesis of Parkinson's disease. A common theory is the formation of reactive oxygen species through the Fenton reaction catalyzed by neuromelanin-bound iron ions and subsequent death of the dopaminergic cells in the substantia nigra. From a physicochemical point of view, this pathway is rather implausible: a highly reactive radical built within a powerful radical scavenger would more promptly be inactivated before it might diffuse within the cell to reach a target to exert its deleterious potential. This review of the literature provides evidence for an interaction of neuromelanin with the calcium signaling pathway in Parkinson's disease and expands the view of the pathophysiological contribution of neuromelanin towards a cytoprotective involvement of this macromolecule in the calcium signaling system. More probably than being directly involved in the production of reactive oxygen species, neuromelanin may act as a calcium reservoir and thus protect dopaminergic cells from cell death. A loss of neuromelanin, as observed in the substantia nigra of Parkinson patients, would lead to enhanced calcium messaging through the loss of an important calcium reservoir and thus finally via the formation of reactive oxygen species to cell death within the substantia nigra.

Extracts of Sideritis scardica as triple monoamine reuptake inhibitors.

Sideritis species are traditionally used within the Mediterranean area as teas, flavouring agents or for therapeutical purposes. The aim of this study was to investigate the effects of Sideritis scardica extracts on the monoamine transporters and to derive and explain possible medicinal applications from the pharmacological profile of the extracts. We have studied the effect of various S. scardica extracts on serotonin, noradrenaline and dopamine uptake in rat brain synaptosomes and serotonin uptake in human JAR cells. All extracts inhibited the uptake of all three monoamines into rat brain synaptosomes by their respective transporters, the alcoholic extracts being more effective than the water extract. EC(50) values were in the range of 30-40 µg/ml. Inhibition of the human serotonin transporter by the methanol extract was even more effective (EC(50) 1.4 µg/ml). Combining Sideritis ethanol extract and fluvoxamine resulted in a leftward shift of the fluvoxamine concentration-response curve. The pharmacological profile of S. scardica extracts as triple monoamine reuptake inhibitors suggests their use in the phytochemical therapy of mental disorders associated with a malfunctioning monoaminergic neurotransmission, such as anxiety disorders, major depression, attention-deficit hyperactivity disorder, mental impairment or neurodegenerative diseases.

Pharmacological studies in an herbal drug combination of St. John's Wort (Hypericum perforatum) and passion flower (Passiflora incarnata): in vitro and in vivo evidence of synergy between Hypericum and Passiflora in antidepressant pharmacological models.

Extracts of Hypericum, Passiflora and Valeriana are used for the treatment of mild depression and anxiety. We were interested whether a combination of Hypericum and Passiflora exerts comparable effects to Hypericum alone. We used two well-established models for investigating extracts for their anti-depressant activity, namely the effects on synaptic uptake of serotonin and the forced-swimming-test. We show here for the first time, that Passiflora significantly enhances the pharmacological potency of Hypericum in both models. Our data suggest that anti-depressive therapeutic effects of Hypericum are possible with lower doses, when it is combined with Passiflora, than with mono-preparations of Hypericum.

Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine.

The fixed combination of aspirin, paracetamol (acetaminophen) and caffeine has been used successfully to treat different kinds of pain including migraine attacks. Even when this formulation has been marketed for a long time, the exact molecular mechanisms underlying its therapeutic effectiveness have not been completely elucidated. In the present investigation, we have studied the effects of the fixed combination of aspirin, paracetamol and caffeine (APC) on the release of dopamine and noradrenaline from rat striatal slices in an attempt to find potential new mechanisms of action of this widely used analgesic combination. We found that APC produced a significant reduction in extracellular dopamine and a dramatic increase in norepinephrine release from the slices incubated with different concentrations of APC (dose relationship 1:1:0.2, corresponding to the dose-relationship of Thomapyrin). These findings suggest that the modulation of catecholaminergic neurotransmission is a new pharmacological effect of APC which could explain the mechanism of action of this formulation, considering that the independent effect of either compound alone does not explain the potent antinociceptive properties when observed in combination.

Cognitive deficits in aged rats correlate with levels of L-arginine, not with nNOS expression or 3,4-DAP-evoked transmitter release in the frontoparietal cortex.

Aging is associated with altered neurotransmitter function in the brain. In this study, we measured release parameters for acetylcholine (ACh), norepinephrine and serotonin in the frontoparietal cortex of young and aged rats. We also determined cortical amino acid concentrations and nitric oxide (NO) synthase function. Prior to sacrifice, the rats had been tested for Morris water-maze performance. In aged, compared with young rats, we observed a reduction in both uptake of choline and acetylcholine release. Serotonin release and L-arginine concentrations (a precursor of NO) showed an aging-related increase; however, L-citrulline/L-arginine ratios were decreased in aged rats. Moreover, while most age-related changes in transmitter release or neurochemical markers were not related to the learning performance, L-arginine concentrations were positively correlated to cognitive deficits. NO synthase concentrations were not affected by aging. It is suggested that events related to L-arginine-to-L-citrulline/NO metabolism in the frontoparietal cortex may take part in age-related cognitive deficits.

Determination of gabapentin-lactam in serum of patients under gabapentin therapy.

Gabapentin (1-(aminomethyl)cyclohexane acetic acid, CAS 601 42-96-3, GBP, Neurontin) and its derivative gabapentin-lactam (8-aza-spiro[5,4]decan-9-one, GBP-L) were determined by HPLC in the serum of patients with focal epilepsy treated with GBP. In patients in whom serum was acquired within 3 h after oral intake, GBP-L could be detected at concentrations up to 8.2 micromol/l. As GBP-L has been previously shown to exert neuroprotective effects in a similar concentration range, this finding suggests that clinically relevant effects of GBP-L may occur in patients treated with GBP. The possible neuroprotective efficacy of GBP-L should be the subject of further preclinical and clinical investigations.

Quantitative measurement of depolarization-induced anandamide release in human and rat neocortex.

It has been suggested that the endocannabinoid anandamide is released from central neurons upon depolarization of the cell membrane. In order to determine whether anandamide levels were increased after K(+) depolarization of fresh human and rat brain slices, we developed a rapid and sensitive method for the isolation and quantitation of anandamide. This included solvent extraction, solid phase separation, and reversed phase high performance liquid chromatography (HPLC) with fluorometric detection. Compared with basal levels, K(+) stimulation enhanced the neocortical anandamide concentration in both species (70.5 vs. 21.1 pmol/g tissue in humans, 14.3 vs. 3.2 pmol/g tissue in rats). Basal anandamide levels in the rat hippocampus (11.1 pmol/g) were significantly higher than in the neocortex. Anandamide was also detected in the human amygdala (67.8 pmol/g). In conclusion, our data provide evidence for the depolarization-induced synthesis of anandamide, supporting the hypothesis of a neuromodulatory action of this endocannabinoid. Furthermore, the presence of anandamide in the limbic system suggests participation in cognition, behavior or reward.