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Biomedical subjects

E Fedele

Publications and source records attributed to E Fedele.

At least 19 recordsLinked to original sources
PubMed2006

Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations.

OBJECTIVE: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. RESULTS: Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged "on-time" duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. CONCLUSIONS: These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.

Aged↗
PubMed2006

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Aged↗
PubMed2004

Temporal administration of entacapone with slow release L-dopa: pharmacokinetic profile and clinical outcome.

Entacapone is a specific, peripherally acting catechol- O-methyltransferase (COMT) inhibitor that prevents peripheral degradation of L-dopa, thus improving its bioavailability. Entacapone is known to have pharmacokinetics similar to standard L-dopa but not to that of controlled-release (CR) L-dopa. The aim was to determine whether delayed entacapone administration may prolong CR L-dopa half-life in comparison to the co-administration modality. We compared plasma L-dopa concentrations after co-administration of CR L-dopa and entacapone or after administration of CR and a delayed (30 and 90 minutes) entacapone dose in 10 parkinsonian patients. The area under the concentration-time curve and other pharmacokinetic parameters were not changed by the delayed administration of entacapone. Different temporal modalities of entacapone administration had similar effects on CR L-dopa pharmacokinetics and on L-dopa-induced clinical improvement.

Aged↗
PubMed2004

Delayed administration may improve entacapone effects in parkinsonian patients non-responding to the drug.

BACKGROUND: Entacapone is a COMT inhibitor used in Parkinson's disease (PD) patients, as an adjunctive therapy to L-dopa in order to prolong its bioavailability and thus its clinical effect. However, previous studies reported entacapone-induced L-dopa to have lower C(max) and delayed t(max) values, coupled with a delayed onset of the clinical effect, possibly suggesting an interference between the two drugs. The aim of our study was to evaluate whether a delayed entacapone administration in association with standard L-dopa/carbidopa, may in some subjects improve the entacapone effects on L-dopa AUC and thus on the clinical 'on time' duration. METHODS: Twenty-eight idiopathic advanced PD patients were blindly evaluated in three different test days, following administration of carbidopa/L-dopa or carbidopa/L-dopa plus co-administered entacapone or plus entacapone administered with 30 min of delay. RESULTS: The AUC, the 'on time' and UPDRS score of the whole group were improved by both modalities of entacapone administration. An ex post analysis showed that the delayed entacapone administration produced a significant improvement in a subgroup of 10 non-responding patients to the co-administration. CONCLUSION: We suggest that the delayed administration should be attempted in the subjects not improved by entacapone co-administration.

Aged↗
PubMed2002

In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms.

Cyclooxygenases (COX) are a family of enzymes involved in the biosynthesis of prostaglandin (PG) and thromboxanes. The inducible enzyme cyclooxygenase-2 (COX-2) is the major isoform found in normal brain, where it is constitutively expressed in neurons and is further up-regulated during several pathological events, including seizures and ischaemia. Emerging evidence suggests that COX-2 is implicated in excitotoxic neurodegenerative phenomena. It remains unclear whether PGs or other products associated to COX activity take part in these processes. Indeed, it has been suggested that reactive oxygen species, produced by COX, could mediate neuronal damage. In order to obtain direct evidence of free radical production during COX activity, we undertook an in vivo microdialysis study to monitor the levels of PGE(2) and 8-epi-PGF(2alpha) following infusion of N-methyl-D-aspartate (NMDA). A 20-min application of 1 mm NMDA caused an immediate, MK-801-sensitive increase of both PGE(2) and 8-epi-PGF(2alpha) basal levels. These effects were largely prevented by the specific cytosolic phospholipase A(2) (cPLA(2) ) inhibitor arachidonyl trifluoromethyl ketone (ATK), by non- selective COX inhibitors indomethacin and flurbiprofen or by the COX-2 selective inhibitor NS-398, suggesting that the NMDA-evoked prostaglandin synthesis and free radical-mediated lipid peroxidation are largely dependent on COX-2 activity. As several lines of evidence suggest that prostaglandins may be potentially neuroprotective, our findings support the hypothesis that free radicals, rather than prostaglandins, mediate the toxicity associated to COX-2 activity.

Animals↗
PubMed2001

Microdialysis in Parkinsonian patient basal ganglia: acute apomorphine-induced clinical and electrophysiological effects not paralleled by changes in the release of neuroactive amino acids.

During stereotaxic neurosurgery for deep brain stimulation in Parkinson's disease (PD), we performed a microdialysis study of the extracellular amino acid (aspartate, glutamate, glycine, and GABA) concentrations. Their levels were measured in the GPe/GPi of five and in the STN of four different PD patients, after prolonged therapy washout. The results show stable values of basal release of the examined amino acids within 1 h. The basal levels of GABA in "OFF" state were significantly higher in the GPi than in the GPe. Acute apomorphine administration, while inducing clinical amelioration and electrophysiological changes in the examined nuclei, did not change amino acid concentrations. This result could be related to a limited microdialysis ability to detect subtle changes in amino acid spontaneous release. Alternatively, it could suggest that dopaminergic receptors located in the output nuclei, possibly present also in humans, might mediate the acute apomorphine clinical effects, not involving amino acid changes along the direct and/or indirect pathway.

Action Potentials↗
PubMed2001

Reduced L-dopa absorption and increased clinical fluctuations in Helicobacter pylori-infected Parkinson's disease patients.

We report that the area under the curve of L-dopa plasma concentration, following the administration of a single 250 mg L-dopa dose, is augmented after Helicobacter pylori (HP) eradication in six Parkinson's disease (PD) patients showing high IgG antibody titer against HP. A prolongation of L-dopa clinical benefit was also observed. We suggest that HP infection-activated gastric alterations may be responsible, at least in part, for the reported erratic efficacy of oral L-dopa therapy in some advanced PD patients. Given the high percentage of HP-positivity in the age cohorts including the largest prevalence of PD patients, we propose that HP eradication be recommended in all PD patients under L-dopa therapy.

Aged↗
PubMed2001

In vivo NO/cGMP signalling in the hippocampus.

In the hippocampus of freely-moving rats, basal extracellular levels of cGMP are inhibited by L-NARG or ODQ whereas they are increased by NO donors or phosphodiesterase inhibitors. Activation of NMDA receptors also augments cGMP dialysate levels in a MK-801 and L-NARG sensitive manner, an effect dramatically diminished during ageing. Experiments with AMPA, AMPA receptor antagonists and cyclothiazide revealed complex relationships with GABAergic circuits that potently control the NO/cGMP pathway. Furthermore, the activity of this neurochemical cascade is also modulated by hippocampal nicotinic receptors via enhancement of endogenous glutamate release and stimulation of NMDA receptors. From a behavioural point of view, increased hippocampal excitation leads to the appearance of epileptic-like manifestations that, however, seem unrelated to the increase of NO/cGMP formation.

Aging↗
PubMed2001

Evidence of a role for cyclic ADP-ribose in calcium signalling and neurotransmitter release in cultured astrocytes.

Astrocytes possess different, efficient ways to generate complex changes in intracellular calcium concentrations, which allow them to communicate with each other and to interact with adjacent neuronal cells. Here we show that cultured hippocampal astrocytes coexpress the ectoenzyme CD38, directly involved in the metabolism of the calcium mobilizer cyclic ADP-ribose, and the NAD+ transporter connexin 43. We also demonstrate that hippocampal astrocytes can release NAD+ and respond to extracellular NAD+ or cyclic ADP-ribose with intracellular calcium increases, suggesting the existence of an autocrine cyclic ADP-ribose-mediated signalling. Cyclic ADP-ribose-induced calcium changes are in turn responsible for an increased glutamate and GABA release, this effect being completely inhibited by the cyclic ADP-ribose specific antagonist 8-NH2-cADPR. Furthermore, addition of NAD+ to astrocyte-neuron co-cultures results in a delayed intracellular calcium transient in neuronal cells, which is strongly but not completely inhibited by glutamate receptor blockers. These data indicate that an astrocyte-to-neuron calcium signalling can be triggered by the CD38/cADPR system, which, through the activation of intracellular calcium responses in astrocytes, is in turn responsible for the increased release of neuromodulators from glial cells.

ADP-ribosyl Cyclase↗
PubMed2000

Benzodiazepine-sensitive GABA(A) receptors limit the activity of the NMDA/NO/cyclic GMP pathway: a microdialysis study in the cerebellum of freely moving rats.

In the cerebellum, infusion of NMDA (200 microM) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABA(A) receptor agonist muscimol (0.01-100 microM) was able to counteract the NMDA effect with an EC(50) of 0.65 microM; the inhibitory effect of muscimol (10 microM) was prevented by bicuculline (50 microM). Diazepam (10 microM) significantly potentiated the muscimol (1 microM) inhibition; furthermore, when coinfused with 0.1 microM muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 microM) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 microM). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 microM), together with muscimol and diazepam, almost completely restored the effect of NMDA on extracellular cGMP levels. It is concluded that GABA(A) receptors potently control the NMDA/nitric oxide/cGMP pathway in the cerebellum in vivo. In terms of the alpha subunit composition, we can deduce that the cerebellar GABA(A) receptor does not contain alpha(6) or beta(4) subunits because it is diazepam-sensitive. Moreover, the observation that zolpidem is active at a rather low concentration, in combination with localization studies present in the literature, tend to exclude the presence of alpha(5) subunits in the receptor composition and suggest the involvement of an alpha(1) subunit.

Animals↗
PubMed1999

Intracerebral administration of L-kynurenine decreases N-methyl-D-aspartate receptor-mediated production of cGMP in the cerebellum and hippocampus of unanaesthetized rats subjected to transcerebral microdialysis.

The effects of intracerebral administration of L-kynurenine (L-KYN) on the N-methyl-D-aspartate (NMDA) receptor-mediated, nitric oxide (NO)-dependent cGMP responses have been studied in vivo in the cerebellum and hippocampus of freely-moving rats subjected to transcerebral microdialysis. Administration of exogenous NMDA in the cerebellum through the dialysis probe evoked a 3-fold increase of basal extracellular levels of cGMP that was concentration-dependently reduced by co-infusion of L-KYN. In the hippocampus, local administration of cyclothiazide caused a significant enhancement of the cyclic nucleotide dialysate concentrations that was accompanied by behavioural manifestations characteristic of preconvulsive states. Co-infusion of L-KYN largely decreased the neurochemical effects of cyclothiazide and completely prevented the appearance of the behavioural episodes. It is concluded that administration of L-KYN by increasing endogenous kynurenic acid concentrations might exert neuroprotective and anticonvulsive effects through blockade of the NMDA receptor/NO/cGMP pathway.

Animals↗
PubMed1999

In vivo studies of the cerebral glutamate receptor/NO/cGMP pathway.

Overwhelming evidence indicates that the glutamate/nitric oxide (NO) synthase/soluble guanylyl cyclase system is of primary importance in a variety of physiological and pathological processes of the brain. Most of our knowledge on this neurochemical pathway derives from in vitro and ex vivo studies but the recent improvement of microdialysis techniques combined with extremely sensitive measurements of the amplified end-product cyclic GMP (cGMP) has given new impulses to the investigation of this cascade of events, its modulation by neurotransmitters and its functional relevance, in a living brain. The first reports, appeared in the early 90's, have demonstrated that microdialysis monitoring of cGMP in the extracellular environment of the cerebellum and hippocampus exactly reflects what is expected to occur at the intracellular level; thus, in vivo extracellular cGMP is sensitive to NO-synthase and soluble guanylyl cyclase inhibitors, can be increased by NO-donors or phosphodiesterase blockers and is modulated by glutamate receptor stimulation in a NO-dependent fashion. Since then, other microdialysis studies have been reported showing that the brain NO synthase/guanylyl cyclase pathway is mainly controlled by NMDA, AMPA and metabotropic glutamate receptors but can be also influenced by other transmitters (GABA, acetylcholine, neuropeptides) through polysynaptic circuits interacting with the glutamatergic system. The available data indicate that this technique, applied to freely-moving animals and combined with behavioural tests, could be useful to get a better insight into the functional roles played by NO and cGMP in physiological and pathological situations such as learning, memory formation, epilepsy, cerebral ischemia and neurodegenerative diseases.

Animals↗
PubMed1999

Native human neocortex release-regulating dopamine D2 type autoreceptors are dopamine D2 subtype.

Dopamine (DA) autoreceptors expressed at DA nerve terminals regulate DA release. Considerable evidence has indicated that, in rodents, these autoreceptors belong to the D2 type of the DA receptor family, which, in turn, comprises the D2, D3 and D4 subtypes. We investigated here, for the first time, the subclassification of native human DA autoreceptors by studying the release of [3H]DA evoked by electrical stimulation in fresh human neocortical slices. The results have been compared with those obtained in three animal systems: rat neocortical and striatal slices and rat mesencephalic neuronal cultures. In human neocortical slices, the D2/D3 receptor agonist quinpirole (1 nM-10 microM) inhibited tritium release with a calculated EC50 of 17 nM and a maximal inhibition of approximately 75% reached at 1 microM. In the presence of the D2/D3 receptor antagonist (-)-sulpiride (0.1 and 1 microM), the concentration-response curve of quinpirole was shifted to the right, and the apparent pA2 mean value was 8.5 (8.14-8.77); on the other hand, the inhibitory effects of quinpirole were not affected by the D3 receptor-selective antagonist [7-N,N-dipropylamino-5,6,7, 8-tetrahydro-naphtho(2,3b) dihydro,2,3-furane] (S 14297) and the D4 receptor-selective antagonist 3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo [2,3-b]pyridine (L-745,870) (0.01-1 microM in each case). Superimposable results have been obtained when the release was elicited from rat striatal slices or dopamine mesencephalic neurons in culture, whereas quantitative differences emerged in the case of rat cortical slices. It is concluded that in human brain, as well as in rat brain, the release of DA in the terminal region of midbrain dopaminergic neurons is regulated through autoreceptors of the D2 subtype.

Adult↗
PubMed1998

Nicotine administration stimulates the in vivo N-methyl-D-aspartate receptor/nitric oxide/cyclic GMP pathway in rat hippocampus through glutamate release.

1. The in vivo effects of nicotine on the nitric oxide (NO) synthase/cyclic GMP pathway of the adult rat hippocampus have been investigated by monitoring the levels of extracellular cyclic GMP during microdialysis in conscious unrestrained animals. 2. Intraperitoneal (i.p.) administration of nicotine caused elevation of cyclic GMP levels which was prevented by mecamylamine. The effect of nicotine was abolished by local infusion of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG) or by the soluble guanylyl cyclase blocker 1H-[1,2,4]oxadiazolo[4.3-a]quinoxaline-1-one (ODQ). 3. Local administration of the NMDA receptor antagonists cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS19755) and dizocilpine (MK-801) inhibited by about 60% the nicotine-induced elevation of cyclic GMP. Nicotine was able to stimulate cyclic GMP outflow also when administered directly into the hippocampus; the effect was sensitive to mecamylamine, L-NOARG, ODQ or MK-801. 4. Nicotine, either administered i.p. or infused locally, produced augmentation of glutamate and aspartate extracellular levels, whereas the outflows of gamma-aminobutyric acid (GABA) and glycine remained unaffected. Following local administration of high concentrations of nicotine, animals displayed symptoms of mild excitation (sniffing, increased motor and exploratory activity) during the first 20-40 min of infusion, followed by wet dog shake episodes; these behavioural effects were prevented by mecamylamine or MK-801, but not by L-NOARG or by ODQ. 5. It is concluded that (a) nicotine stimulates the production of NO and cyclic GMP in the hippocampus; (b) this occurs, at least in part, through release of glutamate/aspartate and activation of NMDA receptors. Modulation of the NMDA receptor/NO synthase/cyclic GMP pathway may be involved in the cognitive activities of nicotine.

Amino Acids↗
PubMed1997

D-serine modulates the NMDA receptor/nitric oxide/cGMP pathway in the rat cerebellum during in vivo microdialysis.

Several lines of investigation indicate that D-serine may be an endogenous ligand for the glycine site of N-methyl-D-aspartate (NMDA) receptors in some CNS regions. We here studied the in vivo effects of D-serine on the NMDA receptor/nitric oxide/cGMP pathway by monitoring extracellular cGMP in the cerebellum of freely-moving rats subjected to transcerebral microdialysis. Local application of NMDA (200, 500 microM) through the dialysis probe for 20 min evoked transient, concentration-dependent cGMP responses which peaked in the fraction of drug administration, the nucleotide levels returning to basal values after 40 min. The NMDA-induced elevation of the extracellular nucleotide was completely inhibited by the selective receptor channel blocker dizocilpine (MK-801) locally co-perfused at the concentration of 10 microM. The non-competitive antagonist had no effect on its own suggesting that endogenous glutamic acid does not tonically activate NMDA receptors. The effect of 200 microM NMDA was largely attenuated by 30 microM 7-chloro-kynurenic acid and completely abrogated when the concentration of the strychnine-insensitive glycine receptor antagonist was raised to 100 microM. D-serine (300 microM), perfused in the presence of 7-chloro-kynurenate (30 microM), was able to fully restore the NMDA (200 microM)-induced increase of cGMP extracellular levels. On the other hand, the D-amino acid directly potentiated in a concentration-dependent manner (0.3, 1 and 10 mM) the NMDA (200 microM)-evoked cGMP production whereas it was inactive on its own. These data show that in vivo the activation of the strychnine-insensitive glycine site is essential for the functioning of the NMDA receptor complex and can be activated by the selective agonist D-serine. They also confirm that cerebellar NMDA receptors do not have their glycine sites saturated.

Animals↗
PubMed1997

The glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats: modulation by cyclothiazide, interaction with GABA and the behavioural consequences.

Monitoring of extracellular cGMP during intracerebral microdialysis in freely moving rats permits the study of the functional changes occurring in the glutamate receptor/nitric oxide (NO) synthase/guanylyl cyclase pathway and the relationship of these changes to animal behaviour. When infused into the rat hippocampus in Mg2+-free medium, cyclothiazide, a blocker of desensitization of the AMPA-preferring receptor, increased cGMP levels. The effect of cyclothiazide (300 microM) was abolished by the NO synthase inhibitor L-NARG (100 microM) or the soluble guanylyl cyclase inhibitor ODQ (100 microM). During cyclothiazide infusion the animals displayed a pre-convulsive behaviour characterized by frequent "wet dog shakes" (WDS). Neither L-NARG nor ODQ decreased the WDS episodes. Both cGMP and WDS responses elicited by cyclothiazide were prevented by blocking NMDA receptor function with the glutamate site antagonist CGS 19755 (100 microM), the channel antagonist MK-801 (30 microM) or Mg2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 microM) and NBQX (100 microM) abolished the WDS episodes but could not inhibit the cyclothiazide-evoked cGMP response. DNQX or NBQX (but not MK-801) elevated, on their own, extracellular cGMP levels. The cGMP response elicited by the antagonists appears to be due to prevention of a glutamate-dependent inhibitory GABAergic tone, since infusion of bicuculline (50 microM) caused a strong cGMP response. The results suggest that (a) AMPA/kainate receptors linked to the NO/cGMP pathway in the hippocampus (but not NMDA receptors) are tonically activated and kept in a desensitized state by endogenous glutamate; (b) blockade of AMPA/kainate receptor desensitization by cyclothiazide leads to endogenous activation of NMDA receptors; (c) the hippocampal NO/cGMP system is under a GABAergic inhibitory tone driven by non-NMDA ionotropic receptors; (d) the pre-convulsive episodes observed depend on hippocampal NMDA receptor activation but not on NO and cGMP production.

Animals↗
PubMed1997

In vivo microdialysis study of GABA(A) and GABA(B) receptors modulating the glutamate receptor/NO/cyclic GMP pathway in the rat hippocampus.

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.

Animals↗