Biomedical subjects

S Sagratella

Publications and source records attributed to S Sagratella.

At least 19 recordsLinked to original sources

PubMed1998

Characterization of the in vitro antiepileptic activity of new and old anticonvulsant drugs.

1. The in vitro antiepileptiform effects of some old and new anticonvulsants in the experimental model of the "epileptiform" hippocampal slice have been reviewed. 2. On the basis of their influence on in vitro epileptogenesis and basal neuronal excitability, anticonvulsants can be classified into three main categories: (1) anticonvulsants (prototypical drug phenytoin) affecting basal neuronal excitability but not epileptogenesis; (2) anticonvulsants (prototypical drugs barbiturates) affecting basal neuronal excitability and epileptogenesis; (3) anticonvulsants (prototypical drug felbamate) affecting epileptogenesis but not basal neuronal excitability. 3. It is concluded that the model of the "epileptiform" hippocampal slices can be considered a previsional test for the study and the screening of new anticonvulsant drugs.

Animals↗

PubMed1997

Glutamate metabotropic receptors modulate the expression of in vitro epileptiform activity in rat hippocampal slices.

The effects of the mixed class I and II mGLUR agonist (+) 1S,3R-trans-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) and antagonists (+) alpha-methyl-4-carboxyphenylglycine (MCPG) and L-2-amino-3-phosphonopropionic acid (L-AP3) on the basal neuronal excitability and on the expression of in vitro epileptiform activity produced by the convulsant drugs picrotoxin and penicillin were investigated in rat hippocampal slices. The duration of the CA1 epileptiform bursting produced by 0.05 mM picrotoxin or 1 mM penicillin or 0.075 mM ACPD was significantly (p<0.05) and dose-dependently decreased by 0.3-0.5 mM MCPG or L-AP3, but not by 0.05 mM ACPD. The data demonstrate an involvement of class I and II mGLURs in the basal neuronal excitability and in the expression of in vitro epileptiform activity produced by some convulsants.

Animals↗

PubMed1996

Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life.

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 micrograms/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml) at 10 days of lactation. A significant (P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30-45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through maternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209-215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data.

Animals↗

PubMed1996

Effects of felbamate, kynurenic acid derivatives and NMDA antagonists on in vitro kainate-induced epileptiform activity.

The effects of the novel anticonvulsant felbamate, which binds to the 5-7 dichlorokynurenic binding sites, were tested towards the CA1 epileptiform activity induced in rat hippocampal slices by kainic acid. The effects of the kynurenic acid derivatives 7-chlorokynurenic acid and 5-7 dichlorokynurenic acid and of the NMDA antagonists CGS 19755, MK-801 and ketamine were also studied for comparison. Slice perfusion with 1 microM kainic acid produced within 30 min the development of an evoked CA1 epileptiform bursting made up by an increase in amplitude of the primary population spikes followed by the appearance of secondary epileptiform population spikes. Slice perfusion with CGS 19755 (100 microM) or MK-801 (100 microM) or ketamine (100 microM) failed to affect within 30 min the CA1 epileptiform activity due to kainic acid. On the contrary, slice perfusion with felbamate (1.3-1.6 mM) or 7-chlorokynurenic acid (100 microM) or 5-7-dichlorokynurenic acid (100 microM) produced within 30 min a significative (p < 0.05) decrease of the kainate-induced epileptiform bursting duration. The results indicate that felbamate and kynurenic acid derivatives but not NMDA antagonists present an inhibitory effect against the epileptiform activity due to kainic acid.

Animals↗

PubMed1996

Selective opposite modulation of dentate granule cells excitability by mu and kappa opioids in rat hippocampal slices.

The effects of opioids having affinity for kappa (U50,488H and U54,494A) and mu receptors (DAMGO and methadone) were tested on the excitability of the dentate and CA1 neurons in rat hippocampal slices. Slice perfusion with 25 microM U50,488H or with 12 microM U54,494A produced within 60 min a significant (P < 0.05) decrease in the amplitude of the primary dentate population spike (PS). A similar decrease occurred on the CA1 PS amplitude only at concentrations higher than 100 microM of U50,488H or 50 microM of U54,494A. Slice perfusion with 0.5 microM DAMGO, or 100 microM methadone produced an increase in the amplitude of the primary dentate and CA1 PS and the appearance of secondary PSs. Slice perfusion with 12 microM U50,488H or with 25 microM of methadone significantly (P < 0.05) decreased or increased, respectively, the rate of appearance of the dentate posttetanic potentiation (PTP) and long-term potentiation (LTP) after a 100 Hz tetanic stimulation of the perforant path. The same concentration of U50,488H or methadone did not affect the rate of appearance of the CA1 PTP and LTP after a 100 Hz tetanic stimulation of the Schaffer collaterals. The data, providing evidence for a selective opposite modulation by mu and kappa opioids on the basal and stimulated dentate neuronal excitability, indicate the dentate area as a target within the hippocampus for an opposite influence between mu and kappa opioids on neuronal excitability.

Animals↗

PubMed1996

In vitro hippocampal dentate frequency potentiation induction as model to detect electrophysiological correlates of some cognitive impairments in striatally-lesioned rats.

1. Hippocampal frequency potentiation, a form of short-term potentiation of hippocampal electrical synaptic potentials that is related to mnemonic and learning processes, is typically damped in aged rats and in certain rat strains with impaired place learning performance. 2. In vitro induction of hippocampal dentate frequency potentiation has been found decreased in striatally-lesioned rats with impaired place learning performance in water maze test. 3. The results demonstrate that also in brain-lesioned rats the poor performances in place learning of the animals are associated with a selective dentate frequency potentiation impairment. Thus in vitro induction of dentate frequency potentiation might be regarded as a model to detect the electrophysiological counterpart of the cognitive impairment in rats with altered place learning.

Animals↗

PubMed1996

7-chlorokynurenic acid prevents in vitro epileptiform and neurotoxic effects due to kainic acid.

1. The effects of 7-chlorokynurenic acid were studied against the epileptiform and neurotoxic effects due to the non-NMDA excitatory amino acid, kainic acid, in rat hippocampal slices. 2. Slice perfusion with 7-chlorokynurenic acid (100 microM), significantly (p < 0.05) decreased the duration of the CA1 epileptiform bursting due to 1 microM kainic acid. 3. Slice perfusion with 7-chlorokynurenic acid (100 microM) significantly (p < 0.05) increased the probability of recovery of the CA1 population spike after a neurotoxic concentration (12 microM) of kainic acid. 4. The results indicate that 7-chlorokynurenic acid affects, with a similar potency, epileptiform and neurotoxic effects due to kainic acid.

Animals↗

PubMed1996

Glutamate-dependent mechanisms in the induction of a calcium long-term potentiation-like phenomenon.

The electric synaptic efficacy, in terms of extracellular electrical potentials, and the intracellular postsynaptic efficacy, in terms of inositol phosphate (IP) accumulation, were evaluated in rat hippocampal slices exposed for a brief period (10 min) to a high concentration of calcium (+2.7 mM). In addition, the effects of N-methyl-D-asparate (NMDA) ionotropic and metabotropic glutamate receptor (mGluR) antagonists on the induction and the establishment or maintenance of enhanced synaptic efficacy of CA1 pyramidal neurons due to high-calcium exposure were also tested. Elevation of the calcium concentration from 1.3-4 mM in the medium bathing hippocampal slices produced a long-lasting (80 over 90 min) increase in the slope of the CA1 somatic excitatory postsynaptic potential and the amplitude of the population spike (PS). Slice perfusion with NMDA antagonists cyclazocine and cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) or with mGluR antagonists L-2-amino-3-phosphonopropionic acid (AP3) or alpha-methyl-4-carboxyphenyl-glycine (all 0.1 mM), during the 10-min period of exposure to high-calcium prevented the induction of such changes. By contrast, slice perfusion with the same concentration of CGS 19755 or L-AP3 did not affect the already established long-lasting increase in amplitude of CA1 PS induced by high-calcium. Moreover, high-calcium failed to produce any significant modification of the basal IP accumulation or of the IP accumulation elicited by mGluR agonist 1S,3R-trans-amino cyclo-pentane-1,3-dicarboxylic acid (ACPD). In conclusion, the results confirm that high-calcium induces a long-lasting increase in synaptic efficacy in rat hippocampal slices. Both NMDA ionotropic and mGluR receptors are involved in the induction, but not in the maintenance, of this phenomenon. In line with these data no modifications of basal or ACPD-induced phosphoinositide hydrolysis have been found during the maintenance stage.

Alanine↗

PubMed1996

Block by N6-L-phenylisopropyl-adenosine of the electrophysiological and morphological correlates of hippocampal ischaemic injury in the gerbil.

1. The effects of the mixed A1 and A2 adenosine receptor agonist N6-L-phenyl-isopropyladenosine (L-PIA) were tested on ischaemia-induced hippocampal neuronal injury in gerbils subjected to 5-min bilateral carotid occlusion. For comparison, the effects of the selective A2 adenosine receptor agonist, CGS 21680 were tested. 2. Five-min bilateral carotid occlusion produced within 1 week an irreversible suppression of the CA1, but not of the dentate extracellular electrical somatic responses, in 30% of gerbil hippocampal slices with respect to controls. In addition, a significant reduction occurred in the density of CA1 hippocampal pyramidal neurones but not of dentate granule cells with respect to controls. 3. Injection 1 h before or after bilateral carotid occlusion of L-PIA (0.8-1.5 mg kg-1, i.p.) but not of CGS 21680 (5 mg kg-1, i.p.), significantly prevented the irreversible disappearance of the CA1 extracellular electrical somatic responses with respect to controls. In addition, the CA1 pyramidal neuronal loss was also prevented. 4. The results show that activation of A1 adenosine receptors is able to prevent or block the electrophysiological and morphological correlates of hippocampal neuronal injury after global ischaemia in the gerbil, suggesting that adenosine receptor agonists might have a useful role in the treatment of neuronal functional and anatomical injury due to ischaemia.

Adenosine↗

PubMed1996

Dexamethasone selective inhibition of acute opioid physical dependence in isolated tissues.

The effect of dexamethasone on acute opiate withdrawal induced by mu, kappa and delta receptor agonists was investigated in vitro. After a 4-min in vitro exposure to morphine (less selective mu agonist), D-Ala2-N-methyl-Phe4-Gly5-ol)-enkephalin (DAGO; highly selective mu agonist) and trans(+/-)-3,4-dichloro-N-methyl-N-[2(1-pyrrolidynyl)cyclohexyl]- benzeneacetamide (U50-488H; highly selective kappa agonist) a strong contracture of guinea pig isolated ileum was observed after the addition of naloxone. This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (highly selective delta agonist). Dexamethasone treatment before or after the opioid agonists tested was capable of both preventing and reverting the naloxone-induced contracture after exposure to mu opiate agonists morphine and DAGO in a concentration- and time-dependent fashion. Also, the steroid reduced naloxone-induced contracture after the exposure to U50-488H only when injected before the kappa opiate agonist. Finally, it did not affect the naloxone contracture after exposure to deltorphin. Pretreatment with RU-38486, a glucocorticoid receptor antagonist, inhibited dexamethasone antagonism on responses to both mu and kappa agonists, whereas pretreatment with cycloheximide, a protein synthesis inhibitor, blocked only the antagonistic effects of dexamethasone on responses to the mu opioid agonists. Overall, these data indicate that dexamethasone induces significant effects on mu-mediated opiate with-drawal in vitro, which suggest an important functional interaction between corticosteroids and the opioid system primarily at the mu receptor level. The ability of RU-38486 and cycloheximide to block dexamethasone effects indicates that the steroid interference on mu-mediated withdrawal involves a protein synthesis-dependent mechanism via glucocorticoid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1995

Opposite modulation of 4-aminopyridine and hypoxic hyperexcitability by A1 and A2 adenosine receptor ligands in rat hippocampal slices.

The effects of the adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), and of the adenosine agonists N6-cyclopentyladenosine (CPA), N6-(2-phenylisopropyl)adenosine (R-PIA), and 2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) were investigated on the hyperexcitability induced in the CA1 area of rat hippocampal slices by hypoxia or the epileptogenic agent 4-aminopiridine. Slice perfusion with the mixed adenosine receptor agonist R-PIA (0.2 microM) significantly (P < 0.05) decreased: (i) the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period; (ii) the duration of the hypoxia-induced epileptiform bursting. Conversely, slice perfusion with the selective A1 adenosine receptor antagonists DPCPX (0.2 microM) or with the selective A2 adenosine receptor agonist CGS 21680 significantly (P < 0.05) increased the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period but did not affect the duration of the hypoxia-induced epileptiform bursting. Neither drug significantly affected the number of slices showing functional recovery after hypoxia. Slice perfusion with DPCPX (0.2 microM) also significantly increased (P < 0.05) the number of slices showing a persistent CA1 epileptiform bursting during the reoxygenation period, while the other drugs failed to affect it. Slice perfusion with the selective A1 adenosine receptor agonist CPA (2 microM) or R-PIA (5 microM) significantly (P < 0.05) decreased the duration of the CA1 epileptiform bursting induced by 100 microM 4-aminopyridine. CGS 21680 (5 microM) perfused together with CPA (2 microM) significantly (P < 0.05) counteracted the inhibitory effects of the A1 adenosine receptor agonist on 4-aminopyridine epileptiform bursting, while it failed by itself to directly affect the 4-aminopyridine epileptiform bursting duration. The results produce evidence for a selective opposite modulation by A1 and A2 adenosine agonists in the control of hippocampal hyperexcitability induced by hypoxia or 4-aminopyridine but not in the post-hypoxic functional recovery.

4-Aminopyridine↗

PubMed1995

Reduced hippocampal CA1 Ca(2+)-induced long-term potentiation is associated with age-dependent impairment of spatial learning.

Expression of Ca(2+)-induced CA1 long-term potentiation (LTP) was analysed in hippocampal slices obtained from (1) 3-month-old and (2) 18-20-month-old Sprague-Dawley rats selected for their performances in the Morris water maze task. In all slices, a transient (10 min) increase of extracellular Ca2+ concentration (4 mM) caused a long-lasting enhancement of potentials evoked by electrical stimulation of radiatum fibers. However, a significant difference was found in the degree of potentiation among groups. In particular, increases of the CA1 response amplitudes were significantly lower in old rats impaired in spatial learning than in young at 30 (P < 0.05), 60, 90 and 120 min (P < 0.01) after restoring the normal Ca2+ concentration. On the contrary, no differences were observed between young animals and the old ones with good performances in spatial learning. The data suggest that amplitude of CA1 Ca(2+)-induced LTP in old rats is related to spatial learning abilities.

Aging↗

PubMed1995

Microanatomical and electrophysiological changes of the rat dentate gyrus caused by lesions of the nucleus basalis magnocellularis.

The effect of unilateral or bilateral lesions of the nucleus basalis magnocellularis (NBM) on the dentate gyrus of the hippocampus were assessed using microanatomical and electrophysiological techniques. NBM is the main cholinergic basal forebrain nucleus that supplies the fronto-parietal cortex. Lesions were induced using the neurotoxin ibotenic acid or a radio-frequency system and did not affect glutamic acid decarboxylase activity both in the frontal cortex and in the hippocampus. At 4 weeks after lesioning, a loss of choline acetyltransferase (ChAT) activity and of ChAT-immunoreactive fibres was observed in the frontal cortex but not in the hippocampus and no changes in the density of granule neurons of the dentate gyrus or in the hippocampal long-term potentiation (LTP) were noticeable. At 8 weeks after lesioning the loss of both ChAT activity and of ChAT-immunoreactive fibres persisted in the frontal cortex of NBM-lesioned rats. Moreover, at this time a significant decrease in the density of granule neurons in the dentate gyrus accompanied by a reduced probability of dentate LTP induction were observed in both ibotenic acid- and radio-frequency-lesioned rats. These findings have shown that although NBM does not send direct cholinergic projections to the hippocampus, lesions of this cholinergic nucleus are accompanied by delayed neurodegenerative changes involving the dentate gyrus. This suggests the occurrence of indirect connections between NBM and the hippocampus, the functional relevance of which should be explored.

Animals↗

PubMed1995

Felbamate selectively blocks in vitro hippocampal kainate-induced irreversible electrical changes.

The influence of the anticonvulsant felbamate has been tested on in vitro excitotoxicity induced by treatment of hippocampal slices with elevated concentrations of NMDA, AMPA and kainic acid. For comparison, the effects of the glutamate antagonist 7-chlorokynurenic acid and of the anticonvulsants pentobarbitone and lamotrigine, were also studied. Slice perfusion with 50 microM NMDA or 25 microM AMPA or 12 microM kainic acid produced within 30 min a disappearance or a pronounced irreversible amplitude reduction of the CA1 electrical synaptic responses. Slice perfusion with 1.2-1.6 mM felbamate or 100 microM lamotrigine significantly decreased the incidence of the irreversible disappearance of the CA1 electrical response induced by kainic acid. On the contrary, slice perfusion with the same concentrations of the drugs did not affect the irreversible disappearance of the CA1 electrical response induced by NMDA or AMPA. By contrast, slice perfusion with 100 microM of 7-chlorokynurenic acid significantly prevented the neurotoxic effects induced by both NMDA and kainic acid, while 100 microM of pentobarbitone failed to affect kainic acid-induced neurotoxicity. The different profile of neuroprotection elicited by felbamate with respect to reference drugs indicates that a different mechanism of action than antagonism of NMDA response or potentiation of GABA response underlies the neuroprotectant effects of felbamate.

Animals↗

PubMed1995

Time-related antiepileptic effects of the synthetic glucocorticoid dexamethasone in rat hippocampal slices.

The in vitro antiepileptic activity of the synthetic glucocorticoid dexamethasone (DEX) was tested in rat hippocampal slices on the CA1 epileptiform activity induced by sodium penicillin (PEN). Slice perfusion with 1 mM PEN produced within 60 min the development of a CA1 epileptiform bursting made up of an increase of the primary CA1 population spike followed by the appearance of secondary epileptiform population spikes. Slice perfusion with 100 microM DEX together with PEN (1 mM) partially prevented but did not block the expression of the CA1 epileptiform bursting as evidenced by a significant (P < 0.05) reduction of the duration of the bursting due to the epileptogenic agent. Slice perfusion with 50 microM DEX together with PEN (1 mM) failed to prevent or block the expression of the CA1 penicillin-induced epileptiform bursting. A 60 min slice pretreatment with 50-100 microM DEX followed by a slice perfusion with 50-100 microM DEX together with PEN (1 mM) prevented the expression of the CA1 epileptiform bursting. Cycloheximide (1 microM), a protein synthesis inhibitor, perfused together with DEX reverted the inhibitory effects of dexamethasone on the expression of the penicillin-induced CA1 epileptiform bursting. The results indicate that the synthetic glucocorticoid DEX presents concentration- and time-related in vitro antiepileptic effects. In addition, the data suggest that this inhibitory effect occurs via a protein synthesis-dependent mechanism.

Action Potentials↗

PubMed1995

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine elicits convulsant effects in mice.

1. The behaviour and EEG effects of the dopamine and sigma (sigma) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice. 2. (+) 3-PPP dose-dependently (60-100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures. 3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.). 4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

Animals↗

PubMed1995

Nucleus basalis magnocellularis lesions decrease histochemically reactive zinc stores in the rat brain: effect of choline alphoscerate treatment.

The effects of monolateral lesioning of the nucleus basalis magnocellularis (NBM) and of choline alphoscerate treatment on histochemically reactive vesicular zinc stores were assessed in the rat brain using the sulphide-silver histochemical technique. Histochemically reactive zinc stores are located primarily within association fibres of the neuropil of the cerebral cortex as well as in the mossy fibres of the hippocampus. The density of cortical and hippocampal sulphide-silver positive fibres, which might have a role in cognitive and mnemonic processes, parallels the density of zinc-containing presynaptic buttons. Unilateral lesions of NBM caused a remarkable decrease of sulphide-silver positive fibres from the 4th week after lesioning in the neuropil of the ipsilateral fronto-parietal cortex and from the 3rd week in the mossy fibres of the ipsilateral hippocampus. Treatment with choline alphoscerate, which is a precursor in the biosynthesis of brain phospholipids that increases the bioavailability of acetylcholine in the nervous tissue, restored, in part, the density and pattern of sulphide-silver positive fibres in the fronto-parietal cortex and in the hippocampus. The data suggest that, analogously to reports from Alzheimer's disease patients, lesions of the NBM cause a decrease of zinc stores in the rat brain. Choline alphoscerate treatment is able to counter the expression of this phenomenon which accompanies experimental lesions of the NBM.

Animals↗

PubMed1994

Felbamate displays in vitro antiepileptic effects as a broad spectrum excitatory amino acid receptor antagonist.

The in vitro antiepileptic activity of the novel anticonvulsant drug felbamate was tested in rat hippocampal slices on the CA1 epileptiform bursting induced by different chemical epileptogenic agents. The effects of felbamate were compared with those of the anticonvulsant drugs diphenylhydantoin and pentobarbitone and with the effects of excitatory amino acid antagonists acting at both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Like the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), felbamate at a minimum effective concentration of 1 mM induced a significant (P < 0.01) reduction of the duration of the CA1 epileptiform bursting due to the K+ channel blocker, 4-aminopyridine, and the excitatory amino acids, kainate and quisqualate. Like the NMDA receptor antagonist ketamine, felbamate (1.6 mM) significantly (P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by 'Mg(2+)-free' solutions. Conversely, felbamate (1.6 mM), CNQX (100 microM) and ketamine (100 microM) failed to affect the epileptiform bursting induced by the GABA antagonist penicillin. Pentobarbitone (100 microM) significantly (P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by 'Mg(2+)-free' solutions, 4-aminopyridine or penicillin, while diphenylhydantoin (up to concentrations of 100 microM) failed to have an effect. The results indicate that felbamate displays a unique profile of in vitro antiepileptic effects as a broad spectrum antagonist of excitatory amino acid transmission.

6-Cyano-7-nitroquinoxaline-2,3-dione↗