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M Balestrino

Publications and source records attributed to M Balestrino.

32 records · Page 2Linked to original sources
PubMed1990

The excitatory amino acid antagonist amino-phosphono-valeric acid (APV) provides protection against penicillin-induced epileptic activity in the rat.

The effects of intraperitoneal injection of 2-amino-5-phosphono-valeric acid (APV) on EEG-monitored penicillin-induced epileptic activity in rats were evaluated. A significant decrease in the frequency of spikes occurred with low APV dosages (10 and 20 mg/kg), while an almost complete disappearance of spike activity was observed at higher APV doses (40 and 160 mg/kg). Our data suggest that excitatory amino acids play a relevant role in penicillin-induced epileptic activity in rats.

2-Amino-5-phosphonovalerate↗
PubMed1990

Clinical trial with 5-fluorouracil and leucovorin.

Many clinical trials with 5-fluorouracil and leucovorin have been reported. This combination therapy seems to play an important role in untreated advanced colorectal cancer. In other neoplasms (gastric, head and neck, breast cancer) further studies are required.

Adenocarcinoma↗
PubMed1990

Spreading depression-like depolarization and selective vulnerability of neurons. A brief review.

If oxygen is withdrawn from rat hippocampal slices, a spreading depression-like response occurs earlier and is of larger amplitude in the CA1 area than in the dentate gyrus. After reoxygenation, recovery of synaptic transmission correlates inversely with the time spent in spreading depression. Recovery occurs more frequently in dentate gyrus than in CA1. Chlorpromazine and the gangliosides GM1 and AGF2 promote recovery from hypoxic depression of synaptic transmission in CA1. Prevention of irreversible loss of function correlates closely with a shortening of the time spent in spreading depression. If Ca2+ is withdrawn before hypoxia, then synaptic function recovers upon restoration of oxygen and [Ca2+]o, despite prolonged spreading depression. When spreading depression lasting more than 6-9 minutes is induced in fully oxygenated slices by superfusion with high-K+ solution, then transient recovery is followed by long-lasting loss of synaptic function. In intact brain of anesthetized rats, synaptic transmission in CA1 recovers after spreading depression-like depolarization lasting more than 30 minutes, but is lost irreversibly after 60 minutes. We conclude that entry of Ca2+ into neurons caused by spreading depression-like depolarization is important in the selective vulnerability of neurons; the duration of depolarization is critical to cell survival; and in the presence of a normal blood supply, neurons resist protracted spreading depression-like depolarization.

Animals↗
PubMed1989

Spreading depression-like hypoxic depolarization in CA1 and fascia dentata of hippocampal slices: relationship to selective vulnerability.

Hippocampal tissue slices were made hypoxic for 4-10 min and then reoxygenated for 60-120 min. Postsynaptic evoked potentials were recorded and extracellular DC potential was monitored continuously in stratum (st.) pyramidale of CA1 and st. granulosum of fascia dentata (FD). In some preparations extracellular potassium ([K+]o) and calcium ([Ca2+]o) were also recorded in both regions. Postsynaptic responses disappeared sooner during hypoxia and were less likely to recover upon reoxygenation in CA1 than in FD. The CA1 region exhibited a spreading depression (SD)-like response to hypoxia more often than did FD. When both regions showed SD-like depolarization, voltage shift and elevation of [K+]o were of greater magnitude and shorter latency in CA1. The probability of posthypoxic recovery of synaptic transmission was inversely related to the time spent in the SD-like state in both CA1 and FD. We conclude that the selective vulnerability of CA1 neurons to hypoxic and ischemic damage may be due, at least in part, to the region's propensity to undergo prolonged and severe SD-like depolarization.

Action Potentials↗
PubMed1988

NMDA antagonists: lack of protective effect against hypoxic damage in CA1 region of hippocampal slices.

Rat hippocampal slices were exposed to a hypoxic insult in control medium or while exposed to the N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-7-phosphonoheptanoic acid (100 microM) or DL-2-amino-5-phosphonovaleric acid (25 or 100 microM). Synaptic transmission between Schaffer collaterals and CA 1 pyramidal cells was evaluated before and after the hypoxic period, and the DC potential in the CA 1 pyramidal cell layer was monitored during the hypoxic period. Neither antagonist significantly increased the proportion of slices in which synaptic transmission recovered following hypoxia, nor did they increase the latency of the spreading depression-like anoxic depolarization. We suggest that NMDA receptors are not involved in neural damage caused by severe hypoxia with sudden onset, while they may play a role in the effects of more moderate, gradual onset hypoxia and in post-ischemic reperfusion effects.

2-Amino-5-phosphonovalerate↗
PubMed1988

Concentration of carbon dioxide, interstitial pH and synaptic transmission in hippocampal formation of the rat.

1. Interstitial pH (pHo) was measured with ion-selective microelectrodes in the fascia dentata of rats anaesthetized with urethane, while CO2 levels were controlled by varying pulmonary ventilation and CO2 content of inspired air. In the CA1 sector of hippocampal tissue slices in vitro pHo was similarly measured and altered by varying CO2 in the gas phase, or by adding HCl or NaOH to the artificial cerebrospinal fluid (ACSF) of the bath, or by changing the concentration of HCO3-. 2. Orthodromically evoked compound action potentials ('population spikes') were depressed in hypercapnia and increased in hypocapnia. In the fascia dentata of intact brains the population spike of the granule cells varied on average by more than 40% of control amplitude for each 0.1 change of pHo. In the CA1 zone of tissue slices in vitro, the change of population spike amplitude was approximately 30% per pH change of 0.1 caused by altered CO2 or HCO3- concentration, but only about 15% per pH change of 0.1 when HCl or NaOH were administered. 3. In anaesthetized rats the focal synaptic potential (FEPSP) evoked by a given stimulus intensity was weakly influenced by varying [CO2]; in tissue slices weak effects on FEPSP were inconsistent. In hippocampus both in situ and in vitro the population spike triggered by a given magnitude of FEPSP increased in hypocapnia and decreased in hypercapnia. This suggests that the main effect of CO2 is on the electric excitability of postsynaptic cells, with minor or no effect on transmitter release and on the interaction of the transmitter with its receptors. 4. Hypercapnia of anaesthetized rats was usually associated with a slight increase of [K+]o in the fascia dentata. Tissue [Ca2+]o changed little and not consistently. Neither of these two ions, nor concomitant changes of blood pressure or tissue partial pressure of oxygen, (Pt, O2), could account for the effects of pH on neuronal excitability. 5. The results show that increasing the extracellular concentration of H+ ions has a moderately depressant effect on the firing threshold of hippocampal neurones. The more powerful effects of elevated [CO2] and of lowered [HCO3-] may probably be explained by a direct effect on the neuronal membrane. The brain, by regulating breathing, controls its own excitability.

Action Potentials↗
PubMed1987

Pathophysiology of pH and Ca2+ in bloodstream and brain.

The highlights of the literature and our work on tetany and hyperventilation are reviewed. Our studies concern the following: (1) the changes of [Ca2+] in circulating plasma caused by respiratory and "metabolic" acidosis and alkalosis; (2) critical plasma [Ca2+] levels associated with signs of tetany and neuromuscular blockade; (3) changes in cerebral [Ca2+]o caused by hypo- and hyper-calcaemia, and the changes in cerebral [Ca2+]o and pHo caused by acute systemic acidosis and alkalosis; and (4) effects of changing [Ca2+]o and pHo levels on synaptic transmission in hippocampal formation. Our main conclusions are (1) changes of plasma [Ca2+] caused by "metabolic" pH changes are greater than those associated with varying CO2 concentration; (2) acute systemic [Ca2+] changes are associated with small cerebral [Ca2+]o changes; (3) the decreases in systemic and cerebral [Ca2+]o caused by hyperventilation are too small to account for the signs and symptoms of hypocapnic tetany; (4) moderate decrease of [Ca2+]o depresses and its increase enhances synaptic transmission in hippocampal formation; and (5) H+ ions in extracellular fluid have a weak depressant effect on neuronal excitability. CO2 is a strong depressant, which is only partly explained by the acidity of its solution. CO2 concentration is a significant factor in controlling cerebral function.

Animals↗
PubMed1986

Chlorpromazine protects brain tissue in hypoxia by delaying spreading depression-mediated calcium influx.

We have investigated the possible protective effect of chlorpromazine in hypoxia of brain tissue, using rat hippocampal slices maintained at 35-36 degrees C. The recovery of synaptic transmission along the Schaffer collaterals to the CA1 pathway after 9 min hypoxia was compared in chlorpromazine-treated and in control slices. Recovery upon reoxygenation was the exception in control slices, while it was observed in approximately 50 and 100% of slices treated with 7 and 70 microM chlorpromazine, respectively. Chlorpromazine also significantly delayed the occurrence of the hypoxia-induced spreading depression (SD). Recovery took place when SD occurred late during hypoxia, not when it occurred early. In those slices in which 7 microM chlorpromazine afforded no protection, SD occurred as early as it did in control slices. In further experiments, we deliberately induced SD during hypoxia in 70 microM-treated slices by topically applying a drop of high-K+ artificial cerebrospinal fluid (ACSF). Recovery was not observed when SD was induced early, but it was observed when it was induced near the end of the hypoxic period. Slices exposed to the same period of hypoxia in Ca2+-free ACSF recovered synaptic transmission (even without chlorpromazine treatment) despite early induction of SD. We conclude that: chlorpromazine protects brain tissue from hypoxia-induced irreversible loss of synaptic transmission; it does so by delaying the occurrence of SD, and hence shortening the time spent in the SD-induced depolarized state; and the harm done by SD in hypoxia is related to the influx of Ca2+ into neurons.

Animals↗
PubMed1986

The effects of moderate changes of extracellular K+ and Ca2+ on synaptic and neural function in the CA1 region of the hippocampal slice.

The effects of moderate changes of the concentration of ions on the function of mammalian central nervous tissue have not exactly been determined. We placed tissue slices from rat hippocampal formation in an interface chamber for study in vitro. Extracellular potentials were recorded in stratum radiatum and stratum pyramidale in response to stimuli of varying intensity applied to the Schaffer collateral bundle. The overall input-output relationship of excitatory synaptic transmission was gauged by expressing postsynaptic population spike amplitude as a function of presynaptic volley amplitude. The components of the transmission process were also examined by plotting the maximal rate of rise (slope) of the focally recorded synaptic potential (fEPSP) as a function of presynaptic volley amplitude, and the population spike amplitude as a function of the fEPSP slope. Raising the concentration of K+ from the normal level of 3.5 mM to 5 mM caused an average increase of 48% in the population spike evoked by a given presynaptic volley. This was due to an increased electrical excitability of pyramidal cells, as indicated by an increase of the population spike evoked by a given magnitude of fEPSP. Conversely, lowering [K+]o from 3.5 to 2 mM caused a decrease of the population spike relative to a given magnitude of either the presynaptic volley or the fEPSP. Changing [K+]o within these limits caused no significant change of the fEPSP evoked by a given presynaptic volley. Raising [Ca2+]o from 1.2 to 1.8 mM caused a 35% increase in both the fEPSP and the population spike evoked by a given presynaptic volley, and lowering [Ca2+]o to 0.8 mM caused a decrease of both these functions. The amplitude of the population spikes evoked by given fEPSPs changed surprisingly little (but consistently) when [Ca2+]o was varied within these limits. We conclude that moderate changes of [K+]o influence mainly the electric excitability of hippocampal pyramidal cells, with little effect on transmitter release or on the response of the postsynaptic membrane to transmitter, while moderate changes of [Ca2+]o affect the release of excitatory synaptic transmitter more than they affect postsynaptic membrane function.

Animals↗
PubMedDate not supplied

Blockade of N-methyl-D-aspartate receptor prevents hypoxic neuronal death and cytokine release.

Neuronal mortality, interleukin-1 beta (IL1 beta) and tumor necrosis factor-alpha (TNF alpha) release were measured in hypoxic hippocampal neuronal cultures. Release of IL 1 beta and TNF alpha was already observed in normoxic cultures, but after hypoxia it was increased approximately 2-fold. Pretreatment with 2-amino-5-phosphonovaleric acid (APV), the N-methyl-D-aspartate (NMDA) receptor antagonist, not only decreased neuronal mortality as expected, but also dramatically lowered cytokine release. However, there was no relationship between the neuronal mortality and the release of each cytokine both in untreated hypoxic cultures and in APV-pretreated ones. We conclude that IL 1 beta and TNF alpha release in hypoxia are dependent on the activation of the NMDA receptor, but that this is not the main mechanism of hypoxia damage in in vitro neuronal cultures.

2-Amino-5-phosphonovalerate↗