Jacques H. Abraini

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.

Ex vivo and in vivo neuroprotection induced by argon when given after an excitotoxic or ischemic insult.

In vitro studies have well established the neuroprotective action of the noble gas argon. However, only limited data from in vivo models are available, and particularly whether postexcitotoxic or postischemic argon can provide neuroprotection in vivo still remains to be demonstrated. Here, we investigated the possible neuroprotective effect of postexcitotoxic-postischemic argon both ex vivo in acute brain slices subjected to ischemia in the form of oxygen and glucose deprivation (OGD), and in vivo in rats subjected to an intrastriatal injection of N-methyl-D-aspartate (NMDA) or to the occlusion of middle-cerebral artery (MCAO). We show that postexcitotoxic-postischemic argon reduces OGD-induced cell injury in brain slices, and further reduces NMDA-induced brain damage and MCAO-induced cortical brain damage in rats. Contrasting with its beneficial effect at the cortical level, we show that postischemic argon increases MCAO-induced subcortical brain damage and provides no improvement of neurologic outcome as compared to control animals. These results extend previous data on the neuroprotective action of argon. Particularly, taken together with previous in vivo data that have shown that intraischemic argon has neuroprotective action at both the cortical and subcortical level, our findings on postischemic argon suggest that this noble gas could be administered during but not after ischemia, i.e. before but not after reperfusion has occurred, in order to provide cortical neuroprotection and to avoid increasing subcortical brain damage. Also, the effects of argon are discussed as regards to the oxygen-like chemical, pharmacological, and physical properties of argon.

Post-ischemic helium provides neuroprotection in rats subjected to middle cerebral artery occlusion-induced ischemia by producing hypothermia

During the past decade, studies on the manipulation of various inhaled inert gases during ischemia and/or reperfusion have led to the conclusion that inert gases may be promising agents for treating acute ischemic stroke and perinatal hypoxia-ischemia insults. Although there is a general consensus that among these gases xenon is a golden standard, the possible widespread clinical use of xenon experiences major obstacles, namely its availability and cost of production. Interestingly, recent findings have shown that helium, which is a cost-efficient inert gas with no anesthetic properties, can provide neuroprotection against acute ischemic stroke in vivo when administered during ischemia and early reperfusion. We have investigated whether helium provides neuroprotection in rats subjected to middle cerebral artery occlusion (MCAO) when administered after reperfusion, a condition prerequisite for the therapeutic viability and possible clinical use of helium. In this study, we show that helium at 75 vol% produces neuroprotection and improvement of neurologic outcome in rats subjected to transient MCAO by producing hypothermia on account of its high specific heat as compared with air.

Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon

Abstract: Despite the beneficial effects of prototypical glutamatergic receptor antagonists in animal models, the pharmacological attempts by the use of such agents have met with very limited clinical success because these compounds produce adverse side effects and possess an intrinsic neurotoxicity at neuroprotective and therapeutic concentrations. Interestingly, nitrous oxide and xenon, which are anesthetic gases with a remarkably safe clinical profile, have been shown to be effective inhibitors of the NMDA receptor. We briefly review accumulating evidence that nitrous oxide and xenon at subanesthetic concentrations may have potentially neuroprotective and therapeutic properties, with a particular focus on their beneficial effects on ischemia‐induced neuronal death and amphetamine‐induced sensitization. Nitrous oxide at 75‐vol% and xenon up to 70‐vol% reduce ischemia‐induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decrease NMDA‐induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. Nitrous oxide at 75‐vol% and xenon at 50‐vol% further reduced amphetamine‐induced locomotor sensitization in rodents. However, at a higher concentration of 75‐vol%, xenon shows potentially neurotoxic properties and adverse side effects. Because both agents are rapidly eliminated from the body, it is plausible that their administration at appropriate subanesthetic neuroprotective and therapeutic concentrations may not be associated, in contrast with prototypical NMDA receptor antagonists, with adverse side effects and potentially neurotoxicity. Finally, the possible therapeutic implications in humans are discussed.

Human recombinant tissue-plasminogen activator (alteplase): why not use the ‘human' dose for stroke studies in rats?

Since a pioneer work that has shown in vitro that the rats fibrinolytic system is 10-fold less sensitive to recombinant tissue-plasminogen activator (rtPA) than the human system, most preclinical studies are performed with 10 instead of 0.9 mg/kg rtPA (the clinical dose in stroke patients). In this study, we compared the effects of these doses on mean time to reperfusion, reperfusion slope, brain infarct volume and edema in a rat model of thrombo-embolic stroke. Our data provide evidence that the dose of 0.9 mg/kg rtPA is as appropriate as that of 10 mg/kg for preclinical stroke studies in rodents.

Xenon is an inhibitor of tissue-plasminogen activator: adverse and beneficial effects in a rat model of thromboembolic stroke.

Preclinical evidence in rodents has proven that xenon may be a very promising neuroprotective agent for treating acute ischemic stroke. This has led to the general thinking that clinical trials with xenon could be initiated in acute stroke patients in a next future. However, an unappreciated physicochemical property of xenon has been that this gas also binds to the active site of a series of serine proteases. Because the active site of serine proteases is structurally conserved, we have hypothesized and investigated whether xenon may alter the catalytic efficiency of tissue-type plasminogen activator (tPA), a serine protease that is the only approved therapy for acute ischemic stroke today. Here, using molecular modeling and in vitro and in vivo studies, we show (1) xenon is a tPA inhibitor; (2) intraischemic xenon dose dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage; (3) postischemic xenon virtually suppresses ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood–brain barrier. Taken together, these data indicate (1) xenon should not be administered before or together with tPA therapy; (2) xenon could be a golden standard for treating acute ischemic stroke if given after tPA-induced reperfusion, with both unique neuroprotective and antiproteolytic (anti-hemorrhaging) properties.

Nitrous Oxide and Xenon Prevent Amphetamine-Induced Carrier-Mediated Dopamine Release in a Memantine-Like Fashion and Protect Against Behavioral Sensitization

BACKGROUND Amphetamine administration induces stimulation-independent dopamine release in the nucleus accumbens (NAcc) through reverse dopamine transport, a critical neurochemical event involved in its psychostimulant action, and furthermore decreases stimulation-dependent vesicular dopamine release. These effects may involve possible indirect glutamatergic mechanisms. METHODS We investigated the effects of nitrous oxide and xenon, which possess antagonistic action at the N-methyl-D-aspartate (NMDA) receptor, on brain slices ex vivo on amphetamine-induced changes in carrier-mediated and KCl-evoked dopamine release in the NAcc, and in vivo on amphetamine-induced locomotor sensitization. RESULTS Like the low-affinity NMDA receptor antagonist memantine, but not the prototypical compound MK-801, nitrous oxide and xenon at appropriate concentrations blocked both the increase in carrier-mediated dopamine release and locomotor sensitization produced by amphetamine. CONCLUSIONS In contrast to what has generally been found using prototypical NMDA receptor antagonists, these data regarding the effect of memantine, nitrous oxide, and xenon support the hypothesis that activation of certain NMDA receptors (possibly those containing the NR1a/NR2D subunit) in the NAcc is involved in the amphetamine-induced increase in carrier-mediated dopamine release and the development of behavioral sensitization to amphetamine. Nitrous oxide, xenon, and memantine may be of therapeutic interest for treating drug dependence.

Sigmoidal compression rate-dependence of inert gas narcotic potency in rats: implication for lipid vs. protein theories of inert gas action in the central nervous system

Inert gases at raised pressure exert anaesthetic effects. It is assumed that anaesthesia by the inert gases is fundamentally similar to anaesthesia produced by general anaesthetics. However, do general anaesthetics bind directly to proteins or influence activity by indirectly perturbing membrane lipids still remains a major question. Although the pressure required to achieve anaesthesia with inert gases has been suggested to exert potentially some pressure antagonism per se, this has not been studied yet to our knowledge. We investigated this possibility using nitrogen, argon, and nitrous oxide. Whatever the narcotic agent used, our results showed that the pressure of narcotic required to induce anaesthetic effects increased, as compression rate increased, in a sigmoid fashion rather than in a linear fashion. Evidence for sigmoïdal responses vs. linear responses depended of the narcotic potency of the anaesthetic agent used (nitrogen: r2=0.973 vs. r2=0.941; argon: r2=0. 971 vs. r2=0.866; nitrous oxide: r2=0.995 vs. r2=0.879). Since a linear antagonism is predicted by lipid theories, we think it likely that these findings indicate that inert gases bind to a modulatory site of a protein receptor and act as allosteric modulators. Since other workers provided evidence for binding processes using volatile anaesthetics, the present findings could indicate that all classes of general anaesthetics, including inert gases, could act by binding directly to proteins rather than by dissolving in some lipids of the cellular membrane.

Neuroprotection by nitrous oxide : Facts and evidence

Background and Objective:Preliminary studies have shown that nitrous oxide, like xenon, may possess potentially neuroprotective properties. However, because of its possible neurotoxic and proneurotoxic effects (obtained under particular conditions) and its bad reputation at anesthetic concentrations, no thorough investigations have been performed on the potentially neuroprotective properties of nitrous oxide. The aim of this study was to investigate the possible neuroprotective effects of nitrous oxide at nonanesthetic concentrations on different models of excitotoxic insult and brain ischemia. Measurements and Main Results:Here, we show using multiple models of ex vivo and in vivo excitotoxic insults and brain ischemia that nitrous oxide, administered alone at nonanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia to reduction of subsequent cell injury. In vivo, in rats subjected to transient cerebral ischemia, nitrous oxide at 50 vol% offers full neuroprotection at both the histologic and neurologic outcome levels when administered up to 2 hrs, but not 3 hrs, after ischemia onset. Conclusions:These data provide experimental evidence that nitrous oxide, which is a cost-efficient and easily available gas, has potentially neuroprotective properties in rodents when given alone at nonanesthetic concentrations. Therefore, because there is a lot at stake for the affected patients and society—in terms of easy access to treatment, profound impact of brain damage, cost of treatment, and subsequent financial cost on society—we believe that further studies should investigate thoroughly the possible potential clinical interest of nitrous oxide for the treatment of ischemic stroke in terms of optimal indications, type of ischemic injury, duration and time points for treatment, and the optimal concentration of gas to be used in clinical circumstances.

Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.