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E T MacKenzie

Publications and source records attributed to E T MacKenzie.

At least 55 records · Page 3Linked to original sources
PubMed1995

Neuroprotection after focal cerebral ischaemia in hyperglycaemic and diabetic rats.

The effects of acute hyperglycaemia and streptozotocin-induced diabetes on infarct size were measured 48 h after middle cerebral artery occlusion (MCAO) in Fischer 344 rats. Both hyperglycaemia (+46%) and diabetes (+68%) increased infarct volume when compared to normoglycaemic rats. Insulin-treated diabetic rats exhibited an infarct size similar to that observed in normoglycaemic rats. Neuroprotection has been difficult to demonstrate in pathological conditions that increase infarct volume such as chronic arterial hypertension. However, administration of the non-competitive NMDA antagonist, dizocilpine (MK-801), after MCAO, reduced the volume of ischaemic damage (by 33-48%) in all groups. The present findings indicate (a) that the detrimental effects of experimental diabetes on infarct volume are largely attributed to hyperglycaemia; and (b) dizocilpine was as neuroprotective in hyperglycaemia and diabetic conditions as in normoglycaemic rats.

Animals↗
PubMed1995

Regional cerebral blood flow responses to neurochemical stimulation of the substantia innominata in the anaesthetized rat.

Since electrical stimulation of neurones may activate not only cell bodies but also neuronal fibres, this study aimed to test a selectively cholinergic neurochemical stimulation of the rat substantia innominata (SI) by the local microinjection of carbachol; the effects of this acetylcholine agonist were compared with glutamate. Cortical and subcortical cerebral blood flow (CBF) were measured in anaesthetized rats with the [14C]iodoantipyrine method by the tissue sampling technique immediately following the intracerebral (SI) microinjection of saline, 50 nmol of carbachol or glutamate. Carbachol microinjection into the SI induced a transient but significant vasodilation in frontoparietal motor (+28%) and temporal (+41%) cortices, that lasted for less than 10 min. Glutamate did not elicit any significant CBF modifications when compared to control rats although a significant interhemispheric asymmetry after microinjection was observed in the frontoparietal motor cortex. This latter observation would suggest that the glutamate-induced cortical response is less pronounced than that elicited by carbachol. Overall, these results demonstrate that a selective cholinergic stimulation of the SI can induce a transient cortical vasodilation and further confirms the hypothesis of a muscarinic modulation of CBF via this basal structure.

Anesthesia↗
PubMed1995

Cholinergic and vasoactive intestinal polypeptidergic innervation of the cerebral arteries.

Acetylcholine and vasoactive intestinal polypeptide are not only two vasoactive agonists that predominantly induce a vasodilatation of the cerebral arteries, but also correspond to neurotransmitters that innervate the various anatomical segments of the cerebral vasculature. The distinct patterns of the cerebrovascular cholinergic and vasoactive intestinal polypeptidergic innervation, their neurochemistry, in vitro and in vivo pharmacology, as well as the putative pathophysiological implications of these neurotransmission systems are critically summarized on the basis of the most recently published literature.

Acetylcholine↗
PubMed1995

Sequential studies of severely hypometabolic tissue volumes after permanent middle cerebral artery occlusion. A positron emission tomographic investigation in anesthetized baboons.

BACKGROUND AND PURPOSE: In the positron emission tomography literature, markedly hypometabolic brain tissue (oxygen metabolism < 1.3 to 1.7 mL.100 g-1.min-1) has often been equated with irreversible damage in the human brain. By serial positron emission tomography measurements, we investigated the temporal evolution of the volume of severely hypometabolic brain tissue after permanent middle cerebral artery occlusion in anesthetized baboons with, as a perspective, the development of rational therapeutic strategies. METHODS: Seven anesthetized and ventilated baboons underwent sequential positron emission tomography examinations with the 15O steady-state technique before and 1, 4, 7, and 24 hours and 14 to 29 days after occlusion. In each baboon the infarct volume was calculated by quantitative histological procedures after 19 to 41 days of occlusion. RESULTS: The sequential measurement of regional oxygen metabolism demonstrated an extension (for > or = 24 hours) of the volume of severely hypometabolic tissue as defined by both absolute and relative metabolic thresholds, and this profile of evolutivity is observed no matter the threshold used. Mean (+/- SEM) infarction volume of 2.4 +/- 0.6 cm3 was comparable to a tissue volume with oxygen consumption < 40% of contralateral metabolism. The volume of hypometabolic tissue was essentially stable at the 1-, 4-, and 7-hour postocclusion studies, increased markedly at the 24-hour study point, and increased even further in the chronic-stage study (on average, 17 days after occlusion). The tissue that eventually displayed a severely hypometabolic state at the final measurement showed a significant decrease of oxygen metabolism and cerebral blood flow at each time analyzed. In that tissue, the oxygen extraction fraction increased significantly at 1 hour (although not thereafter). CONCLUSIONS: The extension of severely hypometabolic volume after middle cerebral artery occlusion reinforces the concept of a dynamic penumbra and suggests the existence of a relatively large window of therapeutic opportunity in which it may be possible to develop neuroprotective strategies. Our study suggests that maximum infarct volume is determined at some time between 24 hours and 17 days after permanent middle cerebral artery occlusion in anesthetized baboons.

Animals↗
PubMed1994

Basal forebrain control of cortical blood flow and tissue gases in conscious aged rats.

Cholinergic projections from the basal forebrain are capable of influencing local cortical blood flow (CoBF). The effect of age on this influence was investigated by measuring CoBF and tissue gas partial pressures (PtO2, PtCO2) by mass spectrometry in conscious young adult (2-4 months) and aged (22-28 months) Fischer 344 rats. Electrical stimulation (50 microA) of the substantia innominata (SI) increased frontal (+100.9%) and parietal (+28.4%) CoBF in young rats, but the effects were less in aged rats (frontal, +48.6%, P < 0.05; parietal, +18.9%, difference N.S.). Frontal PtO2 was increased in young but not aged rats (P < 0.01.). During standard hypercapnia, changes in CoBF, PtO2 and PtCO2 did not differ between young and aged rats. Under physostigmine infusion (0.15 mg/kg/h, i.v.), the CoBF increases to SI stimulation were approximately doubled in both cortices, in young and aged rats, and PtO2 increases were also significantly greater. However, frontal PtO2 increases were significantly smaller in aged (+7.6%) than in young (32.7%) rats, as were frontal PtCO2 reductions. We conclude: (i) the influence of the SI on frontal CoBF and PtO2 is substantially reduced with age; (ii) although physostigmine treatment potentiates this influence in both groups, the beneficial effects are relatively limited for aged rats.

Aging↗
PubMed1994

Immersion and perfusion staining with 2,3,5-triphenyltetrazolium chloride (TTC) compared to mitochondrial enzymes 6 hours after MCA-occlusion in primates.

2,3,5-triphenyltetrazolium chloride (TTC) is commonly applied in rodents and cats as a marker of infarcted tissue as early as 20 min after the onset of focal ischaemia. At this stage it is suggested that it reflects hypoperfusion rather than failure of respiratory chain. Immersion of brain slices in TTC solution is preferable in comparison to perfusion with TTC in order to ensure, that enough TTC enters the post-occlusion tissue. We compared immersion technique versus perfusion technique 6 h after permanent occlusion of the left middle cerebral artery in 18 baboons. In addition, we assessed the function of the respiratory chain enzymes of stained and unstained tissue in three baboons. The immersion technique revealed an absence of TTC staining limited to subcortical structures in two animals. In seven experiments TTC indicated involvement of almost the entire MCA territory. The extent of the ischaemic lesion indicated by the perfusion technique was very similar. Tissue samples from the presumed infarcted areas revealed normal mitochondrial function. We conclude that perfusion and immersion technique do not cause significant different ischaemic delineation 6 h after middle cerebral artery occlusion. TTC staining appears to be a reliable method of evaluating volume of infarction in primates. Furthermore, absence of TTC staining 6 h after stroke onset is caused by energy or oxygen depletion rather than by mitochondrial injury.

Animals↗
PubMed1993

Positron emission tomographic studies of [11C]MDL 72222, a potential 5-HT3 receptor radioligand: distribution, kinetics and binding in the brain of the baboon.

The drug MDL 72222, a selective 5-HT3 receptor antagonist, was labelled with 11C and evaluated for distribution kinetics in brain and in vivo binding to 5-HT3 receptors using cold MDL 72222 challenge and positron emission tomography (PET), in three anaesthetized baboons. After tracer doses of [11C]MDL 72222 (i.v. bolus), 11C radioactivity was equally partitioned between plasma and blood cells and readily crossed the blood-brain barrier; it was distributed heterogeneously into 17 different structures of the brain. The kinetic curves for 11C in tissue showed a rapid initial uptake, followed by a slower ascending phase, up to about the twentieth minute and by a plateau, until the end of experiment (90 min). The plateau values indicated marked uptake in brain which, however, varied according to the region considered. In inhibition studies with cold MDL 72222 (1 mg.kg-1) as pretreatment, co-injection or displacement, no clear-cut effects on the kinetics of [11C] MDL 72222 in brain were detected in any region, including those known to be rich in 5-HT3 receptors. These observations suggest that specific binding to 5-HT3 receptors was not detectable in brain in vivo, because of the high lipophilicity (thus a great capacity for non-specific binding) of MDL 72222. These negative findings may also result from both the possible suboptimal affinity of MDL 72222 for 5-HT3 receptors in vivo and the relatively low density of 5-HT3 receptors present only in selected areas of the mammalian brain. This study is a step in the search of selective 5-HT3 receptor radioligands, adequate for in vivo applications. Slow clearance of [11C]MDL 72222 from brain tissue in baboons, should be accounted for in clinical pharmacokinetic investigations for optimal posology considerations.

Animals↗
PubMed1993

Determination of 18F-fluoro-2-deoxy-D-glucose rate constants in the anesthetized baboon brain with dynamic positron tomography.

We have determined the rate constants (ki*) of 18F-fluorodeoxyglucose (FDG) in the unlesioned baboon brain, for use in positron emission tomography (PET) measurements of glucose utilization. In contrast to earlier reports, we used a radiosynthesis which guarantees production of FDG essentially uncontaminated by fluorodeoxymannose, and an improved determination of ki* by (1) direct measurement of the time-shift between bolus arrival in femoral arterial plasma and brain, (2) rapid initial PET frames, and (3) extended data acquisition (up to 180 min). Young adult baboons were studied under anesthesia with either phencyclidine or etomidate. The FDG time-activity curves obtained from temporal grey matter showed a consistent decline after about 80 min, indicating true product loss. Three-compartment modelling was performed for increasing fitting intervals (20-120 min) with both a 5-parameter (K1*-k4*, and vascular volume (Vo)) and a 4-parameter (K1*-k3*,Vo) model. With the latter, both the calculated FDG net clearance ((K* = K1*.k3*/(k2* + k3*)) and the fitted kinetic constants were dependent on fitting interval, i.e., they showed sustained unstability. With the former, the constant k4*, which presumably represents dephosphorylation, was overestimated and unstable for short fitting times (presumably due to heterogeneous brain compartments in the sample tissue), but stabilized at approximately 0.01 min-1 for fitting times > or = 80 min; K1*-k3* and K* were also stable after this time. These findings were identical for both anesthetic regimen. Thus, in the anesthetized baboon, the FDG ki* values can be reliably determined based on an adequate PET acquisition paradigm and with a model that incorporates k4* and > or = 80 min time-activity data.

Anesthesia↗
PubMed1993

Effects of dorsal raphe nucleus stimulation on cerebral blood flow and flow-metabolism coupling in the conscious rat.

In the present study, we have investigated the effects of an activation of the ascending serotonergic pathway on the cerebral blood supply to a number (63) of well-defined neuroanatomical structures. To this end, we have measured the local cerebral blood flow during electrical stimulation of the dorsal raphe nucleus. Measurement of regional blood flow was performed in the conscious rat through the use of the [14C]iodoantipyrine autoradiographic technique. Stimulation of the dorsal raphe nucleus induced increases (> 15% compared to control) in cerebral blood flow in 17 structures of which statistical significance (P < 0.05) was achieved in nine; raphe stimulation significantly decreased flow in three regions. The greatest increases (+71 and +46%) were found in the frontal sensorimotor and posterior parietal cortices. Other increases were noted in relay stations of the extrapyramidal and limbic systems. Stimulation induced a decrease in two regions of the primary auditory system and in the lateral habenular nucleus. These results show that activation of the serotonergic pathway in the conscious rat effects regional cerebral blood flow heterogeneously, differing from the widespread increase in glucose utilization that we previously observed using the same experimental paradigm. Statistical analyses indicated that activation of the dorsal raphe nucleus resulted in a global modification of the flow-metabolism ratio. Moreover, in 19 out of 31 regions analysed, this ratio is significantly altered as compared to control. The dichotomy between raphe-induced changes in flow and glucose-metabolism could be explained by one or both of two hypotheses; firstly there could be a direct serotonergic innervation of cerebral resistance vessels; secondly, during raphe stimulation it could be that glucose use is not the primary determinant of tissue perfusion.

Animals↗
PubMed1993

In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anesthetized baboon.

BACKGROUND AND PURPOSE: Recent reports have shown an increase in specific binding (in vitro) of [3H]PK 11195 to peripheral-type benzodiazepine receptors in both experimental animals and humans, reflecting a glial/macrophagic reaction within and around focal ischemic insults. We have evaluated by positron emission tomography the time course of changes in brain uptake in vivo of 11C-labeled PK 11195 and flumazenil (an antagonist of central benzodiazepine receptors) as indirect and direct markers of neuronal loss, respectively, after focal cerebral ischemia. METHODS: Ten anesthetized baboons were submitted to sequential positron emission tomography studies between day 1 and day 91 after unilateral middle cerebral artery occlusion. The studies consisted of successive assessments, in the same positron emission tomography session, of [11C]PK 11195, [11C]flumazenil, cerebral blood flow, and oxygen consumption; late computed tomographic scans were obtained to map the approximate contours of infarction and to define a concentric peri-infarct area. RESULTS: We found a significant time-dependent increase in [11C]PK 11195 uptake in the peri-infarcted area, maximum at 20 to 40 days after occlusion. In contrast, there was a time- and perfusion-independent significant decrease in [11C]flumazenil uptake in the infarcted area, stable from day 2 onward, and already present in one baboon at day 1. Challenge studies with saturating doses of cold ligands confirmed that these changes represented alterations in specific binding. [11C]Flumazenil uptake was not affected in hypometabolic (but apparently noninfarcted, ie, deafferented) cortical areas. CONCLUSIONS: The delayed and apparently transient increases in [11C]PK 11195 specific uptake in vivo presumably represent glial/macrophage reaction; the marked depression in [11C]flumazenil specific binding, which appears selective for synaptic damage, is both precocious and sustained and thus may be better suited for the early assessment of ischemic damage in humans.

Animals↗
PubMed1992

Cerebrovascular nerve fibers immunoreactive for tryptophan-5-hydroxylase in the rat: distribution, putative origin and comparison with sympathetic noradrenergic nerves.

The distribution of serotonergic nerves in major basal and isolated small pial arteries (diameter > or = 50 microns) was investigated immunohistochemically using an antibody directed against tryptophan-5-hydroxylase (TPOH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT or serotonin), and compared to that of the noradrenergic system labeled for the selective noradrenaline (NA) synthesizing enzyme, dopamine-beta-hydroxylase (DBH). In addition, the possible peripheral and/or central origins of the cerebrovascular serotonergic (TPOH-positive) nerve fibers were examined. Strongly labeled TPOH-immunoreactive (TPOH-I) fiber bundles were observed in major basal arteries and gave rise to small varicose fibers organized in a meshwork pattern. The highest density of TPOH-I fibers was found in the middle cerebral artery followed by the anterior cerebral and the anterior communicating arteries, with a moderate to low density in the internal carotid and the vertebro-basilar trunk. Of the isolated pial arteries, only the larger ones (diameter > 75 microns) were significantly endowed with TPOH-I varicose fibers. However, free floating TPOH-I nerves were observed coursing through the pia-arachnoid membranes and reaching small pial vessels. In contrast, DBH-I nerve fibers were fine and were visualized primarily as numerous varicosities distributed in a circumferential manner around the vessel wall. A very high density of DBH-I varicosities was seen in the rostral part of the circle of Willis, with the internal carotid being the most richly supplied followed by the anterior cerebral and the anterior communicating arteries; comparatively, the middle cerebral artery was moderately innervated. The differences in distribution pattern and density between TPOH-I and DBH-I cerebrovascular fibers clearly suggest that these two innervation systems are not exactly superimposable. Superior cervical ganglionectomy caused an almost complete disappearance of TPOH-I nerves in all vascular segments, with some residual fibers in selected vessels. Lesion of the central serotonergic component with the neurotoxin 5,7-dihydroxytryptamine had virtually no effect on the TPOH-I fibers in the major basal and isolated pial arteries. These results strongly suggest that the serotonergic innervation of major cerebral as well as pial arteries has a prominent peripheral origin closely related to the sympathetic system. Processing of superior cervical ganglion slices for TPOH immunocytochemistry, however, failed to unequivocally detect TPOH-I neurons.

5,7-Dihydroxytryptamine↗
PubMed1991

Effects of dorsal raphe stimulation on cerebral glucose utilization in the anaesthetized rat.

The aim of this study was to determine the effects of electrical stimulation of the dorsal raphe nucleus on local cerebral glucose utilization (LCGU) in the alpha-chloralose anaesthetized rat. Activation of the dorsal raphe nucleus effected significant increases in LCGU, ranging from 13 to 52% in 8 brain structures out of 33 investigated. Increases were restricted to extrapyramidal and limbic non-specific areas, and no modifications were observed in cortical areas. The comparison with our previous results, showing that a similar raphe activation induced a global decrease in local cerebral blood flow, suggests that the ascending serotonergic system may be of importance in the regulation of the cerebral circulation.

Anesthesia↗
PubMed1991

Brain kinetics and specific binding of [11C]PK 11195 to omega 3 sites in baboons: positron emission tomography study.

We characterized, in vivo, using positron emission tomography in baboons, the kinetics and specific binding of i.v. injected [11C]PK 11195 to omega 3 sites in the brain. Following immediate access to brain tissue, the brain kinetics of [11C] K 11195 showed a slow elimination for the 60 min of study. Both coinjection and pulse-chase (at t = 8 min) with saturating amounts of cold PK 11195 immediately enhanced the availability of radiotracer to brain tissue, but also markedly increased the rate of washout. These effects presumably reflect displacement or inhibition of specifically bound [11C]PK 11195 to both peripheral and central omega 3 sites, respectively. These results indicate that [11C]PK 11195 has easy access and binds with moderate specificity to the normal primate brain in vivo.

Animals↗
PubMed1991

PET studies of [18F]methyl-MK-801, a potential NMDA receptor complex radioligand.

Using positron emission tomography (PET), the potential of 18F-labelled fluoro-methyl-MK-801([18F]FMM) as a radioligand for in vivo studies of the NMDA receptor complex was investigated in baboons. In baseline conditions, there was a slight differential retention of [18F]FMM in cerebral cortex and striatum relative to cerebellum, compatible with specific binding. However, neither pretreatment with pharmacological doses of MK-801 or phencyclidine, nor severe, transient brain hypoxia, were able to clearly alter [18]FMM brain regional kinetics, indicating limited usefulness of this radioligand for in vivo PET investigations of the NMDA receptor.

Animals↗
PubMed1991

Evidence for differing origins of the serotonergic innervation of major cerebral arteries and small pial vessels in the rat.

We have studied the nature and origin of the serotonergic innervation of two distinct anatomical cerebrovascular compartments, namely, small pial vessels and major cerebral arteries, in the rat. To this end, the levels of serotonin [5-hydroxytryptamine (5-HT)] and 5-hydroxyindoleacetic acid (5-HIAA) were measured by HPLC in both cerebrovascular compartments after either bilateral sympathectomy or destruction of the ascending serotonergic pathways, which originate from the raphe nuclei. We first showed that the small pial vessel samples were not contaminated by underlying cortical tissues through the use of an immunohistochemical approach that revealed the glia limitans, the most superficial cortical layer. Superior cervical ganglionectomy caused a marked decrease in noradrenaline concentrations in major cerebral arteries (-77%), although the reduction was less pronounced (-34%) in small pial vessels. Sympathectomy decreased by 33% 5-HT concentrations in the major cerebral arteries but was without effect on 5-HT levels in the small pial vessels. Destruction of the ascending serotonergic pathways (via local administration of 5,7-dihydroxytryptamine into the ventral tegmental area) produced a dramatic fall in 5-HT and 5-HIAA concentrations in both vascular compartments. To establish the authenticity of the serotonergic innervation, the synthesis of 5-HT [as assessed by measuring the accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition] was measured in the two vascular beds under control conditions and after destruction of the ascending serotonergic pathways. The rate of accumulation of 5-HTP was higher in the small pial vessels than in major cerebral arteries, an observation that indicates an important de novo synthesis of 5-HT in small pial vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1990

The quantification of brain lesions with an omega 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration.

Previous investigations have indicated that the detection and quantification of omega 3 (peripheral type benzodiazepine) binding site densities that are associated with reactive astroglia and macrophages could be of widespread applicability in the localization and indirect assessment of neural tissue damage in the central nervous system. In the present study, we analyze the usefulness of this approach in a number of experimental models that are characterized by (or putatively involve) neuronal degeneration. One week after the systemic administration of the excitotoxin, kainate, a marked increase in omega 3 site densities (as assessed by [3H]PK 11195 binding) was noted, an increase that was most prominent in known regions of selective vulnerability (hippocampus and septum). However, the kainate-induced omega 3 site proliferation was not a function of the dose administered, a marked interstudy variation was observed, and the binding increase was prevented by the administration of the anticonvulsant, clonazepam. The densities of omega 3 sites were studied, by autoradiography (using [3H]PK 11195 or [3H]PK 14105 as ligands), in 4 groups of Fischer 344 rats aged 3, 12, 22 and 30 months. No age-related changes were noted except in the 30-month-old group in which discrete and focal increases (reflecting tumoral processes) were observed in various brain regions. In spontaneously hypertensive, stroke-prone rats, omega 3 binding increases were observed concomitant with the development of stroke-related neurological signs. With autoradiography, the omega 3 site increase was localized to focal increases in the boundary zones between major cerebral arteries (and corresponding to regions of ischaemic or haemorrhagic infarction). Focal cerebral ischaemia was studied in rats and mice. Subsequent to middle cerebral artery occlusion in normotensive (Wistar/Kyoto) and spontaneously hypertensive rats, the density of omega 3 sites in the ipsilateral hemisphere was markedly elevated, the increase being greater in the spontaneously hypertensive rats. The increases in omega 3 labelling in these two strains matched the absolute volumes of infarctions, determined previously. Middle cerebral artery occlusion in the mouse also increased hemispheric levels of omega 3 sites; the maximum values were obtained between 4 and 8 days following the induction of focal ischaemia. These results demonstrate the feasibility of using omega 3 sites as a marker of excitotoxic, ischaemic and proliferative damage in the rodent brain. Binding measurement in tissue homogenates is an economic and time-efficient approach, whereas the autoradiographic detection of omega 3 sites allows the localization of brain lesions with a macroscopic or microscopic level of anatomical resolution.(ABSTRACT TRUNCATED AT 400 WORDS)

Affinity Labels↗
PubMed1990

The pharmacotherapy of focal cortical ischaemia in the mouse.

The measurement of cortical omega 3 (peripheral-type benzodiazepine binding) site densities provides an accurate index for the detection and quantification of ischaemic brain lesions following middle cerebral artery occlusion (MCAO) in mice. Here, we have used this marker to assess the neuroprotective activity of potential anti-ischaemic drugs belonging to several chemical classes. In untreated mice, the mean infarcted volume measured 96 h after unilateral coagulation of the middle cerebral artery was 27.9 +/- 4.3 mm3 (17.5% of the hemisphere volume) and omega 3 site densities (measured by incubation with 3H-PK 11195) were increased by 107.3 +/- 4.8% (cortical homogenates) or by 81% (coronal brain sections). The administration of the anti-ischaemic agent SL 82.0715 (10 mg/kg i.p.), 5 min, 6 h and 18 h after the occlusion and then twice daily until sacrifice evoked a decrease of similar magnitude (ca. 60-70%) in the volume of the infarction and in the proliferation of omega 3 sites. The constant tissue sparing effect of SL 82.0715 allowed the examination of the window of therapeutic opportunity. A significant diminution of cortical omega 3 sites was still noted when the first administration was delayed until 3 h post-occlusion. Moreover, the protective effect of SL 82.0715 was enhanced by repeated treatment for the first 36 h but not thereafter. Based on the histological, autoradiographic and homogenate binding results obtained with SL 82.0715, we studied the protective effects of several competitive and non-competitive NMDA receptor antagonists. When administered according to the above-described standard protocol, these drugs reduced omega 3 site levels in cortical homogenates from MCAO mice in a dose-dependent manner. The dose preventing by 50% the increase in omega 3 site levels (in mg/kg i.p.) and the maximal inhibition were respectively: MK-801 (0.2, 93%); TCP (1.6, 66%); kynurenate (260, 58%); ifenprodil (7.0, 58%); SL 82.0715 (1.1, 72%); CGS 19755 (46% at 10 mg/kg); dextromethorphan (46% at 30 mg/kg). In contrast, agents acting preferentially upon sigma (sigma) opiate receptors ((+)-3PPP, 1-10 mg/kg i.p. and haloperidol, 0.3-3 mg/kg i.p.) did not provide a significant protection. In general, calcium channel blockers (nimodipine, flunarizine, verapamil, perhexiline, diltiazem) were devoid of a clear neuroprotective potential when administered at non-toxic doses after the coagulation of the middle cerebral artery. Diltiazem (3 and 10 mg/kg i.p.) provided a significant protection when the first administration was performed 10 min prior to the occlusion. Limited protection was observed with adenosine A1 receptor agonists (N6-cyclohexyladenosine and 2-chloro-adenosine).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗