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L Urban

Publications and source records attributed to L Urban.

At least 73 records · Page 4Linked to original sources
PubMed1994

Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro.

A- and C-fiber evoked ventral root potential (VRP) responses have been examined in isolated spinal cord preparations maintained in vitro that were taken from young rats in which behavioral hyperalgesia (thermal and mechanical) was induced following UV irradiation of one hindpaw. Evoked VRPs were compared with those in naive untreated animals. The duration of both the A- and C-fiber evoked VRP was significantly increased in UV-treated animals. The amplitude of the summated VRP evoked by repeated low-frequency (1.0-5.0 Hz) C-fiber stimulation, a measure of windup, was significantly greater in UV-treated animals. In UV-treated animals, repeated low-frequency (1.0-5.0 Hz) stimulation of A-fiber inputs to the spinal cord also evoked a significant summated VRP, which was not observed in spinal cords from untreated animals. In naive animals the prolonged VRP evoked following single shock C-fiber stimulation was significantly antagonized by the NMDA receptor antagonist D-AP5 and the NK2 receptor antagonist MEN, 10376 but not by the NK1 receptor antagonists CP-96,345 or RP,67580. Summated VRPs evoked by repeated C-fiber stimulation in naive animals were significantly antagonized only by D-AP5. In hyperalgesic animals the prolonged VRP evoked by C-fiber stimulation was significantly reduced by NK1, NK2, and NMDA antagonists. The summated VRP was also significantly reduced by these antagonists. In both untreated and UV-irradiated animals the single shock evoked A-fiber ventral root response was significantly antagonized only by D-AP5. However, the summated VRP evoked by repeated A-fiber stimulation in UV-treated animals was also significantly reduced by NMDA, NK1, and NK2 receptor antagonists. The present study has demonstrated enhanced A- and C-fiber evoked responses in the rat spinal cord in vitro following induction of a peripheral injury by UV irradiation and which was associated with behavioral hyperalgesia to thermal and mechanical stimuli. Under this condition, repetitive stimulation of A-fiber primary afferents was capable of producing an enhancement of spinal excitability similar to that evoked by C-fibers in normal animals. Furthermore, we have observed the expression of an NK1 receptor component to the C-fiber evoked response following the establishment of the peripheral injury. The enhanced ventral root responses and changes in receptor sensitivity may contribute to the phenomenon of central sensitization and may be directly related to the behavioral hyperalgesia observed. Moreover, these findings may be relevant to the mechanisms of enhanced central excitability that occur in clinical conditions of inflammatory hyperalgesia and neuropathic pain.

Animals↗
PubMed1993

Contribution of NK1 and NK2 receptor activation to high threshold afferent fibre evoked ventral root responses in the rat spinal cord in vitro.

The contribution of neurokinin and NMDA receptor activation to the generation of the prolonged high threshold evoked ventral root potential (VRP) and its temporal summation has been assessed in the neonatal rat hemisected spinal cord maintained in vitro. High intensity single shock stimulation of the dorsal roots evoked a prolonged VRP (9.81 +/- 0.9 s, n = 11). A low frequency (1-10 Hz) repetitive stimulation (20 s duration) of high threshold afferent fibres evoked a summated VRP. This summated VRP reflected the temporal summation of EPSP's in spinal cord neurones which underlies the phenomenon of 'Windup'. The integrated area and duration of the high threshold evoked VRP were significantly reduced following superfusion of the spinal cord with the NK2 receptor antagonist MEN,10376 (100 nM). In the presence of D-AP5 (20 microM) the area of the C-fibre evoked VRP was also significantly reduced. The VRP duration was unaffected. Superfusion with either CP-96,345 (500 nM) or RP,67580 (100 nM), both non-peptide NK1 antagonist, did not have any significant effect upon the area or duration of the prolonged VRP following high threshold stimulation. The simultaneous application of D-AP5 (20 microM) with either MEN,10376 (100 nM) or CP-96,345 (500 nM) together produced a reduction in the area of the evoked VRP which was comparable to the value obtained by addition of their individual effects. The amplitude of the summated VRP was significantly reduced following application of D-AP5 (20 microM). No significant effect upon the amplitude was observed following separate application of either MEN,10376 (100 nM), CP-96,345 (500 nM) or RP,67580 (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1993

Actions of capsaicin on mouse dorsal root ganglion cells in vitro.

The effects of capsaicin were investigated on different populations of dorsal root ganglion cells in the in vitro mouse spinal cord-dorsal root ganglion preparation using intracellular electrodes. Dorsal root ganglion cells were characterised by the conduction velocity of their propagated action potential evoked by electrical stimulation of the dorsal root, and by the shape of their action potential. All cells with C-fiber characteristics (conduction velocity < 0.6 m/s; broad action potential with shoulder on the descending slope) were depolarised and generated action potentials when capsaicin (100-700 nM) was added to the bathing solution for 30 s. At these concentrations the membrane potential of DRG cells with myelinated fibers (conduction velocity > 2.0 m/s) was unaffected. Concentrations of capsaicin of 1.0-5.0 microM depolarised 50% of cells with conduction velocity > 10 m/s. During the depolarization of the membrane no action potentials were generated. In 50% of the capsaicin-sensitive neurons with conduction velocity faster than 10 m/s there was an initial hyperpolarization. Electrical stimulation of the dorsal root failed to evoke action potentials during the depolarization in 38% of the DRG cells with myelinated fibers and in all C-fibers tested within 10 min of the onset of the capsaicin effect. Passive depolarization of the membrane by intrasomal current injection mimicked the conduction block in neurons with large myelinated fibers. These observations confirm that capsaicin applied directly to the dorsal root ganglion affects, in a dose-dependent manner, both myelinated and unmyelinated primary afferents with a higher potency for C-neurons. Capsaicin evoked action potentials in C-neurons but not in neurons with myelinated fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

Morphological and membrane properties of young rat lumbar and thoracic dorsal root ganglion cells with unmyelinated axons.

Membrane and morphological properties of thoracic (Th9-13) and lumbar (L2-5) dorsal root ganglion cells have been investigated in an in vitro dorsal root ganglion (DRG) preparation from 14-day-old rats using intracellular recordings and the intracellular injection of Neurobiotin. The passive and active membrane properties of 47 DRG cells with conduction velocities (CV) less than 0.81 m/s were studied, which were considered to possess unmyelinated axons. The action potentials elicited by the stimulation of peripheral nerves or the dorsal roots were characteristic of C-cells, with long duration, inflexion on the falling phase and long lasting after hyperpolarization. Input resistance of the C-cells varied between 16 and 158 M omega and were significantly higher in thoracic than in the lumbar ganglia. Cells in the more cranial levels also tended to be smaller than those in the caudal levels with a mean cross sectional area of 301 +/- 32.5 microns2. Twenty-five percent of the cells from both regions showed an inward rectification. The distribution of CVs, input resistances and cross sectional areas were non-normal. While a weak correlation was found between the conduction velocity and input resistance of the cells, no correlation was present between the size of the perikarya and conduction velocity or the input resistance. These results show that by the 14th day of postnatal development membrane and morphological parameters approach those of adult rats. They also suggest that in cells with unmyelinated fibres, the size of the perikaryon does not predict the thickness of the axon, and that this cell population is heterogeneous.

Action Potentials↗
PubMed1993

Activity of deep dorsal horn neurons in the anaesthetized rat during hyperalgesia of the hindpaw induced by ultraviolet irradiation.

Thermal hyperalgesia was induced by UV irradiation of the glabrous skin of the hindpaw of adult female Sprague-Dawley rats. We have recorded single cell activity and studied excitability changes in wide dynamic range neurons in the lumbar spinal segments during the early phase (days 1-3) and late phase (days 5-7) of thermal hyperalgesia in animals under urethane anaesthesia. The proportion of spontaneously active wide dynamic range cells was increased following UV irradiation and the degree of spontaneous activity was enhanced during the course of hyperalgesia. In addition there was a significant increase in the total number of spikes evoked by standardized mechanical and noxious heat stimuli when tested at days 1-3 and days 5-7. The duration of the evoked responses was also significantly prolonged in both UV-treated groups. The noxious temperature threshold to radiant heat stimulation was significantly decreased on the UV-treated but not on the contralateral hindpaw. The average size of the receptive fields on the UV-treated paws was expanded in comparison to control. To differentiate between possible central and peripheral components of the hyperactivity of wide dynamic range cells we performed in situ dorsal rhizotomy during the recording. Cutting the dorsal roots (L2-5) evoked a significantly larger and more prolonged discharge in wide dynamic range cells in both UV-treated groups in comparison to control. Spontaneous activity in spinal wide dynamic range neurons was reduced after rhizotomy in each group. However, the decrease was only significant at days 1-3 (P < 0.05) but not at days 5-7.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1993

The selective activation of dorsal horn neurons by potassium stimulation of high threshold primary afferent neurons in vitro.

Intracellular recordings from neurons in the dorsal root ganglion and dorsal horn, in an in vitro spinal cord-dorsal root ganglion preparation, were used to investigate the role of large and small afferent fibers in the sensory synaptic transmission of the superficial dorsal horn. Raising the extracellular potassium concentration from 3.1 to 25-50 mM in the dorsal root ganglion compartment evoked a large amplitude depolarization and blocked action potentials in the large neurons of dorsal root ganglion, and it synaptically excited dorsal horn neurons. Excitatory postsynaptic potentials that were evoked by electrical stimulation of large myelinated fibers, but not those evoked by activation of small unmyelinated fibers, were blocked by the potassium treatment of the dorsal root. Tetrodotoxin (0.3-10 microM), when applied to the sensory neurons, abolished action potentials in large myelinated fibers but had no effect on the potassium-induced depolarization of the soma of large neurons of the dorsal root ganglion. Bath application of tetrodotoxin to the dorsal root ganglion blocked the postsynaptic potentials evoked in dorsal horn neurons by electrical stimulation of large fibers (stimulus intensity 10-20V, 0.02 ms) but failed to block postsynaptic potentials induced by electrical stimulation of slow fibers (stimulus intensity > 35 V, 0.5 ms). In addition, the tetrodotoxin failed to block the synaptic activation of dorsal horn neurons which was induced by the application of high potassium to sensory neurons. Capsaicin (10-100 microM, 10 s), applied to the sensory neurons, resulted in a prolonged synaptic activation of the dorsal horn neurons and a subsequent long lasting desensitization. During the period of capsaicin desensitization, synaptic activation of dorsal horn neurons by application of high potassium to the dorsal root ganglion and electrical stimulation of slow fibers was blocked. The opioid receptor agonist (D-Ala2, D-Leu5)-enkephalinamide (1 microM), applied to the spinal cord slice, abolished the dorsal horn neuron excitation evoked by electrical or chemical activation of slow primary afferent fibers. These findings indicate that high concentrations of K+ applied to the dorsal root ganglia selectively activate a primary afferent input to the dorsal horn, which is capsaicin sensitive and tetrodotoxin resistant.

Action Potentials↗
PubMed1993

The role of neurokinin and N-methyl-D-aspartate receptors in synaptic transmission from capsaicin-sensitive primary afferents in the rat spinal cord in vitro.

The rat spinal cord with connected dorsal root ganglia was used to study neurokinin and N-methyl-D-aspartate receptors involved in the sensory synaptic transmission of dorsal horn cells. Selective C-fibre excitation was produced by capsaicin (200-500 nM) administered to the dorsal root ganglions. Sixty-nine per cent of dorsal horn cells responded with a postsynaptic depolarization and enhanced synaptic activity, recorded via intracellular electrodes, to capsaicin-activated primary afferent input. Dorsal horn neurons activated by the capsaicin-evoked input were also excited by a 1-min perfusion of the neurokinin-1 receptor agonists substance P methyl ester or GR73 632 and by the neurokinin-2 agonist neurokinin-A. These cells were also depolarized by N-methyl-D-aspartate. Responses to substance P methyl ester and GR73 632 were selectively reduced by the neurokinin-1 receptor antagonist CP96,345, and responses to neurokinin-A were completely blocked by the neurokinin-2 receptor antagonist MEN10 376. The depolarization evoked by N-methyl-D-aspartate was not altered by either of the antagonists, but was completely blocked by the selective N-methyl-D-aspartate receptor antagonist (-)-2-amino-5-phosphonovaleric acid. Capsaicin-evoked responses in the dorsal horn were inhibited by MEN10,376 (63 +/- 13% inhibition) but no significant change was observed with CP96,345. The N-methyl-D-aspartate receptor antagonist (-)-2-amino-5-phosphonovaleric acid consistently inhibited the capsaicin-induced response by 76 +/- 14%. Combination of (-)-2-amino-5-phosphonovaleric acid and MEN10,376 produced an almost complete abolition of the capsaicin-evoked depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1993

Cobalt uptake enables identification of capsaicin- and bradykinin-sensitive subpopulations of rat dorsal root ganglion cells in vitro.

A novel modification of the stimulated cobalt uptake technique has been used to identify rat dorsal root ganglion cells expressing capsaicin and bradykinin receptors. The technique involves incubating intact dorsal root ganglia in vitro in a modified Krebs solution in which cobalt chloride has been substituted for calcium. Activation of dorsal root ganglion cells by capsaicin or bradykinin in the presence of the cobalt ions results in cobalt influx into the excited cells. Histochemical methods were then used to visualize the intracellular accumulation of cobalt, and labelled cells were counted and characterized. Capsaicin (2 microM) or bradykinin (500 nM) applied for 20 min induced cobalt uptake in 13.8 +/- 0.6 and 9.6 +/- 0.5% of neuronal profiles in dorsal root ganglia (L4), respectively, a significantly larger number than stained in control ganglia (in the absence of agonists: 1.8 +/- 0.7%). The longest diameter of the soma of stained dorsal root ganglion cells following capsaicin and bradykinin perfusion were significantly different from each other and from the non-labelled population (17.5 +/- 0.7 and 24.5 +/- 0.2 microns for capsaicin; 23.2 +/- 0.9 and 25.5 +/- 0.4 microns for bradykinin; labelled and non-labelled cells, respectively). The distribution of cell diameters revealed that while capsaicin-sensitive cells were exclusively small-sized, bradykinin-sensitive cells were predominantly small and medium sized. The selective bradykinin-2 receptor antagonist HOE-140 (5.0 microM) blocked the bradykinin-induced staining (2.16 +/- 0.02%) but not that of capsaicin. The bradykinin-1 agonist [des-Arg9]-bradykinin did not induce any significant increase in stained cells over the control number (2.2 +/- 0.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

An in vitro study of the properties of single vagal afferents innervating guinea-pig airways.

1. A novel preparation of the trachea and main bronchi with attached vagus nerve from the guinea-pig maintained in vitro was used to study the properties of single vagal afferent nerve fibres with identified receptive fields. 2. Recordings were made from twenty-eight C fibres with a mean conduction velocity of 0.9 +/- 0.1 m s-1 and twenty-four A delta fibres with a mean conduction velocity of 8.4 +/- 1.3 m s-1. Receptive fields for C and A delta fibres were of small diameter, distributed throughout the trachea and right bronchus and possessed very low mechanical thresholds of 2.2 +/- 0.4 and 1.1 +/- 0.3 mN respectively. 3. The chemosensitivity of isolated afferents was studied by applying drugs directly onto identified receptive fields. A delta fibres were insensitive to capsaicin (up to 3 microM), bradykinin (3 microM), histamine (10 microM) and 5-hydroxytryptamine (5-HT; 10 microM) applied for up to 1 min. Histamine (10 microM), 5-HT (10 microM) and m-chlorophenylbiguanide (10 microM) were also ineffective in exciting C fibres. 4. Capsaicin, at concentrations ranging from 30 nM to 3 microM, evoked a sustained firing of all C fibres tested when applied for a period of 30 s directly onto receptive fields. Bradykinin (0.1-1 microM) also potently excited C fibres in a concentration-related manner. The effect of bradykinin appeared to be mediated by a B2 receptor since it was not mimicked by the selective B1 receptor agonist [des-Arg9]-bradykinin (3 microM) and was abolished by prior application of the selective B2 receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (HOE 140; 0.1 microM). HOE 140 was without effect against capsaicin-evoked discharge of C fibres. 5. Capsaicin- and bradykinin-evoked discharge of C fibres was present to a similar degree in preparations pretreated with ibuprofen (1 microM), indicating that it was not dependent on, or influenced by, endogenous prostaglandin production. 6. These data demonstrate that single vagal afferents may be studied in vitro and provide the first examination of the properties of sensory fibres innervating guinea-pig airways. C and A delta fibres both exhibit low threshold mechanical sensitivity but show marked differences in terms of their chemosensitivity.

Amino Acid Sequence↗
PubMed1992

Effect of capsaicin and resiniferatoxin on peptidergic neurons in cultured dorsal root ganglion.

The neurotoxic effect of capsaicin has been shown to be selective on a subpopulation of small dorsal root ganglion neurons in newborn animals. The aim of this study was to provide evidence of the long lasting effect of capsaicin and its ultrapotent analog resiniferatoxin (RTX) on sensory peptidergic neurons maintained in organotypic cultures. The effects of the two irritants were examined on neurons that contained substance P (SP) and calcitonin gene-related peptide (CGRP). Exposure of the cultures to 10 microM capsaicin and 100 nM RTX for periods of 2 days or longer resulted in almost complete elimination of SP-immunoreactive (IR) neurites and reduction, but not elimination, of CGRP-IR neurites. In addition, both 10 microM capsaicin and 100 nM RTX significantly reduced the number of SP- and CGRP-IR cell bodies within DRG explants. Capsaicin in 100 microM concentration produced complete elimination of SP-IR fibers and a greater decrease in the number of CGRP-IR fibers, but failed to completely eliminate IR cell bodies. Exposure of the cultures to the irritants in the same concentrations for 90 min did not produce a measurable effect on SP- or CGRP-IR in neurites or cell bodies. It is important to establish that the effect of capsaicin and RTX on cultured neurons was of long duration (longer than 4 days) and is therefore different from depletion of peptides. These findings demonstrate that processes of cultured sensory neurons are much more sensitive to capsaicin and RTX than cell bodies. Furthermore, our results show that SP-IR neuronal elements are more sensitive to capsaicin than CGRP-IR elements. These data suggest that cultured sensory neurons express the functional properties of differentiated sensory neurons in vivo.

Animals↗
PubMed1992

Synaptic activation of dorsal horn neurons by selective C-fibre excitation with capsaicin in the mouse spinal cord in vitro.

Low doses (0.2-0.8 microM) of capsaicin were used to achieve selective excitation of C-fibres and the consequent synaptic activation of dorsal horn neurons (laminae I-VI) in the spinal cord of the 12-20-day-old mouse, maintained in vitro. Most dorsal horn cells were activated by application of capsaicin to dorsal root ganglia. The response consisted of a long-lasting membrane depolarization with increased regenerative (synaptic) activity in 79% of the cells, and in a further 7% only an increased synaptic activity was evoked. These effects of capsaicin were completely blocked by removing extracellular calcium ions from the superfusate to the spinal cord, or by the addition of 1 microM tetrodotoxin, suggesting a presynaptic origin of the capsaicin action. Only 67% of cells excited by capsaicin were sensitive to exogenous substance P. The excitatory amino acid antagonists, kynurenic acid (50-100 microM) or (-)-2-amino-5-phosphonovaleric acid (10-20 microM) completely blocked the capsaicin-evoked response in deep dorsal horn cells, indicating the involvement of excitatory amino acid receptors in the synaptic pathway. However, in superficial dorsal horn neurons these antagonists attenuated, but never completely abolished, the capsaicin-evoked depolarization. The kynurenic acid-resistant component of the capsaicin-evoked excitation in superficial dorsal horn cells suggests the involvement of non-amino acid excitatory transmitters--possibly neuropeptides--in the synaptic transmission. Activation of primary afferents by high-intensity electrical stimulation of the dorsal roots induced a prolonged (0.5-3 s) postsynaptic excitation in the majority of deep dorsal horn cells. The duration of the synaptic response was significantly reduced by (-)-2-amino-5-phosphonovaleric acid. Following repeated application of capsaicin, desensitization of the capsaicin-evoked synaptic activation of dorsal horn cells occurred. This effect was paralleled with the loss of the prolonged (-)-2-amino-5-phosphonovaleric acid-sensitive phase of the excitatory postsynaptic potential evoked by the high-intensity electrical stimulation of dorsal roots. This observation suggested that activation of the N-methyl-D-aspartate receptors in the dorsal horn can be activated by small-calibre capsaicin-sensitive fibres. In summary, our data suggest that the selective activation of C-fibre afferents with capsaicin produces synaptic activity in the dorsal horn which has a strong excitatory amino acid component as well as a non-excitatory amino acid, possibly peptidergic, component.

Animals↗
PubMed1992

Desensitization of bradykinin-induced activation of peripheral nociceptors.

Bradykinin-induced activation of peripheral nociceptors has been studied in an isolated spinal cord/tail preparation from the neonatal rat. Prolonged administration of bradykinin consistently produced a selective desensitization which could be prevented by concanavalin A but not by succinyl concanavalin A or phenylarsine oxide. These data indicate that mannose-containing glycoproteins occur in or close to the bradykinin receptor site. In addition the desensitization observed under the present conditions, did not involve the internalization of bradykinin receptors.

Animals↗
PubMed1991

Capsazepine, a novel capsaicin antagonist, selectively antagonises the effects of capsaicin in the mouse spinal cord in vitro.

The mouse hemisected spinal cord with attached dorsal roots and spinal ganglia in vitro preparation was used to investigate the effects of the capsaicin antagonist, capsazepine (2-[2-(4-chlorophenyl)ethylamino-thiocarbonyl]-7,8-dihydroxy-2,3,4 ,5- tetrahydro-1H-2-benzazepine). The spinal cord and the ganglia were separated by a perspex gap, allowing application of drugs separately to each compartment. Intracellular recordings were made from 37 cells in laminae II-VI of 12 to 20-day-old mice. Brief applications (30 s) of capsaicin (0.8 microM) excited dorsal horn neurones by activating small diameter primary afferent fibres. The response to capsaicin administered to the spinal cord or to the spinal ganglia was antagonised by the capsaicin antagonist, capsazepine (1.5 microM), administered to the same site. Excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the dorsal root were not affected by capsazepine. Capsazepine itself (5 microM) did not affect the membrane potential of the dorsal horn cells. Capsazepine did not depress the depolarization evoked by substance P. When capsazepine was applied to the spinal cord and capsaicin to the dorsal root ganglion the capsaicin effect was not antagonised. These data suggest that capsaicin-induced depolarization of spinal dorsal horn neurones was mediated via activation of a specific receptor on primary afferent neurones.

Action Potentials↗
PubMed1990

An NMDA-mediated component of excitatory synaptic input to dentate granule cells in 'epileptic' human hippocampus studied in vitro.

Recordings were made from human hippocampal tissue surgically removed for treatment of epilepsy. In 70% of cases, an N-methyl-D-aspartate (NMDA) receptor-mediated component was present in excitatory synaptic input to gyrus dentatus. NMDA receptors are normally present, but do not participate in low-frequency synaptic transmission, in this region of the mammalian brain. These findings suggest that recruitment of normally dormant excitatory amino acid receptors may be a feature of the epileptic brain.

2-Amino-5-phosphonovalerate↗
PubMed1990

Effects of transient forebrain ischemia in area CA1 of the gerbil hippocampus: an in vitro study.

Selective delayed post-ischemic degeneration of CA1b neurons takes place in tissue slices in vitro as it does in brain in situ. Therefore neither selectivity nor the delay of the process can be explained by vascular factors. Changes of orthodromic evoked potentials precede morphologic signs of degeneration, but antidromic activation of neurons fails pari passu with histopathologic degeneration. The marked, transient, enhancement of excitatory synaptic potentials is compatible with the idea that increased release of excitatory amino acids contributes to neuron damage. The fact that degeneration proceeds in the absence of spontaneous activity or overt electrographic seizures indicates, however, that increased excitation cannot be the sole cause of the damage. Postsynaptic excitability of neurons decreases even while synaptic potentials are enhanced. The mechanism of decreased excitability is not clear, but its development could be interpreted as a compensatory change, counteracting enhanced excitatory transmission. We confirmed that it is possible to save neurons by drug treatment administered after the ischemic insult, and demonstrated that such protection is not due to an effect on blood vessels. These findings are relevant to the proposed clinical use of NMDA receptor antagonists to prevent ischemic brain damage (Meldrum, 1985; Rothman and Olney, 1986; Choi, 1988).

Animals↗
PubMed1990

Postischemic synaptic excitation and N-methyl-D-aspartate receptor activation in gerbils.

Transient forebrain ischemia leads to the delayed degeneration of CA1b hippocampal pyramidal cells. In previous studies using the gerbil carotid occlusion model, we demonstrated that CA1b pyramidal cell degeneration is preceded by a period of enhanced excitatory transmission. Experiments with hippocampal slices prepared after 5 minutes of bilateral carotid artery occlusion show that ischemia enhances excitatory synaptic transmission and reduces pyramidal cell excitability before it abolishes synaptic function. In the present study, we tested the hypothesis that these effects require the activation of N-methyl-D-aspartate receptors during the postischemic period. Hippocampal slices were prepared 20-30 minutes after carotid occlusion, and Schaffer collateral-commissural input-output curves were constructed from recordings made every 30-60 minutes for 11-14 hours. Inclusion of the selective, reversible N-methyl-D-aspartate receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid in the superfusion medium completely prevented the progressive loss of pyramidal cell excitability that normally follows this ischemic insult. This antagonist also prevented the postischemic increases in the duration and initial slope of the focally-recorded excitatory postsynaptic potential. The antagonist could still partially block the effects of transient forebrain ischemia when treatment was delayed for 4 hours. Our results confirm that the deleterious electrophysiologic changes in area CA1b depend on the continuing activation of N-methyl-D-aspartate receptors. Delayed ischemic neuronal death may result, in part, from excessive synaptic excitation during the postischemic period. However, other factors that are eliminated by preparing hippocampal slices appear to play an important role as well.

Animals↗