Biomedical subjects

F Block

Publications and source records attributed to F Block.

At least 73 records · Page 4Linked to original sources

PubMed1996

Memantine reduces functional and morphological consequences induced by global ischemia in rats.

In this study the effect of memantine, an antagonist at the N-methyl-D-aspartate receptor, on spatial learning deficit and on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Memantine was administered 20 min before induction of ischemia at a dose of 10 or 20 mg/kg. One week after surgery spatial learning was tested in the Morris water maze. Treatment with the higher dose of memantine reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated by 20 mg/kg memantine. Treatment with the lower dose of memantine had no influence on the deficit in spatial learning and the neuronal damage resulting from ischemia. The present data demonstrate that treatment with a neuroprotective agent like memantine can reduce functional as well as morphological sequelae induced by ischemia.

Animals↗

PubMed1996

Antiparkinsonian effect of flupirtine in monoamine-depleted rats.

Excitatory amino acid receptor antagonists lead to marked suppression of parkinsonian-like symptoms in rodent and primate models of Parkinson's disease and are able to potentiate the ability of L-DOPA to reverse akinesia and ameliorate muscular rigidity displayed in these animal models. Flupirtine, which is clinically used as a non-opioid analgesic agent, has some N-methyl-D-aspartate (NMDA) antagonistic properties in several in vivo and in vitro experiments. We now report that in monoamine depleted rats (pretreated with reserpine, 5 mg/kg, and alpha-methyl-para-tyrosine, 250 mg/ kg i.p.) flupirtine dose-dependently (1-20 mg/kg i.p.) suppressed rigidity, measured as tonic EMG activity in the gastrocnemius muscle, but had no effect on akinesia, measured as locomotor activity. In addition, it potentiated the antiparkinsonian effect of L-DOPA on akinesia and rigidity in this rodent model of Parkinson's disease. These effects of flupirtine are of particular clinical relevance, since flupirtine is devoid of the typical side effects of NMDA-receptor antagonists.

Aminopyridines↗

PubMed1996

Pretreatment but not posttreatment with GYKI 52466 reduces functional deficits and neuronal damage after global ischemia in rats.

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of GYKI 52466, an antagonist at the non-N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. GYKI 52466 (30 mg/kg i.p.) was administered either 20 min before induction of ischemia or immediately after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damaged was assessed. GYKI 52466 reduced the increase in escape latency and in swim distance induced by 4VO when given before ischemia but not when applied after ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was significantly attenuated by pretreatment but not by posttreatment with GYKI 52466. Striatal neuronal damage was not affected by either treatment with GYKI 52466. GYKI 52466 had neuroprotective effects in a rat model of global cerebral ischemia. Pretreatment with GYKI 52466 protected rats against behavioural deficits and hippocampal neuronal damage induced by 4VO.

Animals↗

PubMed1995

The antioxidant LY 231617 ameliorates functional and morphological sequelae induced by global ischemia in rats.

In this study the effect of LY 231617, an antioxidant, on spatial learning deficit and on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. LY 231617 (20 mg/kg i.p.) was administered after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. LY 231617 reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CAI sector of the hippocampus produced by 4VO was significantly attenuated by LY 231617. The present data demonstrate that posttreatment with LY 231617 exerts a protective effect on hippocampal neuronal damage and deficits in spatial learning induced by 4VO.

Animals↗

PubMed1995

N-methyl-D-aspartate and alpha 2-adrenergic mechanisms are involved in the depressant action of flupirtine on spinal reflexes in rats.

In urethane-chloralose anesthetised rats the muscle relaxant activity of flupirtine was investigated on the monosynaptic Hoffmann reflex recorded from plantar foot muscles and on the polysynaptic flexor reflex recorded from tibialis muscle. Intraperitoneal (i.p.; 2.5-25 mumol/kg) and intrathecal (i.t.; 33-330 nmol) administration of flupirtine depressed the polysynaptic flexor reflex in anesthetised rats in a dose-dependent manner without affecting the monosynaptic Hoffmann reflex. Flupirtine produced a similar pattern on spinal reflexes as NMDA receptor antagonists, such as (-)-2-amino-7-phosphonoheptanoic acid (500 nmol i.t.) and memantine (125 mumol/kg i.p.), the benzodiazepines diazepam (18 mumol/kg i.p.) and midazolam (80 nmol i.t.), and the alpha 2-adrenoceptor agonist tizanidine (2 mumol/kg). In contrast, the GABAA receptor agonist muscimol (21 mumol/kg i.p.; 20 nmol i.t.) and the GABAB receptor agonist baclofen (47 mumol/kg i.p.; 2 nmol i.t.) reduced the magnitude of both the flexor and the Hoffmann reflex, whereas the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 nmol i.t.) depressed the Hoffmann reflex without affecting the flexor reflex. The effect of i.t. injection of flupirtine was prevented by coadministration of the mixed alpha 1/alpha 2-adrenoceptor antagonist yohimbine (10 nmol) and the excitatory amino acid N-methyl-D-aspartate (NMDA; 0.1 nmol), but neither by coadministration of the alpha 1-adrenoceptor antagonist prazosine (10 nmol), the GABAA receptor antagonist bicuculline (1 nmol), the GABAB receptor antagonist phaclofen (100 nmol), the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid (ATPA; 0.1 pmol) nor by pre-treatment with the benzodiazepine receptor antagonist flumazenil (16 mumol/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Rapid appearance of beta-amyloid precursor protein immunoreactivity in glial cells following excitotoxic brain injury.

Clinical and experimental data have indicated an up-regulation of amyloid precursor protein (APP) after various types of CNS injury. In the present study the cellular source of lesion-induced APP has been investigated in a neurotoxic CNS model. Quinolinic acid injection into the striatum results in neuronal degeneration, while glial cells survive. APP immunoreactivity was detected in glial cells starting at postoperative day 3 and persisted until day 21, the last time point studied. Double immunocytochemistry identified the majority of APP-immunoreactive cells as glial fibrillary acidic protein-immunoreactive astrocytes. There was no evidence of amyloid fibril deposition during this time. It is concluded that following excitotoxic neuronal degneration APP is mainly produced by reactive astrocytes in the lesioned area.

Amyloid beta-Protein Precursor↗

PubMed1995

Posttreatment with EPC-K1, an inhibitor of lipid peroxidation and of phospholipase A2 activity, reduces functional deficits after global ischemia in rats.

In this study the effect of an inhibitor of lipid peroxidation and of phospholipase A2 activity, EPC-K1, on spatial learning deficit and neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. EPC-K1 (10 mg/kg IP) was administered either a) 15 min before induction of ischemia, b) immediately after, or c) 30 min after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. EPC-K1 reduced the deficit in spatial learning when given immediately or 30 min after the onset of reperfusion but not when applied 15 min before ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was slightly, but not significantly attenuated by posttreatment. The present data demonstrate that posttreatment with EPC-K1 exerts a protective effect on deficits in spatial learning induced by 4VO. These results support the hypothesis that lipid peroxidation and activation of phospholipase A2 contribute to functional alterations of the brain during reperfusion following forebrain ischemia.

Animals↗

PubMed1995

Altered pattern of immunohistochemical staining for glial fibrillary acidic protein (GFAP) in the forebrain and cerebellum of the mutant spastic rat.

The spastic rat is a neurological mutant of the Han-Wistar strain with prominent spasticity, tremor, and ataxia. Neurodegeneration is found in the CA3 sector of the hippocampus and in Purkinje cells of the cerebellum. We examined the forebrain and cerebellum of spastic rats for glial reactions by using immunolabelling for the astrocytic marker, glial fibrillary acidic protein (GFAP). First, a map of the GFAP-distribution was made representing a systematic series of frontal sections in controls. Reactive astrocytes with increased GFAP should occur in the areas with established neuronal degeneration, but they could also demarcate further regions with pathology in this rat strain. Since the baseline levels of GFAP-immunoreactivity differ between brain regions, control rats and clinically normal littermates served as controls to judge relative increases in major structures. In the CA3 sector and hilus of the dorsal hippocampus, a massive gliosis was detected. In the cerebellum, a patchy increase of GFAP labelling in Bergmann glia was found. Further increases of GFAP-labelling in reactive astrocytes occurred in fiber tracts, the ventral thalamic nuclei, medial geniculate nuclei, pontine region and optic layer of the superior colliculus. Inconsistent changes were noted in cortex and pallidum. No defects of glial labelling or malformations in glial architectonics were found. The reactive changes of astroglial cells in hippocampus and cerebellum are in proportion to the neuronal degeneration. The glial reactions in the other brain regions possibly reflect a reaction to fiber degeneration and incipient neuronal degeneration or functional alterations of glial cells in response to neuronal dysfunction.

Animals↗

PubMed1994

Immunohistochemical evidence for flupirtine acting as an antagonist on the N-methyl-D-aspartate and homocysteic acid-induced release of GABA in the rabbit retina.

When rabbit retinas are exposed in vitro to specific excitatory amino acid receptor agonists certain GABAergic amacrine cells are activated to cause a release of GABA. The GABA that is not released can be detected by immunohistochemistry. Exposure of tissues to kainate or NMDA each caused a characteristic change in the GABA immunoreactivity. CNQX antagonised the kainate effect specifically while MK-801 counteracted the influence of NMDA. The effect produced by kainate was mimicked by domoic acid while the influence of homocysteic acid was identical with NMDA. Flupirtine alone did not influence the nature of the GABA immunoreactivity and so did not act as a kainate or NMDA agonist. However, flupirtine counteracted the influence produced by NMDA and homocysteic acid but had no effect on the kainate and domoic acid responses. Thus in this system flupirtine acts as an NMDA antagonist.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Flupirtine protects against ischaemic retinal dysfunction in rats.

The present study investigated whether flupirtine attenuates the depression and enhances the recovery of the b-wave of the electroretinogram (ERG) in response to retinal ischaemia. The ERG was recorded from pentobarbital-anaesthetized rats before, during and after transient (24 min) occlusion of both common carotid arteries. Flupirtine administered 20 min before ischaemia reduced the depression of the b-wave during occlusion and accelerated recovery during reperfusion. When given at the onset of ischaemia flupirtine led to attenuation of the reduction of the b-wave during occlusion and to enhancement of the recovery during reperfusion. The present results suggest that flupirtine provides protection against ischaemic retinal dysfunction.

Aminopyridines↗

PubMed1994

Expression of GFAP in the striatum and its projection areas in response to striatal quinolinic acid lesion in rats.

Injection of quinolinic acid (QA) into the rat striatum is known to produce neuropathological and neurochemical features of Huntington's disease (HD). In the present study the astrocytic response two weeks following intrastriatal injection of either QA (240 nmol) or solvent (1 microliter) was examined using immunohistochemistry for GFAP. Striatal QA lesion resulted in a marked GFAP expression within the whole striatum which is due to neuronal degeneration. Furthermore, the reticular part of substantia nigra, globus pallidus and ventromedial thalamic nucleus revealed increases in GFAP expression without neuronal damage. As this remote astrocytic response is located only in striatal projection areas it seems to reflect transsynaptic changes in response to the lesion.

Animals↗

PubMed1994

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of flupirtine in rats.

The present study examined in urethane-chloralose anaesthetized rats whether N-methyl-D-aspartate (NMDA) is involved in the depressant effect of flupirtine on the monosynaptic Hoffmann (H)-reflex recorded from plantar foot muscles and on polysynaptic flexor reflexes recorded from tibialis muscle. Intrathecal administration of both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and of flupirtine depressed the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex without affecting the flexor reflex. The depressant effect of flupirtine on the flexor reflex was prevented by co-administration of NMDA, but not by co-administration of the non-NMDA agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid. These observations suggest that NMDA might be involved in the action of flupirtine.

Aminopyridines↗

PubMed1994

The depressant effect of GYKI 52466 on spinal reflex transmission in rats is mediated via non-NMDA and benzodiazepine receptors.

The present study examined the mechanisms by which GYKI 52466 (1-(amino-phenyl)-4-methyl-7,8-methyldioxy-5H-2,3-benzodiazepine) exerts its muscle relaxant effects. Intrathecal injection of the specific N-methyl-D-aspartate (NMDA) receptor antagonist (-)-2-amino-7-phosphonoheptanoate (AP7, 50-500 nmol) and systemic application of the benzodiazepine diazepam (0.2-5 mg/kg) dose dependently reduced the integrated area of the polysynaptic flexor reflex without affecting the monoxynaptic H-reflex. In contrast, intrathecal administration of the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 0.1-10 nmol) depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of GYKI 52466 on the flexor reflex was reduced by coadministration with flumazenil (5 mg/kg i.p.), an antagonist at the benzodiazepine receptor, whereas coadministration of the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazole-propionic acid (ATPA, 0.1 pmol) with GYKI 52466 attenuated the reduction of the H-reflex induced by GYKI 52466. The chosen doses of flumazenil and ATPA did not affect spinal reflex transmission when given alone. These data suggest that GYKI 52466 depresses spinal reflex transmission via an action on non-NMDA receptors and on benzodiazepine receptors.

2-Amino-5-phosphonovalerate↗

PubMed1994

Stimulation of N-methyl-D-aspartate receptors in the rat nucleus reticularis thalami suppresses somatosensory evoked potentials.

The role of excitatory amino acid receptors in the rat nucleus reticularis thalami (NRT) for the modulation of cortical somatosensory evoked potentials (SEPs) was examined. The effects of microapplication of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), an agonist at the non-NMDA receptors, into the NRT on the amplitude and latency of cortical SEPs were measured. SEPs were recorded from the somatosensory cortex of anaesthetized rats, in response to single shock stimulation of the contralateral forepaw. Injection of NMDA into the NRT resulted in a decrease in amplitude and increase in latency of SEPs. These effects were dose-dependent over the range from 0.05 to 0.5 nmol. Co-administration of (-)-2-amino-7-phosphono-heptanoate, a specific NMDA antagonist, with NMDA into the NRT prevented these changes. The depressant action of NMDA on cortical SEPs was site-specific for the NRT. Application of AMPA into the NRT did not affect cortical SEPs. The present results are in line with the assumption that an excitatory amino acid serves as transmitter to stimulate NRT neurons which in turn leads to suppression of cortical SEPs. NMDA receptors within the NRT appear to be involved in this depressant action.

2-Amino-5-phosphonovalerate↗

PubMed1994

Visual and somatosensory evoked potentials are mediated by excitatory amino acid receptors in the thalamus.

In pentobarbital-anaesthetized rats early somatosensory evoked potentials (SEPs) were recorded from the sensory cortex in response to electrical stimulation of the contralateral forepaw and visual evoked potentials (VEPs) from the primary visual cortex in response to single light flashes. Microapplication of the specific non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the ventro-basal thalamus (VB) resulted in a pronounced decrease in amplitude and an increase in latency of SEPs, whereas injection of DNQX into the dorsal lateral geniculate nucleus (DGL) induced a pronounced decrease in amplitude and an increase in latency of VEPs. These changes were: (1) dose-dependent (DNQX 0.01-1.0 nmol), (2) receptor-specific, and (3) site-specific. In contrast, the specific NMDA antagonist 2-amino-7-phosphonoheptanoate (AP7; 0.5-5 nmol) did not affect SEPs after microapplication into the BV and less potently reduced the amplitude and increased the latency of VEPs after microapplication into the DGL. The present findings are consistent with the assumption that an excitatory amino acid serves as transmitter at synapses in the rat thalamus mediating the nervous impulses responsible for the generation of SEPs and of VEPs. In addition the results suggest that this transmitter preferentially interacts with non-NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1994

Differential effects of transient occlusion of common carotid arteries in normotensive rats on the somatosensory and visual system.

The effect of transient occlusion of both carotid arteries in normotensive rats (BCCA) on the electrical function of the central nervous system was monitored by recording somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs) and electroretinogram (ERG). The amplitude and latency of cortical SEPs were not affected by BCCA. In contrast, the latency of P1 and N1 of VEPs were increased and the peak-to-peak amplitude (P1-N1) decreased. The amplitude of the b-wave of the ERG was reduced and its latency increased during BCCA. These changes in VEPs and ERG were limited to the period of BCCA. During the first hour of reperfusion VEPs and the b-wave of the ERG revealed no differences between former occluded animals and sham-operated controls. The present results suggest that both sensory pathways display a different susceptibility to BCCA.

Animals↗

PubMed1993

Pentamidine, an inhibitor of spinal flexor reflexes in rats, is a potent N-methyl-D-aspartate (NMDA) antagonist in vivo.

The present study examined whether the antimicrobial agent pentamidine exerts an antagonistic action at the N-methyl-D-aspartate (NMDA) receptor as tested on spinal reflexes in rats in vivo. After intrathecal injection both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and pentamidine dose-dependently reduced the magnitude of the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of pentamidine on the flexor reflex was prevented by coadministration with NMDA but not with the non-NMDA agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. These data suggest that pentamidine exerts an antagonistic action at the NMDA receptor in vivo.

2-Amino-5-phosphonovalerate↗

PubMed1993

Visual evoked potentials in the rat quinolinic acid model of Huntington's disease.

Intrastriatal injection of quinolinic acid (QA) in rats induces some of the neuropathological and neurochemical alterations observed in the striatum of patients suffering from Huntington's disease (HD). In addition this animal model mimics the diminution of the amplitude of early cortical somatosensory evoked potentials (SEPs) seen in HD patients. The present study investigated whether the QA model also exhibits abnormalities of early cortical visual evoked potentials (VEPs) observed in HD patients. Two weeks after unilateral intrastriatal injection of QA (240 nmol) early VEPs elicited in response to light flashes were not significantly altered in lightly pentobarbital-anaesthetized rats. It is concluded that (1) the QA animal model of HD does not mimic the VEP abnormalities seen in HD patients, and (2) a striatal lesion does not modulate transmission of visual input to the cortex in rats.

Animals↗