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ABSTRACT: This study investigated the effect of amphetamine (AMP) on skilled forelimb use following focal cortical ischaemic lesions in the rat. Unilateral lesions were produced by a novel method of intracortical microinjection of endothelin-1 (ET-1), intended to principally target the forelimb representation zone in primary motor-primary somatosensory cortex. Lesions were placed in the hemisphere contralateral to the preferred limb and produced deficits in skilled forelimb use on two tasks: the paw reach (PR) test and the foot fault (FF) test. Beginning on post-lesion day (D) 2, animals received injections of 2 mg/kg AMP and were injected every third day until D26. Animals were tested both during, and 24 h after, AMP administration. AMP facilitated recovery of skilled forelimb use on the PR test when assessed during drug-free test sessions. No such effect was seen on the FF test. These results demonstrate that sub-acute administration of AMP following a unilateral focal ischaemic lesion of FL can facilitate task-dependent recovery of skilled forelimb use in the rat. They also demonstrate that different behavioural tasks measuring superficially similar behavioural outputs may show different sensitivities to such drug effects.
Behavioural Brain Research 12/2005; 165(1):98-109. · 3.42 Impact Factor
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ABSTRACT: Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.
European Journal of Pharmacology 03/2004; 486(2):163-74. · 2.52 Impact Factor
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ABSTRACT: Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.
Brain Research 01/2004; 993(1-2):42-53. · 2.73 Impact Factor
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Tracey K Murray,
Katherine Whalley,
Christine S Robinson, Mark A Ward,
Caroline A Hicks,
David Lodge,
Jim L Vandergriff,
Polly Baumbarger,
Edward Siuda,
Mary Gates,
Ann M Ogden,
Phil Skolnick,
Dennis M Zimmerman,
Eric S Nisenbaum,
David Bleakman,
Michael J O'Neill
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ABSTRACT: Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLUA1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLUA1, GLUA2, GLUA3, or GLUA4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.
Journal of Pharmacology and Experimental Therapeutics 09/2003; 306(2):752-62. · 3.83 Impact Factor
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ABSTRACT: The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.
Pharmacology Biochemistry and Behavior 10/2002; 73(2):455-66. · 2.53 Impact Factor
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Michael J O’Neill,
Caroline A Hicks, Mark A Ward,
David J Osborne,
Graham Wishart,
Kusum S Mathews,
Daniel P McLaughlin,
Jonathan A Stamford,
Deborah R McCarty,
Kelly E Patrick,
Carlos Roman,
Jerome H Fleisch,
Jeremy Gilmore,
John R Boot
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ABSTRACT: In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia–hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia–hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia–hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.
Brain Research 02/2001; · 2.73 Impact Factor
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ABSTRACT: Recent studies have shown that a brief `pre-conditioning' ischaemic insult reduces the hippocampal cell death caused by a subsequent more severe test insult. In the present studies, we have examined the effects of the non-competitive NMDA receptor antagonist ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, MK-801) a competitive NMDA receptor antagonist, LY202157, AMPA receptor antagonist ((3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoquinoline-3-carboxylic acid, LY293558), a non-competitive AMPA receptor antagonist ((−)-1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-acetyl-2,3-benzodiazepine, LY300164), and a mixed NMDA/AMPA receptor antagonist, LY246492, in a gerbil model of ischaemic tolerance. Ischaemic tolerance was induced by subjecting gerbils to a 2-min `pre-conditioning' ischaemia (bilateral carotid occlusion) 2 days prior to a 3-min test ischaemia. The effects of MK-801 (2 mg/kg i.p.), LY293558 (20 mg/kg i.p., followed by 4×10 mg/kg at 3 h intervals), LY300164 (4×10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4×20 mg/kg i.p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4×15 mg/kg i.p. at 2 h intervals) were then examined in this model. Initial dosing commenced 30 min prior to the 2-min `pre-conditioning' ischaemia. Results indicated that a 2-min `pre-conditioning' ischaemia produced ischaemic tolerance in all cases. The non-competitive NMDA receptor antagonist, MK-801, produced a significant (P<0.01) reduction in the induced tolerance, while the competitive NMDA receptor antagonist, LY202157, also attenuated (P<0.05) the induction of tolerance. In contrast, two AMPA receptor antagonists (LY293558 and LY300164) and a mixed NMDA/AMPA receptor antagonist (LY246492) had no effect on the induction of tolerance. These results suggest that NMDA receptor activation, but not AMPA receptor activation is involved in the phenomenon of ischaemic tolerance.
European Journal of Pharmacology 10/1999; · 2.52 Impact Factor
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Paulien G M Ravenstijn,
Mario Merlini,
Marjolijn Hameetman,
Tracey K Murray, Mark A Ward,
Hywel Lewis,
Gareth Ball,
Cathy Mottart,
Christine de Ville de Goyet,
Thomas Lemarchand,
Kristel van Belle,
Michael J O'Neill,
Meindert Danhof,
Elizabeth C M de Lange
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ABSTRACT: In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat.
Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis.
SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days.
SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.
Journal of Pharmacological and Toxicological Methods 57(2):114-30. · 2.32 Impact Factor
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ABSTRACT: In the present studies, we have evaluated the activity of a series of glutamate receptor antagonists from the decahydroisoquinoline group of compounds both in vitro and in vivo. Compound activity at α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors was assessed using ligand binding to cloned iGluR2 and iGluR5 receptors and on responses evoked by AMPA and N-methyl-d-aspartate (NMDA) in the cortical wedge preparation. In vivo, compounds were examined for antagonist activity electrophysiologically in the rat spinal cord preparation and in the gerbil model of global cerebral ischaemia. Compounds tested were LY293558, which has been shown to protect in models of focal cerebral ischaemia, LY202157 (an NMDA antagonist), LY246492 (an NMDA and AMPA receptor antagonist), LY302679, LY292025, LY307190, LY280263, LY289178, LY289525, LY294486 (AMPA/kainate antagonists) and LY382884 (an iGluR5 selective antagonist). Results obtained support a role for AMPA receptors in cerebral ischemia. LY377770 (a mixed AMPA/iGluR5 antagonist and active isomer of LY294486) demonstrated good neuroprotection with a 2-h time window and may therefore be useful in the treatment of ischaemic conditions.
Neuropharmacology · 4.81 Impact Factor
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ABSTRACT: We have evaluated the neuroprotective effects of the decahydroisoquinoline LY377770, a novel iGlu5 kainate receptor antagonist, in two models of cerebral ischaemia.Global ischaemia, induced in gerbils by bilateral carotid artery occlusion (BCAO) for 5 min, produced a large increase in locomotor activity at 96 hr post-occlusion and a severe loss of CA1 cells in the hippocampus histologically at 120 hr post-occlusion. LY377770 (80 mg/kg i.p. 30 min before or 30 min after BCAO followed by 40 mg/kg i.p. administered at 3 and 6 hr after the initial dose) attenuated the ischaemia-induced hyperactivity and provided (92%) and (29%) protection in the CA1 cells respectively. This protection was greater than that seen with maximally tolerated doses of other glutamate receptor antagonists (CGS19755, CPP, MK-801, ifenprodil, eliprodil, HA-966, ACEA1021, L701,324, NBQX, LY293558, GYKI52466 and LY300164).Focal ischaemia was induced by infusing 200 pmol of endothelin-1 (Et-1) adjacent to the middle cerebral artery and LY377770 was administered at 80 mg/kg i.p. immediately, 1 or 2 hr post-occlusion followed by 40 mg/kg i.p. 3 and 6 hr after the first dose. The infarct volume, measured 72 hr later, was reduced by LY377770 when given immediately (P<0.01), at 1 hr (P<0.05) but not significantly at 2 hr post-occlusion. Reference compounds, LY293558 (20 mg/kg i.p. and then 10 mg/kg as above) and MK-801 (2.5 mg/kg i.p.), both administered immediately post-occlusion produced significant (P<0.05) but somewhat less neuroprotection. In parallel microdialysis studies, LY377770 (75 mg/kg i.p.) attenuated ischaemia-induced increases in extracellular levels of glutamate, but not of dopamine.In conclusion, these results indicated that iGlu5 kainate receptors play a central role in ischaemic brain damage following global and focal cerebral ischaemia. LY377770 is a novel, soluble, systemically active iGlu5 antagonist with efficacy in global and focal ischaemia, even when administered post-occlusion. LY377770 may therefore be useful as a neuroprotectant in man.
Neuropharmacology.
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Michael J. O’Neill,
Tracey K. Murray,
Deborah R. McCarty,
Caroline A. Hicks,
Colin P. Dell,
Kelly E. Patrick, Mark A. Ward,
David J. Osborne,
Todd R. Wiernicki,
Carlos R. Roman,
David Lodge,
Jerome H. Fleisch,
JaiPal Singh
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ABSTRACT: In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions.
Brain Research.
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ABSTRACT: This study investigated the effect of amphetamine (AMP) on skilled forelimb use following focal cortical ischaemic lesions in the rat. Unilateral lesions were produced by a novel method of intracortical microinjection of endothelin-1 (ET-1), intended to principally target the forelimb representation zone in primary motor–primary somatosensory cortex. Lesions were placed in the hemisphere contralateral to the preferred limb and produced deficits in skilled forelimb use on two tasks: the paw reach (PR) test and the foot fault (FF) test. Beginning on post-lesion day (D) 2, animals received injections of 2 mg/kg AMP and were injected every third day until D26. Animals were tested both during, and 24 h after, AMP administration. AMP facilitated recovery of skilled forelimb use on the PR test when assessed during drug-free test sessions. No such effect was seen on the FF test. These results demonstrate that sub-acute administration of AMP following a unilateral focal ischaemic lesion of FL can facilitate task-dependent recovery of skilled forelimb use in the rat. They also demonstrate that different behavioural tasks measuring superficially similar behavioural outputs may show different sensitivities to such drug effects.
Behavioural Brain Research.
