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D Lodge

Publications and source records attributed to D Lodge.

At least 37 records · Page 2Linked to original sources
PubMed1998

Human autoantibodies specific for the alpha1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons.

The pharmacological properties of voltage-dependent calcium channel (VDCC) subtypes appear mainly to be determined by the alpha1 pore-forming subunit but, whether P-and Q-type VDCCs are encoded by the same alpha1 gene presently is unresolved. To investigate this, we used IgG antibodies to presynaptic VDCCs at motor nerve terminals that underlie muscle weakness in the autoimmune Lambert-Eaton myasthenic syndrome (LEMS). We first studied their action on changes in intracellular free Ca2+ concentration [Ca2+]i in human embryonic kidney (HEK293) cell lines expressing different combinations of human recombinant VDCC subunits. Incubation for 18 h with LEMS IgG (2 mg/ml) caused a significant dose-dependent reduction in the K+-stimulated [Ca2+]i increase in the alpha1A cell line but not in the alpha1B, alpha1C, alpha1D, and alpha1E cell lines, establishing the alpha1A subunit as the target for these autoantibodies. Exploiting this specificity, we incubated cultured rat cerebellar neurones with LEMS IgG and observed a reduction in P-type current in Purkinje cells and both P- and Q-type currents in granule cells. These data are consistent with the hypothesis that the alpha1A gene encodes for the pore-forming subunit of both P-type and Q-type VDCCs.

Animals↗
PubMed1998

Neuroprotective effects of a systemically active group II metabotropic glutamate receptor agonist LY354740 in a gerbil model of global ischaemia.

The neuroprotective effects of a novel Group II metabotropic glutamate receptor (mGluR) agonist, LY354740, have been evaluated in a gerbil model of global ischaemia. When administered at 50 mg/kg, i.p., 30 min and 6 h after a 3 min period of bilateral carotid artery occlusion (BCAO), the compound reduced the damage to CA1 hippocampal neurones to a significant level. However, when the ischaemic insult was made more severe, by increasing the period of occlusion to 4 and 5 min, the neuroprotective effects of LY354740 were reduced. From these findings, it would appear that Group II mGluRs may play a role in ischaemic damage in the gerbil hippocampus and that agonists at these receptors are potential neuroprotective agents.

Animals↗
PubMed1998

Sulphur-containing amino acids are agonists for group 1 metabotropic receptors expressed in clonal RGT cell lines.

Comparison of the pharmacological effects of a range of sulphur-containing amino acids on human mGluR1alpha and mGluR5a has been undertaken. cDNAs of each mGluR were transfected into a Syrian hamster tumour cell line AV12-664 that was previously transfected with the rat glutamate-aspartate transporter protein (GLAST). The L-isomers of cysteine sulphinic acid (CSA), homocysteine sulphinic acid (HCSA), cysteic acid (CA) and serine-O-sulphate (SOS) stimulated PI hydrolysis in human mGluR1alpha and mGluR5a cells with full agonist effects. D-CSA, the only active D-isomer, was a partial agonist for mGluR5a whereas L-sulphocysteine (S-CYS) showed weak agonist-like effects at high concentrations on both mGluR1alpha and mGluR5a. L-Homocysteic acid was inactive on both mGluR1alpha and mGluR5a cells. Treatment of mGluR cultures with glutamate pyruvate transaminase did not alter the potencies of the S-amino acids on PI hydrolysis responses. Inhibitor constants (Ki) obtained for L-HCSA, L-CSA, L-CA and L-SOS in [3H]glutamate receptor binding studies with mGluR1alpha cells indicated that L-HCSA, L-CSA, L-CA and L-SOS can bind specifically to mGluR1 with L-HCSA showing the highest affinity. These results confirm that certain endogenously produced S-amino acids may interact directly with group 1 mGluRs.

Amino Acids, Sulfur↗
PubMed1998

The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity.

Understanding the roles of metabotropic glutamate (mGlu) receptors has been severely hampered by the lack of potent antagonists. LY341495 (2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l)propanoic acid) has been shown to block group II mGlu receptors in low nanomolar concentrations (Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D., 1998. LY341495 is a nanomolar potent and selective antagonist at group II metabotropic glutamate receptors. Neuropharmacology 37, 1-12) but can be used in higher concentrations to block all hippocampal mGlu receptors, identified so far by molecular cloning (mGlu1-5,7,8). Here we have further characterised the mGlu receptor antagonist activity of LY341495 and have used this compound to investigate roles of mGlu receptors in hippocampal long-term potentiation (LTP) and long-term depression (LTD). LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu1 or mGlu5 receptors with Ki-values of 7.0 and 7.6 microM, respectively. When tested against 10 microM L-glutamate-stimulated Ca2+ mobilisation in rat mGlu5 expressing CHO cells, it produced substantial or complete block at a concentration of 100 microM. In rat hippocampal slices, LY341495 eliminated 30 microM DHPG-stimulated PI hydrolysis and 100 microM (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 microM, respectively. In area CA1, it antagonised DHPG-mediated potentiation of NMDA-induced depolarisations and DHPG-induced long-lasting depression of AMPA receptor-mediated synaptic transmission. LY341495 also blocked NMDA receptor-independent depotentiation and setting of a molecular switch involved in the induction of LTP; effects which have previously been shown to be blocked by the mGlu receptor antagonist (S)-MCPG. These effects may therefore be due to activation of cloned mGlu receptors. In contrast, LY341495 did not affect NMDA receptor-dependent homosynaptic LTD; an effect which may therefore be independent of cloned mGlu receptors. Finally, LY341495 failed to antagonise NMDA receptor-dependent LTP and, in area CA3, NMDA receptor-independent, mossy fibre LTP. Since in the same inputs these forms of LTP were blocked by (S)-MCPG, a novel type of mGlu receptor may be involved in their induction.

Aging↗
PubMed1997

A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission.

The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, acts on three classes of ionotripic glutamate receptors, named after the agonists AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA (N-methyl-D-aspartate) and kainate. The development of selective pharmacological agents has led to a detailed understanding of the physiological and pathological roles of AMPA and NMDA receptors. In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the roles of kainate receptors. Here we describe the effects of a potent and selective agonist, ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor. We have used these agents to show that kainate receptors, comprised of or containing GluR5 subunits, regulate synaptic inhibition in the hippocampus, an action that could contribute to the epileptogenic effects of kainate.

Animals↗
PubMed1997

A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740.

Non-specific metabotropic glutamate receptor (mGluR) agonists have previously been shown to potentiate responses of spinal neurones to ionotropic glutamate receptor agonists. In this study we show that LY354740, which is a highly selective Group 2 mGluR agonist with nanomolar potency in vitro, also mimics the above effects following local ejection on spinal neurones in vivo, an action which is blocked by a Group 2 antagonist. Despite its polar nature, LY354740 is also active given either by the i.v. or the oral route (2.5-20 mg/kg) and thus will be a useful agent for investigating the role of Group 2 mGluRs both physiologically and clinically.

Administration, Oral↗
PubMed1997

Identification of pore-forming subunit of P-type calcium channels: an antisense study on rat cerebellar Purkinje cells in culture.

Treatment of cerebellar neurones in culture with an antisense oligonucleotide (ODN) against alpha1A, reduced the whole-cell P-type calcium channel current relative to mismatch ODN treated controls (p < 0.001). Therefore, AgaIVA (50 nM) reduced whole-cell calcium current in mismatch and antisense treated cells by 70 +/- 4 and 19 +/- 3%, respectively.

Animals↗
PubMed1997

Irreversible inhibition of high-affinity [3H]kainate binding by a novel photoactivatable analogue: (2'S,3'S,4'R)-2'-carboxy-4'-(2-diazo-1-oxo-3, 3,3-trifluoropropyl)-3'-pyrrolidinyl acetate.

A photolabile trifluoromethyldiazoketone derivative of kainate (KA), (2'S,3'S,4'R)-2'-carboxy-4'-(2-diazo-1-oxo-3, 3,3-trifluoropropyl)-3'-pyrrolidinyl acetate (DZKA), was synthesized and evaluated as an irreversible inhibitor of the high-affinity KA site on rat forebrain synaptic plasma membranes (SPMs). In the absence of UV irradiation, DZKA preferentially blocked [3H]KA binding with an IC50 of 0.63 microM, a concentration that produced little or no inhibition at AMPA or NMDA sites. At 100 microM, however, DZKA inhibited [3H]AMPA and L-[3H]glutamate binding by approximately 50%. When examined electrophysiologically in HEK293 cells expressing human KA (GluR6) or AMPA (GluR1) subtypes, DZKA acted preferentially at KA receptors as a weak agonist. DZKA also exhibited little or no excitotoxic activity in mixed rat cortical cultures. Irreversible inhibition was assessed by pretreating SPMs with DZKA (50 microM) in the presence of UV irradiation, removing unbound DZKA, and then assaying the reisolated SPMs for radioligand binding. This protocol produced a selective and irreversible loss of approximately 50% of the [3H]KA sites. The binding was recoverable in SPMs pretreated with DZKA or UV alone. Coincubation with L-glutamate prevented the loss in [3H]KA binding, suggesting that the inactivation occurred at or near the ligand binding site. These results are consistent with the action of DZKA as a photoaffinity ligand for the KA site and identify the analogue as a valuable probe for future investigations of receptor structure and function.

Affinity Labels↗
PubMed1996

Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase.

The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

Adenylyl Cyclases↗
PubMed1996

The use of invertebrate peptide toxins to establish Ca2+ channel identity of CA3-CA1 neurotransmission in rat hippocampal slices.

The relative contribution(s) of different Ca2+ channel subtypes to synaptic transmission between Schaffer collaterals of hippocampal CA3 pyramidal cells and CA1 pyramidal cell dendrites has been assessed using the synthetic invertebrate peptide toxins omega-conotoxin GVIA to block N-type Ca2+ channels, omega-agatoxin-IVA to block P-type Ca2+ channels and omega-conotoxin MVIIC to block N-, P- and Q-type Ca2+ channels. Omega-Agatoxin-IVA, omega-conotoxin GVIA and omega-conotoxin MVIIC all produced dose-dependent inhibitions of the excitatory post-synaptic field potential (fEPSP) recorded from the CA1 region of transverse hippocampal slices. Application of 300 nM omega-conotoxin GVIA generally produced no further inhibition to that observed with 100 nM, resulting in a maximal 50% inhibition of the fEPSP. By contrast, 30 nM omega-agatoxin-IVA reduced the fEPSP slope by only 4.6 +/- 11.1% (mean +/- S.D., n = 3), suggesting the lack of involvement of classical P-type Ca2+ channels, whereas 300 nM omega-agatoxin-IVA reduced the fEPSP slope by 85.7 +/- 15.3% (n = 3) at the end of 44 min application. Similar applications of 100 and 300 nM sigma-conotoxin MVIIC reduced the fEPSP slope by 30.9 +/- 6.6% and 79.7 +/- 5.7% respectively. Application of 30 nM omega-agatoxin-IVA together with omega-conotoxin GVIA (300 nM) produced no greater inhibition of the fEPSP than that observed with omega-conotoxin GVIA alone, suggesting that the omega-agatoxin-IVA-sensitive and omega-conotoxin MVIIC-sensitive component presents a pharmacology similar to the reported Q-type Ca2+ channel. The inhibition produced by omega-conotoxin GVIA and omega-conotoxin MVIIC showed no recovery with prolonged washing (1-2 h) whereas that produced by omega-agatoxin-IVA was slowly reversible. The observation that omega-agatoxin-IVA, which does not effect N-type Ca2+ channels (Mintz et al. (1992a) Neuron 9, 85), is capable of completely suppressing the fEPSP suggests that, whilst N-type Ca2+ channels may contribute to normal synaptic transmission at Schaffer collateral-CA1 synapses, they are not capable of supporting transmission when Q-type channels are blocked.

Action Potentials↗
PubMed1996

Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of stereochemistry, chain length, and chain substitution.

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared as excitatory amino acid (EAA) receptor antagonists. These compounds are antagonists at the N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl) propanoic acid (AMPA) subclasses of ligand gated ion channel (ionotropic) EAA receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5-yl)ethyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9) is a potent, selective and systemically active AMPA antagonist. Other analogs from this series, including (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and (3S,4aR,6S,8aR)-6- (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-ca rboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms, the effect of heteroatom substitution in the position adjacent to the bicyclic nucleus and substitution with methyl or phenyl on the chain. Compounds were evaluated on rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). Our findings revealed that the optimal stereochemical array was the same for both NMDA (32 and 61) and AMPA (9) antagonists identified in this series and that the tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen or nitrogen on the chain in the position adjacent to the bicyclic nucleus significantly reduced activity, while substitution with a methyl or phenyl group on the chain was well tolerated.

Animals↗
PubMed1996

Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric substitution, absolute stereochemical preferences, and in vivo activity.

We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.

Animals↗
PubMed1996

Activation of group I mGluRs potentiates NMDA responses in rat hippocampal slices.

The pharmacology of the metabotropic glutamate receptor (mGluR)-mediated potentiation of N-methyl-D-aspartate (NMDA)-evoked depolarisations in the CA1 region of rat hippocampal slices was investigated using an extracellular grease-gap method. The group I and II mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD; 10 mu M) potentiated responses to NMDA (15-25 mu M), giving a dose ratio of 0.84 +/- 0.02. The mGluR group I specific agonist (RS3,5-dihydroxyphenylglycine (DHPG) (3-10 mu M) also induced a dose-dependent and reversible enhancement of responses to NMDA (dose ratio for 10 mu M DHPG was 0.77 +/- 0.02). In contrast, the group II selective agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV; 0.5-1 mu M) and the group III specific agonist (S)-2-amino-4-phosphonobutanoate (L-AP4; 50 mu M) caused little or no potentiation of responses to NMDA. The potentiation induced by 3-5 mu M DHPG was reversibly antagonised by the group I and II antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG; 1 mM). The present findings demonstrate that activation of group I mGluRs enhance NMDA responses in the hippocampus.

Animals↗
PubMed1996

New developments in the molecular pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and kainate receptors.

Separation of non-N-methyl-D-aspartate subtypes of glutamate receptors, known as alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate receptors, is traced through conventional pharmacology to molecular biology. The physiology and pharmacology of recombinant receptor subtypes (GluR1-7 and KA1-2) are described. Competitive antagonists, e.g., the quinoxalinedione, 2,3-dihyroxy-6-nitro-7-sulphamoyl-benz(F)quinoxaline, and the decahydroisoquinoline, 3S,4aR,6R, 8aR-6-[2-(1(2)H-tetrazol-5-yl)ethyl]-decahydroisoquinolin e-3-carboxylate, have a broad antagonist spectrum, except that the latter is inactive on GluR6. The 2,3-benzodiazepines noncompetitively antagonise the AMPA receptor GluR1-4. Desensitisation of AMPA (GluR1-4) and kainate (GluR5-7 and KA1-2) receptors is blocked by cyclothiazide and concanavalin A, respectively. Polyamine toxins block AMPA receptors not containing GluR2 and unedited kainate receptors (GluR5-6). These data correlate well with results on native neurons characterised by techniques such as in situ hybridisation.

Allosteric Regulation↗
PubMed1996

Distribution of alpha 1A, alpha 1B and alpha 1E voltage-dependent calcium channel subunits in the human hippocampus and parahippocampal gyrus.

The distribution of voltage-dependent calcium channel subunits in the central nervous system may provide information about the function of these channels. The present study examined the distribution of three alpha-1 subunits, alpha 1A, alpha 1B and alpha 1E, in the normal human hippocampal formation and parahippocampal gyrus using the techniques of in situ hybridization and immunocytochemistry. All three subunit mRNAs appeared to be similarly localized, with high levels of expression in the dentate granule and CA pyramidal layer. At the protein level, alpha 1A, alpha 1B and alpha 1E subunits were differentially localized. In general, alpha 1A-immunoreactivity was most intense in cell bodies and dendritic processes, including dentate granule cells, CA3 pyramidal cells and entorhinal cortex pre-alpha and pri-alpha cells. The alpha 1B antibody exhibited relatively weak staining of cell bodies but stronger staining of neuropil, especially in certain regions of high synaptic density such as the polymorphic layer of the dentate gyrus and the stratum lucidum and radiatum of the CA regions. The alpha 1E staining pattern shared features in common with both alpha 1A and alpha 1B, with strong immunoreactivity in dentate granule, CA3 pyramidal and entorhinal cortex pri-alpha cells, as well as staining of the CA3 stratum lucidum. These findings suggest regions in which particular subunits may be involved in synaptic communication. For example, comparison of alpha 1B and alpha 1E staining in the CA3 stratum lucidum with calbindin-immuno-reactivity suggested that these two calcium channels subunits may be localized presynaptically in mossy fibre terminals and therefore may be involved in neurotransmitter release from these terminals.

Aged↗
PubMed1996

Stereoselective effects-of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies.

The stereoselectivity and potency of 3N-substituted 2,3-benzodiazepines were examined in vivo against excitation of spinal neurones induced by electrophoretic ejection of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate in anaesthetised rats. AMPA receptor antagonist activity resided in the (-) isomers, LY300164 and LY303070, which were effective given electrophoretically, intravenously (2.5-5 mg/kg) or orally (10 mg/kg). The same stereoselectivity was observed in neuroprotection studies. Thus, systemic administration of the (-) isomer, but not the (+) isomer, of these 2,3-benzodiazepines before or immediately after bilateral carotid artery occlusion in the gerbil was neuroprotective. For example, 10 mg/kg of LY300164 intraperitoneally or orally provided survival of up to 25% of hippocampal CA1 neurones.

Animals↗