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Biomedical subjects

M J O'Neill

Publications and source records attributed to M J O'Neill.

At least 19 recordsLinked to original sources
PubMed2000

Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays.

A number of plant species used in traditional medicine for the relief of pain have been selected from the medicinal and scientific literature of China, South America, Asia and West Africa. Extracts were prepared and tested in three in vitro receptor radioligand binding assays to determine whether there was an indication of biological activity, in particular their selectivity to a single receptor implicated in the mediation of pain. The three neuropeptide receptors chosen were Bradykinin (BK II), expressed in Chinese hamster ovary cells (CHO), neurokinin 1 (NK 1) expressed in astrocytoma cells, and calcitonin gene related peptide (CGRP) which were all implicated in the mediation of acute pain in the mammaliancentral nervous system. The plant species chosen to investigate were Ageratum conyzoides, Barringtonia edulis, Croton tiglium, Ipomea pes-caprae, Panax ginseng, Physostigma venenosum, Sinomenium acutum, Solidago virgaurea, Symplocos leptophylla and Typhonium giganteum. The results showed that there was a strong indication of biological activity for some of the plants which are used ethnomedicinally to treat pain, in the three in vitro receptor binding assays used, and particular plant extracts exhibited selective action to a single receptor.

Analgesics, Non-Narcotic↗
PubMed2000

Allelic expression of IGF2 in marsupials and birds.

Genomic imprinting, the parent-of-origin- specific expression of genes, has been observed in a variety of eutherian mammals. One gene that has been shown to be imprinted in all eutherians examined is the IGF2 gene. This gene encodes a potent fetal-specific growth factor that is expressed almost exclusively from the paternal chromosome. Several other imprinted genes in the IGF2 pathway are imprinted as well, suggesting that IGF2 is a focal point for the selective pressure leading to imprinted gene expression. This observation is in keeping with a proposal that imprinting arose as the result of a genetic conflict between parents over the allocation of maternal resources to the embryo. One prediction of this model is that imprinting exists in species in which there is at least some contribution of maternal resources to the embryo, and in which polyandry is observed. To test this prediction the allelic expression of the IGF2 gene was examined in two noneutherian species. The IGF2 gene was shown to be expressed in a paternal-specific manner identical to that in eutherians in Monodelphis domestica, a placental South American opossum. In contrast, the IGF2 gene is biallelic in expression in chickens, which are oviparous, and make no postfertilization contribution of maternal resources to the offspring.

Alleles↗
PubMed2000

Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus.

Crosses between the two North American rodent species Peromyscus polionotus (PO) and Peromyscus maniculatus (BW) yield parent-of-origin effects on both embryonic and placental growth. The two species are approximately the same size, but a female BW crossed with a male PO produces offspring that are smaller than either parent. In the reciprocal cross, the offspring are oversized and typically die before birth. Rare survivors are exclusively female, consistent with Haldane's rule, which states that in instances of hybrid sterility or inviability, the heterogametic sex tends to be more severely affected. To understand these sex- and parent-of-origin-specific patterns of overgrowth, we analysed reciprocal backcrosses. Our studies reveal that hybrid inviability is partially due to a maternally expressed X-linked PO locus and an imprinted paternally expressed autosomal BW locus. In addition, the hybrids display skewing of X-chromosome inactivation in favour of the expression of the BW X chromosome. The most severe overgrowth is accompanied by widespread relaxation of imprinting of mostly paternally expressed genes. Both genetic and epigenetic mechanisms underlie hybrid inviability in Peromyscus and hence have a role in the establishment and maintenance of reproductive isolation barriers in mammals.

Animals↗
PubMed1999

LY379268, a potent and selective Group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia.

The neuroprotective effects of a selective Group II metabotropic glutamate receptor (mGluR) agonist, LY379268, have been evaluated against global and focal cerebral ischaemia. Loss of CA1 hippocampal neurones following 5 min bilateral occlusion of the carotid artery (BCAO) in the gerbil was almost completely prevented by LY379268 (10 mg/kg, i.p.) given 30 min post-occlusion (P < 0.001); 10 mg/kg 1 h after and 20 mg/kg 2 h after BCAO also produced significant neuroprotection (P < 0.05). Similarly the BCAO-induced increase in TUNEL positive cells at 5 days post-occlusion was reduced by LY379268. By contrast the size of the infarct following middle cerebral artery occlusion (MCAO) induced by endothelin-1 infusion in the rat was unaffected by either 10 or 20 mg/kg i.p. of LY379268. This contrast between the results from these two animal models with LY379268, agrees with previous data on a less potent but similarly selective mGluR2/3 agonist, LY354740. It further suggests that mGluR Group II agonists are likely to have more utility in global, than in focal, cerebral ischaemia.

Amino Acids↗
PubMed1999

Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia.

We have investigated the neuroprotective effects of combining an NMDA or AMPA receptor antagonist with a nitric oxide synthase (NOS) inhibitor in the gerbil model of global cerebral ischaemia. Ischaemia was induced by occlusion of the common carotid arteries for 5 min. (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801, 2.5 mg/kg i.p.) or (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoq uinoline-3-carboxylic acid (LY293558, 20 mg/kg i.p.) and 7-nitroindazole (25 mg/kg i.p.) or N-[4-(2-[[(3-chlorophenyl)methyl]amino]ethyl) phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL17477, 25 mg/kg i.p.) were administered alone or in combination (i.e., MK-801 with 7-nitroindazole or ARL17477 or LY293558 with 7-nitroindazole or ARL17477). In the present studies, both MK-801 and LY293558 provided significant degree of neuroprotection, while 7-nitroindazole and ARL17477 also provided some neuroprotection, which failed to reach significance in every case. However, the combination of MK-801 with 7-nitroindazole or ARL17477 provided 21% or 44% greater protection than the total protection or either alone. Likewise, the combination of LY293558 with 7-nitroindazole or ARL17477 provided 14.5% and 35% greater protection than total protection of either compound alone. These results indicate that several pathways contribute to ischaemic cell death and combining excitatory amino antagonists and NOS inhibitors provides greater protection than either alone. Therefore, combination therapy should be considered as an approach for treating ischaemic conditions.

Amidines↗
PubMed1999

NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus.

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)]decahydroiso quinoline-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 x 10 mg/kg at 3 h intervals), LY300164 (4 x 10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4 x 20 mg/kg i.p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4 x 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.

Animals↗
PubMed1999

Ascorbic acid is neuroprotective against global ischaemia in striatum but not hippocampus: histological and voltammetric data.

Following reports that ascorbic acid (AA) blocks NMDA receptors, we examined its possible neuroprotective properties in vivo (gerbil bilateral carotid artery occlusion model: BCAO) and in vitro (ischaemia-induced dopamine (DA) release in brain slices). Five minutes of BCAO caused substantial cell loss of 90-95% and 40-50% in gerbil CA1 hippocampus and striatum, respectively, measured in haematoxylin and eosin-stained sections, 5 days post-insult. AA (500 mg kg(-1) day(-1) i.p. for 312 days, first dose 1 h before occlusion) significantly (P<0.05) reduced striatal cell loss (from 40 to 13%) while only reducing CA1 cell loss from 95 to 88%. A lower dose (250 mg kg(-1) day(-1) i.p. for 312 days) was ineffective in either region. AA (750 mg kg(-1) day(-1) i.p. for 312 days) caused significant striatal protection (cell loss reduced from 49 to 20%) if treatment was initiated 1 h before occlusion. Initiation of treatment immediately post occlusion did not cause significant protection. Neither treatment regime protected CA1 hippocampus. In separate experiments we examined the effect of AA on DA release, monitored by voltammetry, in an in vitro model of striatal ischaemia. Four DA release variables were measured: T(on)--time from initiation of ischaemia to the onset of DA release, T(pk)--the time from onset of DA release to maximum, deltaDA/deltat--the mean rate of DA release and [DA](max)-- the maximum extracellular DA concentration. Control values in drug-naive slices were: T(on)=193+/-8 s, T(pk) = 24 +/- 4 s, [DA](max) = 69 +/- 6 microM and deltaDA/deltat = 4.2 +/- 0.7 microM s(-1) (means+/-S.E.M., n=15). 212 h pretreatment with AA (0.4 to 10 mM) did not affect T(on) or [DA](max) but increased T(pk) and decreased deltaDA/deltat (P<0.05) with an EC50 of 1.66 mM. NMDA (100 microM) shortened T(on). N-ethylmaleimide (20 microM) had no effect on the response to AA but potentiated the action of NMDA on T(on). AA (2 or 10 mM) had no effect on the response to NMDA. We conclude that AA is neuroprotective against global ischaemia in the striatum and that some of this action may be due to attenuation of ischaemia-induced DA release. This action is mediated neither by blockade of the NMDA receptor nor modulation of its redox status.

Alkylating Agents↗
PubMed1999

Neuroprotection by metabotropic glutamate receptor glutamate receptor agonists: LY354740, LY379268 and LY389795.

In rat cortical neuronal cultures, metabotropic glutamate (mGlu) receptor agonists: LY354740 (+)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate); LY379268 (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate, and LY389795 (-)-2-thia-4-aminobicyclo[3.1.0]-hexane-4,6-dicarboxylate, were neuroprotective against toxicity induced by N-methyl-D-aspartic acid (NMDA), kainic acid and staurosporine as measured by release of lactate dehydrogenase (LDH) activity into culture supernatants and DNA fragmentation by oligonucleosome formation. The potencies of the agonists were at least 100 times greater in reducing nucleosome formation than LDH release indicating a differential effect on neurons dying by apoptosis than by necrosis. In vivo studies showed that LY354740 was able to mediate a partial protection against apoptosis in CA1 hippocampal cells under ischaemic conditions where substantial CA1 cell loss occurred. The effects of the agonists in vitro were: (a) reversed by mGlu receptor antagonist LY341495, (b) enhanced by the presence of glial cells, (c) abrogated by RNA and protein synthesis inhibitors, and (d) unaltered by inhibition of endogenous adenosine activity. These results suggest that group II mGlu receptor agonists may represent a novel therapeutic strategy for the treatment of neurodegenerative diseases.

Amino Acids↗
PubMed1999

Evaluation of glycine site antagonists of the NMDA receptor in global cerebral ischaemia.

In the present studies we have investigated the effects of a range of glycine site antagonists of the N-methyl-d-aspartate (NMDA) receptor in the gerbil model of global cerebral ischaemia. The compounds tested were (+)-3-amino-1-hydroxy-2-pyrrolidone (HA 966, 15 mg/kg), 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)-quinolinone) (L-701,324, 40 mg/kg), 7-chloro-3-(cyclopropylcarbonyl)-4-hydroxy-2(1H)-quinolinone) (L-701, 252, 50 mg/kg), (3-(3-hydroxyphenyl)prop-2-ynyl 7-chloro-4 hydroxy-2(1H)-quinolone-3-carboxylate) (L-701,273, 50 mg/kg), 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021, 25 mg/kg) and [(E)-3[(phenylcarbamoyl) ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt (GV 150526A, 40 mg/kg). All compounds were administered via the i.p. route 30 min before and again at 2 h 30 min after 5 min bilateral carotid artery occlusion (BCAO) in the gerbil. For comparison we also evaluated a non-competitive NMDA antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine (MK-801, 2 mg/kg) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, (3S,4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoquinoline-3-car boxylic acid (LY293558, 20 mg/kg). In the present studies L-701,252, L-701, 324 and L-701,273 provided a small degree of neuroprotection. ACEA 1021, GV 150526A and HA 966 failed to provide any neuroprotection, while MK-801 provided significant (20%) protection. In contrast LY293558 provided good (55%) neuroprotection. These results indicate that glycine site antagonists and competitive NMDA antagonists provide a small degree of neuroprotection in global cerebral ischaemia. In contrast, AMPA receptor antagonists provide more robust neuroprotection in global cerebral ischaemia.

Animals↗
PubMed1999

Neuroprotective activity of the potent and selective mGlu1a metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385): comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlu1a and mGlu5 receptors.

(+)-2-Methyl-4-carboxyphenylglycine (LY367385), a potent and selective antagonist of mGlu1a metabotropic glutamate receptors, was neuroprotective in the following in vitro and in vivo models of excitotoxic death: (i) mixed cultures of murine cortical cells transiently exposed to N-methyl-D-aspartate (NMDA); (ii) rats monolaterally infused with NMDA into the caudate nucleus; and (iii) gerbils subjected to transient global ischemia. We have compared the activity of LY367385 with that of the novel compound (+/-)-alpha-thioxantylmethyl-4-carboxyphenylglycine (LY367366), which antagonizes both mGlu1a and -5 receptors at low micromolar concentrations, but also recruits other subtypes at higher concentrations. Although LY367366 was neuroprotective, it was in general less efficacious than LY357385, suggesting that inhibition of mGlu1 receptors is sufficient to confer significant neuroprotection. We conclude that endogenous activation of mGlu1a receptors (or perhaps other mGlu1 receptor splice variants) contributes to the development of neuronal degeneration of excitotoxic origin.

Animals↗
PubMed1999

Neuroprotective actions of novel and potent ligands of group I and group II metabotropic glutamate receptors.

The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia. Previous studies have also shown that activation of group II mGlu receptors may contribute to neuroprotective mechanisms in vitro and in vivo. Three potent group II mGlu agonists--LY354740, LY379268 and LY389795--were found to attenuate both NMDA excitotoxicity and staurosporine-induced neuronal cell death. LY354740 and LY379268 were protective against transient global ischemia in gerbils when dosed intraperitoneally. These results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful agents in the therapeutic treatment of neurodegenerative disease.

Animals↗
PubMed1998

Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia.

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Undermethylation associated with retroelement activation and chromosome remodelling in an interspecific mammalian hybrid.

Genetic models predict that genomic rearrangement in hybrids can facilitate reproductive isolation and the formation of new species by preventing gene flow between the parent species and hybrid (sunflowers are an example). The mechanism underlying hybridization-induced chromosome remodelling is as yet unknown, although mobile element activity has been shown to be involved in DNA rearrangement in some dysgenic Drosophila hybrids. It has been proposed that DNA methylation evolved as a means of repressing the movement of mobile elements (the host defence model). If such a protective mechanism were to fail, mobile elements could be activated, and could cause major and rapid genome alterations. Here we demonstrate the occurrence of genome-wide undermethylation, retroviral element amplification and chromosome remodelling in an interspecific mammalian hybrid (Macropus eugenii x Wallabia bicolor). Atypically extended centromeres of Macropus eugenii derived autosomes in the hybrid were composed primarily of an unmethylated, amplified retroviral element not detectable in either parent species. These results, taken with the observation of deficient methylation and de novo chromosome change in other mammalian hybrids, indicate that the failure of DNA methylation and subsequent mobile-element activity in hybrids could facilitate rapid karyotypic evolution.

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

Isolation of translactone-containing triterpenes with thrombin inhibitory activities from the leaves of Lantana camara.

Methanolic extracts prepared from the leaves of Lantana camara have been found to inhibit human thrombin. An assay, in which thrombin activity is measured as a function of clot formation from fibrinogen, was used to guide the fractionation and purification of five principal active constituents (1-5), which were all characterized as 5,5-trans-fused cyclic lactone-containing euphane triterpenes.

Carbohydrate Sequence↗
PubMed1998

Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.

Kallmann syndrome is an inherited disease which is characterised by anosmia (inability to smell) and hypogonadotropic hypogonadism both of which are thought to occur as a result of a failure of correct neuronal migration. To date the only genetic lesions identified are mutations in the X-linked gene, KAL. We conducted a mutation screen of the KAL gene in a family with Kallmann syndrome. This identified a new mutation in the KAL gene which removed an acceptor site at the junction of exon 6/intron 5. Exon 6 of the KAL gene encodes the C-terminal portion of a fibronectin type III domain may be involved in axonal pathfinding. We presume that the described mutation would result in the removal of exon 6 resulting in a frame shift which terminates the protein prematurely. It has been proposed that both mental illness and vesico-ureteric reflux are associated with mutations in the KAL gene. However, results from the family presented here do not show an association between either trait and the KAL gene mutation.

Child↗