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Biomedical subjects

B E Leonard

Publications and source records attributed to B E Leonard.

At least 91 records · Page 5Linked to original sources
PubMed1996

Stress and the immune system in the etiology of anxiety and depression.

There is clinical and experimental evidence that various aspects of the immune and endocrine systems are severely compromised in chronic stress and depression. For example, it has been shown that a reduced lymphocyte response occurs to mitogens in depressed patients, effects that are not reversed by chronic antidepressant treatment. By contrast, monocyte phagocytosis is increased, while neutrophil phagocytosis is decreased in depressed patients. Such changes are normalized by effective antidepressant treatment. The results of such studies and others that demonstrate alterations in noncellular immune processed in depression indicate that the changes in immune function correlate with the severity and duration of the external and/or internal stressful stimuli. There is evidence that some of the immune changes are a reflection of increased plasma glucocorticoids that characterize both stress and depression. However, it is also apparent that the cytokines, prostaglandins, and corticotrophic releasing factor (CRF) also play an important role in initiating the behavioral and pathophysiological changes that are characteristic of both depression and chronic stress. This review attempts to critically assess the interplay between CRF, the immune and neurotransmitter systems, and behavior in chronic stress and depression.

Animals↗
PubMed1996

The novel sigma ligand JO 1994 protects against ischaemia-induced behavioural changes, cell death and receptor dysfunction in the gerbil.

To assess the effects of the novel sigma ligand JO 1994 on behavioural, histological and autoradiographical changes following global ischaemia, the Mongolian gerbil was used. Three experiments were carried out and in each case ischaemia was induced by bilateral carotid occlusion (BCO) for 5 min. In the first experiment we examined the effects of JO 1994 administered at doses of 0.25, 0.5 and 1 mg/kg i.p. 1 h before 5 min BCO on histological parameters 96 h after surgery. In the second experiment the effects of JO 1994 administered at doses of 2.5, 5, 10 and 20 mg/kg i.p. 1 h before 5 min BCO on locomotor activity 24, 48 and 72 h after surgery and on histological parameters 96 h after surgery was examined. In the third experiment the effects of JO 1994 (2.5 and 5 mg/kg i.p.), BMY 14802 (1 and 10 mg/kg i.p.) and MK-801 (2.5 mg/kg i.p.) administered 30 min, 6, 24, 48, 72, 96 and 120 h post-surgery on the densities of M1 and M2 muscarinic receptors in 35 brain regions, 7 days after surgery was examined. Results indicated that 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. JO 1994 attenuated this hyperactivity. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min BCO animals 96 h after surgery. The low doses of JO 1994 (0.25, 0.5 and 1 mg/kg) had no effect on the ischaemia-induced cell death. However JO 1994 (2.5, 5, 10 and 20 mg/kg i.p.) protected against the neuronal death of cells in the CA1 layer (P < 0.01-0.03). There was a large loss of M1 and M2 receptors in the CA1 regions of the hippocampus. MK-801, BMY 14802 and JO 1994 provided significant (P < 0.01) protection against this ischaemia-induced receptor loss.

Animals↗
PubMed1996

Behavioural and immunological effects of the antihistamine terfenadine in olfactory bulbectomized rats.

The effects of chronic treatment with the non-sedative histamine H1 receptor antagonist terfenadine (5 mg/kg, i.p.) for 16 days on some behavioural and immunological parameters were studied in the olfactory bulbectomized (OB) rat model of depression. In the open field apparatus, OB rats showed a significant increase in ambulation and rearing scores. Following terfenadine treatment, this hyperactivity was significantly attenuated. In untreated OB rats, neutrophils phagocytosis and lymphocyte proliferation were significantly suppressed. Terfenadine administration markedly reversed the suppression of these immunological parameters in the treated OB animals, but did not reverse the abnormalities in the differential white blood cell count caused by bulbectomy. These results suggest that the histamine H1 receptor antagonist terfenadine may have antidepressant properties and that terfenadine is effective in reversing some of behavioural and immune changes in the olfactory bulbectomized rat model of depression.

Animals↗
PubMed1996

High 222Rn levels, enhanced surface deposition, increased diffusion coefficient, humidity, and air change effects.

Measurements have been made of surface deposition rates for 218Po radon decay products in a small (0.283m3) aluminum test chamber for 222Rn levels from 1 to 1,600 kBq m-3. an increase in macroscopic surface deposition rate has been found to be induced by the high 222Rn concentrations. A distinct 222Rn level threshold has been found below which plateout is constant at the normal rate for ambient residential conditions. Above the threshold, an increase in plateout is observed and the transition quickly reaches a constant, higher plateout. With all environmental conditions remaining constant and varying humidity, the threshold 222Rn level decreases with increasing relative humidity. The rate of rise to the new plateau is found to increase with increasing humidity. For the constant air change rate of ACH = 0.2 h-1, the fraction of airborne 218Po lost by the enhanced plateout was consistently 0.4 +or- 0.25 for seven values of humidity from 8 to 54% RH. For a fixed RH = 40 +or- 2%, it was found that the threshold increases from 5 to 58 kBq m-3 for a change in ACH from 0 1.06 h-1. In converting the deposition data to values of diffusion coefficient D, using Crump and Seinfeld's theory, a very high D of 0.18 cm2s-1 is assumed for ambient air conditions. Results indicate an ambient D = 0.027 cm2s-1. The results may impact on research utilizing high levels in test chambers and diffusion coefficients and attached and unattached fractions, and also for cancer studies using animals with 222Rn levels as much as 10(4) times greater than ambient residential levels.

Air Pollutants, Radioactive↗
PubMed1996

Pharmacokinetics of milnacipran in comparison with other antidepressants.

Despite the large number of antidepressants currently available, it is still necessary to develop new drugs that combine the efficacy of the older antidepressant with improved safety, tolerability and therapeutic profile that will allow them to be used in depressed patients who are elderly or with cardiac, renal or hepatic disease. This article reviews the pharmacokinetic characteristics of the tricyclic antidepressants, the selective serotonin reuptake inhibitors (SSRIs) and more recently introduced antidepressants such as venlafaxine and nefazodone. Milnacipran (Ixel), a novel drug, combines antidepressant efficacy with some unique pharmacokinetic features. A summary of its pharmacokinetic profile shows that milnacipran has a high bioavailability, low plasma protein binding and that it is largely eliminated in the urine as parent drug or as a glucuronide. These features suggest that the likelihood of interactions with other drugs given concurrently is lower than would occur with most second generation antidepressants and the tricyclic antidepressants. Furthermore, studies in patients with liver dysfunction, and in the elderly, suggest that dose adjustment is not necessary when milnacipran is administered to these patients. The decrease in milnacipran elimination is correlated to the degree of renal impairment, allowing adjustment of schedules. In comparison to earlier antidepressants, milnacipran combines efficacy and a relatively low side-effect profile with the added advantage of fewer interactions with drugs that may be given concurrently.

Adrenergic Uptake Inhibitors↗
PubMed1996

The characterization of oxotremorine-induced hypothermic response in the rat.

Oxotremorine is a muscarinic receptor agonist that induces a variety of physiological and behavioural effects including hypothermia in mice. These effects are antagonized dose-dependently by classical anticholinergic compounds such as atropine. Although the oxotremorine-induced hypothermic response has been demonstrated in mice, few studies of the effects of this muscarinic agonist have been made in the rat. The following studies were made in male Sprague Dawley rats: 1. an investigation of the dose-response relationship between oxotremorine and hypothermia; 2. an examination of the effect of housing on the oxotremorine-induced hypothermic response, and 3, an investigation of the acute administration of various doses of atropine sulphate on the hypothermia caused by oxotremorine. The results indicate that the dose-response relationship between oxotremorine and the antagonism of hypothermia is similar in rat as it is in mice. The results also showed that this effect did not occur in group-housed animals.

Animals↗
PubMed1996

The sigma ligand JO 1784 prevents trimethyltin-induced behavioural and sigma-receptor dysfunction in the rat.

Recently much research interest has focused on the possible therapeutic uses of sigma-receptor ligands in psychiatric and neurodegenerative disorders. In the present study, the potential neuroprotective effects of chronic (52 days) administration of (+) cinnamyl-l-phenyl-l-N-methyl-N-cyclo propylene (JO 1784) (1 and 3 mg/kg subcutaneously), a potent and selective sigma receptor ligand, were assessed in the trimethyltin (8 mg/kg intraperitoneally) model of memory dysfunction. JO 1784 (3 mg/kg subcutaneously) prevented the trimethyltin-induced deficits in locomotor activity, passive avoidance and radial maze performance, while the lower dose of JO 1784 had little or no effect. Trimethyltin was also shown to produce a marked reduction in the binding of [3H] (+)-pentazocine to sigma-receptor sites in limbic brain structures, as detected by quantitative autoradiography, which was particularly evident in the hippocampal pyramidal cells. JO 1784 (3 mg/kg subcutaneously) successfully attenuated this loss of [3H] (+)-pentazocine binding sites in the hippocampus (CA1, CA3 and CA4 regions) and in the substantia innominata. This neuroprotective effect of JO 1784 in the trimethyltin model would seem to be related to the modulatory effects of this sigma ligand on trimethyltin-induced glutamate neurotoxicity.

Animals↗
PubMed1996

The dopamine agonists lisuride and piribedil protect against behavioural and histological changes following 4-vessel occlusion in the rat.

The 4-vessel occlusion model of ischaemia in the rat was used to assess the effects of two dopaminergic agonists, lisuride and piribedil, on some behavioural and histological changes. Animals were either sham-operated, subjected to 20 min 4-vessel occlusion, or administered lisuride (0.5 mg/kg i.p.) or piribedil (10 mg/kg i.p.) 1 h before 20 min 4-vessel occlusion. Both drugs attenuated deficits in neurological testing, Morris water maze and 14-unit T-maze (p < 0.05). Extensive neuronal death was observed in the CA1, CA3 and CA4 regions of the hippocampus of 4-vessel-occluded animals. Pretreatment with both lisuride and piribedil provided protection against cell death in the hippocampal regions. These findings suggest dopamine may play a role in cerebral ischaemia and dopaminergic agonists may be beneficial in preventing ischaemia-induced neurodegeneration.

Animals↗
PubMed1996

New approaches to the treatment of depression.

This review considers the various modes of action and possible advantages of the different types of second generation antidepressants. The biochemical changes that may be causally related to depression and the mechanisms whereby these changes may be attenuated by antidepressant treatment are briefly considered. Whereas the monoamine theory of depression and the receptor adaptation hypothesis of antidepressant action have been influential in helping to unify the mechanisms of action of antidepressants with the possible pathologic basis of depression, the introduction of novel antidepressants and the development of treatment strategies suggestive of a rapid onset of antidepressant response may initiate a revision of these concepts. The review ends with a consideration of the nonaminergic changes that may be of fundamental importance not only in the pathologic basis of depression but also to the means whereby antidepressants bring about their clinical effects.

Antidepressive Agents, Second-Generation↗
PubMed1995

Behavioral, neurochemical, and immunological responses to CRF administration. Is CRF a mediator of stress?

The effect of subacute intracerebroventricular (icv 0.1, 0.5, and 1.0 microgram) administration of corticotropin-releasing factor (CRF) for 5 days on behavior, neurotransmitter concentrations, and immune functions was studied in rats. The results showed that CRF administration produced a dose-dependent increase in locomotor activity in the "open field" test compared with controls; rearing scores were also significantly increased. In the elevated plus maze apparatus, rats given 1.0 microgram CRF spent considerably less time on the open arms when compared with controls. Following 0.5 and 1.0 microgram of CRF infusion, the concentrations of noradrenaline (NA), dopamine (DA) and 5-hydroxy indole acetic acid (5-HIAA) were significantly increased in the hypothalamus. There was no significant change in the concentrations of neurotransmitters in the other brain regions. CRF administration also produced a dose-dependent increase in the levels of corticosterone in the serum. The immunological results clearly showed that subacute icv CRF administration caused a reduction of lymphocyte proliferation, a decrease in the percentage of lymphocytes, and an increase in neutrophil percentage in the differential white blood cell (WBC) count, a decrease in neutrophil phagocytosis, and elevated leucocyte adhesiveness/aggregation (LAA) compared with control animals. These results suggest that icv subacute administration of CRF has anxiogenic effects, increases biogenic amine concentrations in the hypothalamus, and changes in some aspects of immune functions that may reflect the stress-inducing properties of the peptide. These effects are time and dose dependent.

Animals↗
PubMed1995

NG-nitro-L-arginine methyl ester protects against lipid peroxidation in the gerbil following cerebral ischaemia.

The aim of this study was to assess the role of nitric oxide (NO) in lipid peroxidation following 5 min of bilateral carotid occlusion in the Mongolian gerbil. The study consisted of 4 experimental groups (n = 10). Animals were either sham operated, subjected to bilateral carotid occlusion or administered the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg i.p.) 30 min, 6, 24 and 48 h following sham operation or 5 min bilateral carotid occlusion. Animals were killed 96 h post surgery and changes in the concentrations of malonaldehyde and 4 hydroxyalkenals (the main decomposition products of peroxides derived from polyunsaturated fatty acids and related esters) were measured in the hippocampus and cortex using the LPO-586 colorimetric method. The results showed a significant increase in the concentrations of both decomposition products following 5 min of bilateral carotid occlusion. L-NAME administered to sham operated controls had no effect, but in those animals subjected to 5 min of bilateral carotid occlusion L-NAME significantly decreased the levels of both decomposition products. These results suggest that inhibition of NO synthase activity decreases lipid peroxidation in the gerbil model of cerebral ischaemia.

Animals↗
PubMed1995

The sigma receptor ligand JO 1784 (igmesine hydrochloride) is neuroprotective in the gerbil model of global cerebral ischaemia.

To assess the effects of the novel sigma receptor ligand JO 1784 ((+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride or igmesine hydrochloride) on behavioural and histological changes following cerebral ischaemia, the gerbil model of cerebral ischaemia was used. Two experiments were carried out. In the first animals were either sham operated, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bilateral carotid occlusion and histological evaluation carried out 96 h after surgery. In the second experiment the effects of JO 1784 administered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery on home cage activity and nitric oxide (NO) synthase activity in the cortex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided significant protection against this ischaemia-induced cell death (P < 0.03-0.005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0.0018-0.02). A large increase in NO synthase activity was observed in all brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The effect of 2-amino-3-phosphonopropionic acid (AP-3) in the gerbil model of cerebral ischaemia.

The effect of 2-amino-3-phosphonopropionate (AP-3), a metabotropic glutamate receptor antagonist on behavioral and histological changes following global ischaemia was investigated on the Mongolian gerbil. Ischaemia was induced by bilateral carotid occlusion for 5 min. AP-3 was administered i.p. (25 or 250 mg/kg) 30 min before and 24 h after surgery. Significant neuroprotection was observed 96 h after surgery to cells in the CA1 region of the hippocampus in drug treated animals. AP-3 (250 mg/kg) significantly attenuated the increase in locomotor activity measured 72 h after surgery. These results suggest that metabotropic glutamate receptors play a role in the neurodegeneration seen following ischaemia.

Alanine↗
PubMed1995

Further characterization of the inhibition of platelet aggregation by a plasma factor(s) in unmedicated unipolar depressed patients.

To investigate further the inhibition of platelet aggregation by a plasma factor(s) in unipolar depression, a series of assays were performed in which the platelet-rich plasma of a male volunteer was preincubated with the plasma of either unmedicated unipolar depressed patients or age-matched controls. Platelet aggregation was initiated by the following aggregating agents; ADP (10 and 2.5 microM), ADP/5HT (0.5 microM ADP + 50 microM 5HT and 0.5 microM ADP + 25 microM 5HT) and adrenaline (10 and 1 microM) (that act on different platelet membrane receptors) and by the following agents; sodium fluoride (20 mM), calcium ionophore A23,187 (19 microM) and phorbol-12-myristate-13-acetate (3.24 microM) (that act at specific intracellular sites). The plasma of depressed patients significantly reduced the platelet aggregatory response for each of the aggregating agents at each of the concentrations tested. Therefore, it is concluded that the inhibition of platelet aggregation by a plasma factor(s) may be irreversible in nature and may have an intracellular site(s) of action, possibly at, or beyond, the site of activated protein kinase C.

Adenosine Diphosphate↗
PubMed1995

Some behavioural and neurochemical aspects of subacute (+/-)3,4-methylenedioxymethamphetamine administration in rats.

(+/-)3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"), an increasingly popular recreational drug, is known to damage brain serotonin (5-hydroxytryptamine [5-HT]) neurons, whilst also having a less pronounced effect on the dopaminergic system. Treatment with MDMA results in an increased locomotor activity, elevated basal serum corticosterone concentrations, decreased exploratory activity, and changes in body temperature. The aim of this study was to examine the dose related effects of subacute administration of MDMA (5, 10, and 20 mg/kg IP twice daily for 4 days) on home cage locomotor activity, "open field" and "step-down passive avoidance" behaviours, changes due to an 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) challenge, and on plasma corticosterone and brain neurotransmitter concentrations. Total locomotor activity counts were significantly increased by both 10 and 20 mg/kg MDMA for the 4 days of drug administration. There were no significant differences seen in the "open field" or "step down passive avoidance" behaviour, in the 8-OH-DPAT induced hypothermia, or in basal serum corticosterone concentrations. MDMA caused a significant depletion of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex and amygdala and a significant elevation of dopamine and noradrenaline in the hippocampus. Apart from the increase in locomotor activity following subacute administration, the observed behaviour of the MDMA treated rats would not appear to reflect the substantial changes in brain biogenic amine neurotransmitters.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Effects of JO 1784, a selective sigma ligand, on the autoradiographic localization of M1 and M2 muscarinic receptor subtypes in trimethyltin treated rats.

The distribution patterns of M1 and M2 muscarinic receptor subtypes following TMT and JO 1784 administration in the male Sprague-Dawley rat were investigated. In the present study, JO 1784 was injected in doses of 1, 4 and 16 mg/kg i.p. for one week prior to the single injection of TMT (8 mg/kg i.p.) and subsequently for 33 days. The effects of JO 1784 on the density of muscarinic receptor sub-types (M1 and M2) in the control and trimethyltin (TMT) treated rats were then evaluated. The topographic distribution and changes in muscarinic (M1 and M2) receptor densities were determined by means of autoradiography using [3H]quinuclidinylbenzilate (QNB). Both sub-types of muscarinic receptors contributed to the observed decrease in total muscarinic receptor binding in TMT-treated rats. In control rats, JO 1784 alone decreased M1 receptor density in the amygdaloid nuclei, basal ganglia, cortex and hippocampus and decreased M2 receptor density in the amygdaloid nuclei, basal ganglia, cortex, hippocampus, hypothalamus and septal regions. In TMT treated rats, chronic JO 1784 administration has a "neuroprotective effect" on both M1 and M2 receptors subtypes. Thus, following chronic administration of JO 1784 to TMT treated rats, both increases and decreases in M1 receptor density were observed relative to TMT animals. A significant increase in M1 receptor density was found in the cortex, olfactory regions, septum, thalamus and basal forebrain nuclei. In the hippocampus (CA2 and CA3), a significant decrease in M1 receptor density was observed. In TMT-treated rats, JO 1784 produced a significant increase in M2, receptor density in several brain regions with the most marked effects occurring in the amygdaloid nuclei, basal ganglia, cortex, hippocampus and hypothalamus. The ability of the selective sigma ligand, JO 1784, to attenuate the loss of muscarinic receptors in TMT treated rats could be of importance in the development of novel neuroprotective drugs.

Animals↗
PubMed1995

222Rn progeny surface deposition and resuspension--residential materials.

The radiological hazard of radon gas to occupants in residential environments is from the particulate progeny 218Po, 214Pb, 214Bi, and 214Po, rather than 222Rn itself. Attachment to aerosols, plateout, and resuspension impact on the progeny airborne concentrations. Plateout rate and resuspension factors were measured for air change (ventilation) rates, 0.01 to 1.0 h-1, in a 0.28 m3 test chamber for interior residential materials of wallboard, drapery, carpet, ceiling tile, and concrete, and from 0.05 to 2.5 h-i for hardwood and glass. The overall accuracy of the plateout rate values is estimated to be +/- 13% standard deviation. For the different materials, the plateout rates for 218Po progeny varied by a factor of nearly six. Drapery gave the largest plateout rates. Resuspension rate factors, R, were measured for hardwood, wallboard, drapery, carpet, and glass by a new time-dependent measurement method based on the difference in buildup rate of 214Po to equilibrium caused by resuspension. Values for R obtained for hardwood, wallboard, drapery, carpet and glass were 0.31, 0.29, 0.44, 0.55, and 0.36, respectively ( +/- 30% standard deviation). All measurements were made in a continuous air conditioned interior environment maintaining temperature at 22.2 +/- 1.1 degrees C and relative humidity of 30% +/- 10%. Computations were made of equivalent plateout rates and equilibrium fractions for a standard 5 m x 5 m x 3 m high room to provide values to compare with other work.

Construction Materials↗