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Biomedical subjects

P H Yu

Publications and source records attributed to P H Yu.

At least 73 records · Page 4Linked to original sources
PubMed1997

Enhanced tolerance of neuroblastoma cells towards the neurotoxin 6-hydroxydopamine following specific cell-cell interaction with primary astrocytes.

Dopamine neuroblastoma (SH-SY5Y) cells exhibit a high affinity of adhesion for primary astroglial cells. The homophilic aggregation of SH-SY5Y cells is greatly reduced and the neuroprocesses are enhanced when co-cultured with the astrocytes. However, such affinity was not detected in the mouse when these cells were co-cultured with fibroblast and endothelial cells. SH-SY5Y cells in monoculture are very sensitive towards the neurotoxin 6-hydroxydopamine, but this sensitivity is substantially reduced in co-culture with astrocytes. The acquired cytoprotection of the neuroblastoma cells in co-culture against 6-hydroxydopamine is time dependent following adhesion with the astrocytes. There is no evidence to indicate that the increase in survival of the SH-SY5Y cells against 6-hydroxydopamine is due to inactivation of 6-hydroxydopamine induced by the extracellular factors secreted from the astrocytes, neither is there any indication suggesting the removal of 6-hydroxydopamine by an astrocyte uptake mechanism. The release of trophic factors by the astrocytes does not seem to play a role in the protection of the neuroblastoma cells against 6-hydroxydopamine. The neuroblastoma cells became susceptible to 6-hydroxydopamine in the astrocyte co-cultures when they were physically separated from the astroglial cells by trans-well inserts. Neither non-selective adhesions, such as adhesion with denatured astrocytes or with other types of cells (i.e. endothelial or fibroblast cells), nor adhesion enhanced by chemical agents can increase the cytoprotection of SH-SY5Y against 6-hydroxydopamine. These results suggest that the increase in survival of neuroblastoma cells against 6-hydroxydopamine in the astrocyte co-cultures is probably a result of specific cell-cell adhesion and the subsequent interactions.

Animals↗
PubMed1997

Formation of formaldehyde from adrenaline in vivo; a potential risk factor for stress-related angiopathy.

Cardiovascular and cerebrovascular disorders are well known to be associated with stress related behaviors. Stress enhances excretion of adrenaline, which is deaminated by monoamine oxidase and methylamine is formed. This product can be further deaminated by semicarbazide-sensitive amine oxidase (SSAO) and converted to toxic formaldehyde, hydrogen peroxide and ammonia. SSAO is located in the cardiovascular smooth muscles and circulated in the blood. We investigated whether formaldehyde can be derived from adrenaline in vivo. Methylamine was confirmed to be a product of adrenaline catalyzed by type A monoamine oxidase (MAO-A). Irreversible and long-lasting radioactive residual activity was detected in different tissues following administration of 1-[N-methyl-3H]-adrenaline. Such irreversible linkage could be blocked by selective MAO-A or SSAO inhibitors. Endothelial cells are quite sensitive to formaldehyde and relatively resistant to hydrogen peroxide. It is possible that stimulation of adrenaline excretion by chronic stress could increase the levels of circulatory formaldehyde. Such chronic "formaldehyde" stress may be involved in the initiation of endothelial injury and subsequently angiopathy.

Amine Oxidase (Copper-Containing)↗
PubMed1997

Prevention of kainic acid-induced limbic seizures and Fos expression by the GABA-A receptor agonist muscimol.

Fos oncoprotein expression has been shown to be a sensitive marker for sequential neuronal activation in response to a specific stimulus. The present study investigated the effect of the gamma-aminobutyric acid (GABA)-A receptor agonist muscimol on kainic acid (KA)-induced limbic seizures and Fos expression in the rat forebrain. One hour after KA injection, a substantial Fos expression was observed in the hippocampal dentate gyrus, whereas only a low level of Fos induction was seen in CA1-3 fields. Six hours post-injection a prominent increase of Fos expression occurred in most forebrain structures, including the whole hippocampus. Following 0.5 mg/kg muscimol treatment a remarkable decrease of Fos expression occurred but only in the caudate putamen and core of the accumbens nucleus. Treatment with 1 mg/kg muscimol led to further significant decreases of Fos expression in CA1-3 pyramidal neurons and the disappearance of Fos induction in the cerebral cortex above the rhinal fissure, reticular thalamic nucleus, claustrum, fundus striati, ventral pallidum, septal nucleus, lateral habenular nucleus, and lateral amygdaloid nucleus. When 2 mg/kg muscimol was injected, animals exhibited "absence seizures' instead of limbic seizures, and Fos expression in the hippocampus was effectively blocked. These results suggest that a reduction of GABAergic inhibition plays a crucial role not only in limbic seizure genesis in the dentate gyrus, but also in the seizure spread mechanism in many brain structures, among which the hippocampal CA1-3 fields are most markedly involved, less marked in the cerebral cortex and some other structures, and least marked in the caudate putamen and core of the accumbens nucleus.

Animals↗
PubMed1997

Gradation of kainic acid-induced rat limbic seizures and expression of hippocampal heat shock protein-70.

Systemic injection of kainic acid (KA) induces limbic seizures in rats, which resemble human temporal lobe epilepsy, the most common form of adult human epilepsy. In this study, we have investigated KA-elicited limbic seizures in the rats by correlating the severity of the seizure attacks with the expression of hippocampal heat shock protein-70 (HSP70) which has been suggested to be a marker for neuronal injury/death in this model of seizures. After a systemic injection of KA, six stages of limbic seizures have been classified, namely, staring (stage 1), wet dog shake (stage 2), hyperactivity (stage 3), rearing (stage 4), rearing and falling (stage 5), and jumping (stage 6). Stages 4, 5 and 6 were further divided into mild and severe sub-stages. HSP70 expression was not detected in animals with stages 1 and 2 seizures. At stage 3 a small amount of HSP70 immunoreactive neurons was detected in the CA3 field and the dentate hilus. From stage 4 to stage 5 the degree of HSP70 immunoreactivity increased in the CA1 field from a few positive cells in stage 4 mild to large numbers of immunoreactive neurons in stage 5 severe. HSP70 became detectable in pyramidal cells in the CA2 field from stage 5 severe and higher. In animals with stage 6 seizures, the majority of HSP70 expression became located in glial cells throughout the whole hippocampus. We concluded that HSP70 expression in the hippocampus positively correlates with the severity of KA-elicited limbic seizures.

Adult↗
PubMed1997

Effects of a quaternary pyridinium metabolite of haloperidol (HP+) on the viability and catecholamine levels of cultured PC12 cells.

Haloperidol has been found to be metabolized to a pyridinium ion (HP+; 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium). HP+ is structurally similar to the toxic metabolite of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), N-methyl-4-phenylpyridinium (MPP+). HP+ is toxic towards dopaminergic neurons and was proposed to be associated with some of the extrapyramidal side effects of haloperidol. We therefore investigated the neurotoxicity of HP+ towards cultured PC12 cells. At high concentrations, HP+ reduced the viability of PC12 cells as measured by trypan blue exclusion and the MTT method. However, HP+ decreased intracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA) levels at lower concentrations than those required to compromise cell viability. The immunoreactivity of tyrosine hydroxylase was not affected by the treatment with HP+. It was subsequently demonstrated that HP+ can release [3H]DA preloaded in rat striatum slices. Thus, it is proposed that HP+ decreases dopamine content in PC12 cells through actively releasing amines from the cells and (or) blocking the reuptake of the released amines.

Animals↗
PubMed1996

MK-801 induces apoptotic neuronal death in the rat retrosplenial cortex: prevention by cycloheximide and R(-)-2-hexyl-N-methylpropargylamine.

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which can prevent excitatory neuronal death. At higher concentrations, however, it can also induce neuronal death in the limbic system. This MK-801-induced selective neuro-toxicity has been proposed as an animal model for dementia and psychosis. We have investigated the effects of the protein synthesis inhibitor cycloheximide and the neurorescue agent 2-hexyl-N-methylpro-pargylamine [R(-)-2HxMP] on MK-801-induced neuronal death in the retrosplenial cortex in the rat. Cycloheximide [2 mg/kg, subcutaneously (sc)] administered either 1 hr before, or after, injection of MK-801 (5 mg/kg, sc) prevented almost completely neuronal shrinkage and nuclear condensation of the granular retrosplenial cortex as assessed by hematoxylin-eosin staining. The results suggest that the MK-801-induced neuronal death was apoptotic. This neurorescue effect by cycloheximide was time dependent: after 4 hr the effect was reduced to about 50% and by 8 hr had disappeared. R(-)-2HxMP (0.25 mg/kg, sc), which does not inhibit protein synthesis in vitro, was also found to be effective at preventing MK-801-induced neuronal death.

Animals↗
PubMed1996

Fos oncoprotein expression in the rat forebrain following muscimol-induced absence seizures.

Fos oncoprotein expression is a marker of neuronal activation following seizures. Here, using this method we examined the anatomical locations of muscimol-induced absence seizures in the rat forebrain. Six hours after a systemic injection of muscimol a massive Fos immunoreactivity appeared in the olfactory system, retrosplenial cortex and paraventricular thalamic nucleus, whereas other cortical areas contained low level of Fos expression. These results provide the first functional morphological evidence suggesting that these forebrain structures with Fos expression may play an important role in the pathophysiology of muscimol-induced absence seizures.

Animals↗
PubMed1996

Immunohistochemical evidence of neuroprotection by R(-)-deprenyl and N-(2-hexyl)-N-methylpropargylamine on DSP-4-induced degeneration of rat brain noradrenergic axons and terminals.

DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] is a potent neurotoxin highly selective to the locus coeruleus noradrenaline (NA) system. Previous biochemical studies have shown that the monoamine oxidase-B (MAO-B) inhibitors, R(-)-deprenyl and (+/-)2-HxMP [N-(2-hexyl)-N-methylpropargylamine], are able to prevent DSP-4 induced NA depletion in the mouse hippocampus. It is not quite certain, however, whether this actually represents neuroprotection of NA axons or a metabolic effect due to inhibition of MAO activity. Employing dopamine-beta-hydroxylase immunohistochemical and image analysis methods, we have shown that 92% and 84% of NA nerve fibers in the rat hippocampus are spared from DSP-4 neurotoxicity by a single pretreatment dose of either R(-)-deprenyl or (+/-)2-HxMP respectively. Similar neuroprotective effects of R(-)-deprenyl and (+/-)2-HxMP were also observed in the cerebral cortex, thalamus, amygdaloid complex and cerebellum. This is the first morphological evidence demonstrating that R(-)-deprenyl and (+/-)2-HxMP can indeed protect noradrenergic axons of locus coeruleus origin against DSP-4 neurotoxicity.

Animals↗
PubMed1996

Formaldehyde produced endogenously via deamination of methylamine. A potential risk factor for initiation of endothelial injury.

Methylamine can be converted by semicarbazide-sensitive amine oxidase (SSAO) to formaldehyde and hydrogen peroxide, which have been proven to be toxic towards cultured endothelial cells. We investigated whether or not these deaminated products from methylamine can exert potentially hazardous toxic effects in vivo. Long lasting residual radioactivity in different tissues was detected following administration of [14C]-methylamine in the mouse. Approximately 10% of the total administered radioactivity could even be detected 5 days after injection of [14C]-methylamine. Eighty percent of the formation of irreversible adducts can be blocked by a highly selective SSAO inhibitor, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride (MDL-72974A). The residual radioactivity was primarily associated with the insoluble tissue components and the soluble macromolecules. Radioactively labelled macromolecules were fragmented following enzymatic proteolysis. Results suggest that the formaldehyde derived from methylamine interacts with proteins in vivo. In the streptozotocin-induced diabetic mice, both SSAO activity and the formation of residual radioactivity were found to be significantly increased in the kidney. Chronic administration of methylamine enhances blood prorenin level, which strongly suggests that uncontrolled deamination of methylamine may be a risk factor for initiation of endothelial injury, and subsequent genesis of atherosclerosis.

Allyl Compounds↗
PubMed1996

Expression of heat shock protein-70 and limbic seizure-induced neuronal death in the rat brain.

The effect of MK-801, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, on the kainic acid-induced expression of the inducible heat shock protein 70 kDa (HSP70) and on neuronal death in the rat hippocampus was investigated. HSP70 is expressed in approximately 80% of the pyramidal neurons in the CA1 field 1 day after kainic acid injection. The majority of these HSP70-immunopositive neurons exhibited swelling and a hollow appearance in the perikaryon, indicating that they had been injured following kainic acid-elicited limbic seizures. Four days after administration of kainic acid, 87% of the pyramidal neurons in the CA1 field were dead. When a single dose of MK-801 was administered 1 h before kainic acid injection, the number of rats suffering with seizures was reduced, the severity of limbic seizures was attenuated and seizure onset was delayed. Neither HSP70 expression on day 1 nor neuronal loss on day 4 in the CA1 pyramidal cell layer was observed in these animals. A considerable number of HSP70-immunopositive neurons was detected in the dentate hilus, however, and somewhat fewer in the CA3a and CA3c subfields on day 1. Severe neuronal damage in these regions followed on day 4. Interestingly, little HSP70 expression or neuronal loss was observed in the CA3b subfield in these same animals. When a single dose of MK-801 was given 4 h after kainic acid treatment, HSP70 expression was partially blocked; 18% of neurons expressed HSP70 on day 1 and 37% on day 4 in CA1 pyramidal neurons in comparison to the kainic acid controls. About 50% neuronal death was detected in the CA1 pyramidal cell layer 4 days after kainic acid treatment followed by MK-801. When the animals were treated with MK-801 4 h after kainic acid treatment followed by additional daily administration for 3 days, a negligible number of pyramidal neurons expressed HSP70, and the survival of pyramidal cells was significantly increased in the CA1 field. Limbic seizure-induced HSP70 expression not only indicates neuronal injury in the pyramidal cell layer of the hippocampus but also predicts delayed neuronal death, at least in the case of the CA1 field of animals that suffered stage IV-V seizures.

Animals↗
PubMed1995

Neuroprotection by R(-)-deprenyl and N-2-hexyl-N-methylpropargylamine on DSP-4, a neurotoxin, induced degeneration of noradrenergic neurons in the rat locus coeruleus.

N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a neurotoxin and capable of selectively depleting noradrenergic axons and subsequently causing lesions of locus coeruleus (LC) noradrenergic neurons in the rat. R(-)-deprenyl and N-(2-hexyl)-N-methylpropargylamine (2-HxMP) have been previously shown to be quite effective in protecting NA nerve fibers in different brain tissues against DSP-4. The present report reveals the neuroprotective effect of these drugs on the LC noradrenergic cell bodies using a histochemical method. Neurons were quantitatively assessed using Nissl-stained sections. DSP-4 induced a 34% loss of LC perikarya neurons 3 months after a single systemic administration in comparison to control animals. Approximately 90% and 88% of neurons in the same regions survived against DSP-4 induced insult following multiple injections of R(-)-deprenyl and 2-HxMP, respectively. The neuroprotective effect towards the LC neurons against DSP-4 is probably due to prevention of retrograde degeneration of NA axons.

Adrenergic Agents↗
PubMed1995

Aliphatic propargylamines, a new series of potent selective, irreversible non-amphetamine-like MAO-B inhibitors. Their structures, function and pharmacological implications.

1-Deprenyl, a selective irreversible MAO-B inhibitor, has been shown to prolong the onset of disability in Parkinson's patients and to improve cognitive behavior in Alzheimer's disease. It has been claimed that 1-deprenyl exhibits neuroprotective and neurorescue effects in several animal models. The precise mechanism of these effects is unknown. It is yet to be established whether or not the effects are unique to 1-deprenyl; a drug which possesses, in addition to inhibition of MAO-B activity, an amphetamine moiety. Based on the fact that several N-methylpropargylamine derivatives have been shown to be MAO inhibitors and that aliphatic amines are typical MAO-B substrates with a high affinity for the enzyme, we have synthesized a series of aliphatic propargylamines which have turned out to be highly potent, selective and irreversible MAO-B inhibitors, structurally unrelated to amphetamine. The potency of these inhibitors is related to their chain length and the substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO-I activity, as assessed in vitro, increased as the aliphatic carbon chain length increased; substitution of the hydrogen at the aliphatic chain terminal by hydroxyl, carboxyl or carboethoxyl groups or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced their inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent at inhibiting brain MAO-B activity in vivo especially after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Inhibition of MAO-B by (-)-deprenyl alters dopamine metabolism in the macaque (Macaca facicularis) brain.

The present study has examined whether MAO-B has a role in DA metabolism in the primate CNS in situ. Eleven macaques (macaca facicularis) were used in this study to examine the effects of (-)-deprenyl (1 mg/kg, i.v., 2 and 24 hours). (-)-Deprenyl administration completely and selectively blocked MAO-B activity and blocked DA metabolism in the caudate nucleus and frontal cortex. DA metabolism in the substantia nigra was not affected by MAO-B inhibition. Changes in DA metabolism were accompanied by changes in 5-hydroxytryptamine (5HT) turnover: 5-hydroxyindole acetic acid (5HIAA) levels increased in the caudate and decreased in the frontal cortex. Levels of 2-phenylethylamine (PE), a putative modulator of dopaminergic transmission, were increased by MAO-B inhibition in all three brain regions examined. It is concluded that in some regions of the primate brain, in contrast to the rat, MAO-B has an important role in DA metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia.

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP+ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 microM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 microM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 microM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.

Blood Platelets↗