Biomedical subjects

Y Dwivedi

Publications and source records attributed to Y Dwivedi.

At least 19 recordsLinked to original sources

PubMed1999

The phenotypic characteristics of heterozygous reeler mouse.

Histological and behavioral traits are associated with reelin (Reln) haplo-insufficiency in heterozygous reeler mouse (rl+/-). These phenotypic traits are an approximately 50% decrease of brain Reln mRNA and Reln protein, an accumulation of nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d)-positive neurons in subcortical white matter, an age-dependent decrease in prepulse inhibition of startle (PPI), and neophobic behavior on the elevated plus-maze. Possible analogies between these rl+/- phenotypic traits and signs of psychosis vulnerability are discussed.

Aging↗

PubMed1999

Administration of dexamethasone up-regulates protein kinase C activity and the expression of gamma and epsilon protein kinase C isozymes in the rat brain.

Altered hypothalamic-pituitary-adrenal (HPA) function (increased plasma cortisol level) has been shown to be associated with mood and behavior. Protein kinase C (PKC), an important component of the phosphatidyl-inositol signal transduction system, plays a major role in mediating various physiological functions. The present study investigates the effects of acute (single) and repeated (10-day) administrations of 0.5 or 1.0 mg/kg doses of dexamethasone (DEX), a synthetic glucocorticoid, on Bmax and KD of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, PKC activity, and protein expression of PKC isozymes alpha, beta, gamma, delta, and epsilon in the membrane and the cytosolic fractions of rat cortex and hippocampus. It was observed that repeated administration of 1.0 mg/kg DEX for 10 days caused a significant increase in Bmax of [3H]PDBu binding to PKC, in PKC activity, and in expressed protein levels of the gamma and epsilon isozymes in both the cytosolic and the membrane fractions of the cortex and the hippocampus, whereas a lower dose of DEX (0.5 mg/kg for 10 days) caused these changes only in the hippocampus. On the other hand, a single administration of DEX (0.5 or 1.0 mg/kg) had no significant effect on PKC in the cortex or in the hippocampus. These results suggest that alterations in HPA function from repeated administration of glucocorticoids may modulate PKC-mediated functions.

Animals↗

PubMed1999

Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain.

In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily); they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration.

5-Lipoxygenase-Activating Proteins↗

PubMed1999

Repeated administration of dexamethasone increases phosphoinositide-specific phospholipase C activity and mRNA and protein expression of the phospholipase C beta 1 isozyme in rat brain.

Altered hypothalamic-pituitary-adrenal (HPA) function has been shown to be associated with changes in mood and behavior. The enzyme phosphoinositide-specific phospholipase C (PI-PLC), an important component of the PI signal transduction system, plays a major role in mediating various physiological functions. In the present study, we investigated the effects of a single dose and of repeated administration (0.5 or 1.0 mg/kg for 10 days) of dexamethasone (DEX), a synthetic glucocorticoid, on PI-PLC activity and on expression of PLC isozymes (beta1, delta1, and gamma1) in rat brain. Repeated administration of DEX (1.0 mg/kg) caused a significant increase in PI-PLC activity and in protein expression of the PLC beta1 isozyme in both membrane and cytosol fractions of cortex and hippocampus; however, the repeated administration of a smaller dose of DEX (0.5 mg/kg) caused these changes only in hippocampus but not in cortex. The increase in PLC beta1 protein was associated with an increase in its mRNA level, as measured by competitive RT-PCR. A single administration of DEX (0.5 or 1.0 mg/kg) to rats had no significant effects on PI-PLC activity or on the protein expression of PLC isozymes. These results suggest that DEX up-regulates PI-PLC in rat brain, which presumably is due to a selective increase in expression of the PLC beta1 isozyme, and that these changes in PI-PLC may be related to HPA axis-mediated changes in mood and behavior.

Affect↗

PubMed1999

Low phosphoinositide-specific phospholipase C activity and expression of phospholipase C beta1 protein in the prefrontal cortex of teenage suicide subjects.

OBJECTIVE: The enzyme phosphoinositide-specific phospholipase C (PI-PLC) is a component of the phosphoinositide signal transduction system. Other components of this system have been found to be abnormal in adults and adolescents who have committed suicide, and so the authors examined whether PI-PLC activity and protein expression of PLC isozymes are abnormal in postmortem brains of teenage suicide subjects. METHOD: PI-PLC activity and protein expression of the PLC beta1, delta1, and gamma1 isozymes were examined in Brodmann's areas 8 and 9 of postmortem brains obtained from 18 teenage suicide subjects and 18 matched comparison subjects. PI-PLC activity was determined by enzymatic assay, and protein expression of the PLC isozymes was determined by the Western blot technique. RESULTS: Compared with the normal subjects, the teenage suicide subjects had significantly lower PI-PLC activity and immunolabeling of the specific PLC beta1 isozyme in both membrane and cytosol fractions of Brodmann's areas 8 and 9 combined (prefrontal cortex). There was also a significant correlation between PI-PLC activity and protein levels of the PLC beta1 isozyme in the brains of the teenage suicide subjects. There was no significant difference in PI-PLC activity or level of PLC beta1 protein between the suicide subjects with a history of mental disorders and those with no history of mental disorders; however, both groups had significantly lower PI-PLC activity and expression of PLC beta1 protein than the normal subjects. CONCLUSIONS: Low PI-PLC activity and expressed levels of the PLC beta1 isozyme in postmortem brains of suicide subjects may have clinical relevance in the pathophysiology of suicidal behavior.

Adolescent↗

PubMed1999

Effects of treatment with haloperidol, chlorpromazine, and clozapine on protein kinase C (PKC) and phosphoinositide-specific phospholipase C (PI-PLC) activity and on mRNA and protein expression of PKC and PLC isozymes in rat brain.

The effects of acute (single) and chronic (21-day) administration of haloperidol (HAL), chlorpromazine (CPZ), or clozapine (CLOZ) on components of the phosphoinositide (PI)-signaling pathway were studied in rat brain. Chronic administration of HAL decreased protein kinase C (PKC) activity and mRNA and protein levels of PKC alpha and epsilon isozymes in both membrane and cytosol fractions of cortex, hippocampus, and striatum. Chronic administration of CPZ, however, decreased PKC activity only in the membrane fraction of cortex, hippocampus, and striatum, and had no effect on the levels of any PKC isozymes. On the other hand, chronic administration of CLOZ decreased PKC activity and mRNA and protein levels of PKC alpha, gamma, and epsilon isozymes in membrane and cytosol fractions of cortex, hippocampus, and cerebellum. Studies of the effects on phospholipase C (PLC) revealed that only chronic administration of CPZ significantly decreased PI-PLC activity and mRNA and protein levels of the specific PLC beta(1) isozyme in membrane and cytosol fractions of cortex, hippocampus, cerebellum, and striatum. Acute-treatment data suggest that CPZ or CLOZ had no significant effects on PI-PLC or PKC; however, HAL translocated PKC, as evidenced from increased PKC activity and protein levels of PKC alpha and epsilon isozymes in the membrane fraction and the decrease in these parameters in the cytosol fraction of cortex, hippocampus, and striatum. Our results thus suggest that the interaction of antipsychotic drugs with PKC and PLC may be associated with their mechanisms of action.

Animals↗

PubMed1998

A decrease of reelin expression as a putative vulnerability factor in schizophrenia.

Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects were compared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of the brain areas studied, RELN and its mRNA were significantly reduced (approximately 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. To exclude possible artifacts caused by postmortem mRNA degradation, we measured the mRNAs in the same PFC extracts from gamma-aminobutyric acid (GABA)A receptors alpha1 and alpha5 and nicotinic acetylcholine receptor alpha7 subunits. Whereas the expression of the alpha7 nicotinic acetylcholine receptor subunit was normal, that of the alpha1 and alpha5 receptor subunits of GABAA was increased when schizophrenia was present. RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum. A protein putatively functioning as an intracellular target for the signal-transduction cascade triggered by RELN protein released into the extracellular matrix is termed mouse disabled-1 (DAB1) and is expressed at comparable levels in the neuroplasm of the PFC and hippocampal pyramidal neurons, cerebellar Purkinje neurons of schizophrenia patients, and nonpsychiatric subjects; these three types of neurons do not express RELN protein. In the same samples of temporal cortex, we found a decrease in RELN protein of approximately 50% but no changes in DAB1 protein expression. We also observed a large (up to 70%) decrease of GAD67 but only a small decrease of GAD65 protein content. These findings are interpreted within a neurodevelopmental/vulnerability "two-hit" model for the etiology of schizophrenia.

Age of Onset↗

PubMed1998

Quantitation of 5HT2A receptor mRNA in human postmortem brain using competitive RT-PCR.

We describe quantitation of the absolute amounts of 5HT2A receptor mRNA in various areas of human postmortem brain using a very sensitive and specific technique: competitive reverse transcription polymerase chain reaction (RT-PCR). With this procedure, we were able to show that the highest levels of 5HT2A receptor mRNA are in cerebral cortical areas, i.e., Brodmann's areas 8, 9, 10, 18, 19, 22, 24, and 46, and that intermediate levels occur in the hippocampus, the amygdala, the nucleus accumbens, and the hypothalamus. Very low levels of 5HT2A receptor mRNA were found in the cerebellum, the thalamus, the caudate, and the putamen. Our results confirm the heterogeneous distribution of 5HT2A receptor mRNA in human postmortem brain and suggest that competitive RT-PCR is a highly sensitive and specific procedure for the quantitative measurement of 5HT2A receptor mRNA expression. The study of 5HT2A receptor mRNA in different brain areas will help clarify the regulation of 5HT2A receptors at the transcriptional level in various neuropsychiatric diseases.

Binding, Competitive↗

PubMed1998

Protein kinase C in platelets of depressed patients.

BACKGROUND: We studied the role of protein kinase C (PKC), a major regulatory enzyme and an important component of the phosphoinositide signaling system, in depression. METHODS: PKC was determined using [3H]phorbol dibutyrate (PDBu) as the radioligand in the membranal and cytosolic fractions of platelets obtained from hospitalized drug-free depressed patients during a baseline period and from drug-free normal control subjects. RESULTS: We observed that the [3H]PDBu binding was significantly higher in the cytosolic fraction obtained from platelets of depressed patients compared to normal control subjects. CONCLUSIONS: Our studies indicate increased formation of PKC in platelets of depressed patients. The significance and mechanisms involved in increased PKC in the cytosolic fraction of platelets are unclear, but they suggest that increased PKC may be associated with the pathophysiology of depressive illness.

Adult↗

PubMed1998

Elevated [3H]inositol 1,4,5-trisphosphate binding sites and expressed inositol 1,4,5-trisphosphate receptor protein level in platelets of depressed patients.

Several reports suggest that serotonin2A (5HT2A) receptors and this receptor-mediated phosphatidyl inositol (PI) hydrolysis signal transduction system are altered in platelets of depressed patients. Inositol 1,4,5-trisphosphate (Ins[1,4,5]P3), an important component of the PI signaling system, plays a crucial role in various physiological processes by releasing Ca2+ from intracellular stores after binding with Ins(1,4,5)P3 receptors. To examine the role of Ins(1,4,5)P3 receptors in depression, we determined [3H]Ins(1,4,5)P3 binding sites and expressed protein levels of Ins(1,4,5)P3 receptors in platelets of depressed patients (n=15) and normal control subjects (n=17). We observed that the mean Bmax of [3H]Ins(1,4,5)P3 binding to Ins(1,4,5)P3 receptors was significantly higher in platelets of depressed subjects compared with normal control subjects, whereas there was no significant difference in K(D) between these two groups. The immuno-detectable expressed level of Ins(1,4,5)P3 receptor protein was also significantly increased in depressed patients in contrast to the levels of normal control subjects. Moreover, a significant correlation was observed in Bmax and the protein level of Ins(1,4,5)P3 receptors. The increase in the number of [3H]Ins(1,4,5)P3 binding sites in platelets of depressed subjects appears to be due to an increase in the amount of Ins(1,4,5)P3 receptor proteins. These results suggest that Ins(1,4,5)P3 receptors may be involved in the pathophysiology of depression.

Adult↗

PubMed1997

Protein kinase C in the postmortem brain of teenage suicide victims.

Increased serotonin2A (5-HT2A) receptors have been reported in the postmortem brain of suicide victims. To examine if this increase is associated with the dysregulation of postreceptor sites in the signaling cascade, we determined [3H]phorbol dibutyrate (PDBU) binding to protein kinase C (PKC) in postmortem brain samples (Brodmann's areas 8 and 9) obtained from teenage suicide victims and control subjects. [3H]PDBU binding to PKC was determined in membranal and cytosolic fractions. We observed that Bmax of [3H]PDBU binding sites was significantly decreased in both membranal and cytosolic fractions in brain samples from Brodmann's areas 8-9 compared to matched controls. These results thus suggest that PKC may play a role in the pathophysiology of suicidal behavior.

Adolescent↗

PubMed1997

Effects of subchronic administration of antidepressants and anxiolytics on levels of the alpha subunits of G proteins in the rat brain.

The aim of this study was to examine the effects of subchronic administration of psychoactive drugs on the alpha subunits of G proteins in the rat brain, and also to determine if different classes of psychoactive drugs share a common property, i.e., of altering levels of these proteins. For this purpose, we selected the psychoactive drugs desipramine and phenelzine (antidepressants), lithium (antimanic), alprazolam and buspirone (anxiolytics), and metachlorophenylpiperazine (anxiogenic). The levels of alpha subunits of G proteins (Gs, Gi 1/2, Gq/11) expressed in cortical, hippocampal, and cerebellar brain regions were studied by the Western blot technique. We observed that subchronic treatment with lithium significantly decreased, and with phenelzine significantly increased levels of Gi 1/2 alpha protein in the cortex and the hippocampus. On the other hand, buspirone significantly decreased levels of Gi 1/2 alpha protein only in the cerebellum. Other psychoactive drugs, however, namely desipramine, meta-chlorophenylpiperazine, and alprazolam, did not alter levels of Gs, Gi 1/2, or Gq/11 alpha proteins in any of the brain regions studied. Since other studies have shown the involvement of G proteins in the mechanism of action of psychoactive drugs, our results demonstrate that expressed protein levels of the alpha subunit of G proteins are not altered by all the psychoactive drugs.

Animals↗

PubMed1995

Platelet serotonin-2A receptors: a potential biological marker for suicidal behavior.

OBJECTIVE: Abnormalities in the serotonergic system have been implicated in suicidal behavior. Higher numbers of serotonin-2 (5-HT2) receptors have been reported in the post-mortem brain of suicide victims. In order to further examine the role of 5-HT2A receptors in suicidal behavior, the authors studied 5-HT2A receptors in platelets of suicidal and nonsuicidal patients as well as normal comparison subjects. METHOD: 5-HT2A receptor levels were determined by using [125I]LSD as a radioligand in platelets obtained from hospitalized psychiatric patients (N = 131) and nonhospitalized normal comparison subjects (N = 40) during a drug-free baseline period. Patients were diagnosed according to DSM-III-R criteria, and suicidal behavior was identified by using the Hamilton Depression Rating Scale. RESULTS: The mean maximum number of binding sites (Bmax) of platelet 5-HT2A receptors for all suicidal patients was significantly higher than for nonsuicidal patients or normal comparison subjects. This significant difference remained when subgroups of suicidal patients with depression, schizophrenia, schizoaffective disorder, or bipolar illness were compared to the other two subject groups. The higher number of platelet 5-HT2A receptors in suicidal patients was independent of diagnosis. While there was no significant difference in Bmax between patients with serious suicidal ideation and those who made suicidal attempts, both groups had significantly higher Bmax than normal comparison subjects. CONCLUSIONS: The observed higher number of platelet 5-HT2A receptors in suicidal patients is independent of diagnosis and appears to be associated with both the brain and the platelets of suicidal patients. These results thus suggest the potential usefulness of platelet 5-HT2A receptors as a biological marker for identifying suicide-prone patients.

Adult↗

PubMed1993

Perfusion with picroliv reverses biochemical changes induced in livers of rats toxicated with galactosamine or thioacetamide.

Perfusion of liver of rats toxicated with galactosamine or thioacetamide with a 0.02% solution of picroliv (glycoside fraction of Picrorhiza kurroa) for 30 min (1 ml/min; 6 mg/rat), significantly reversed toxicant-induced changes in the activities of several enzymes. Galactosamine induced increases in the activities of alkaline phosphatase, gamma-glutamyl transpeptidase, acid ribonuclease, acid phosphatase, succinate dehydrogenase and decreases in the activities of Na(+)-K(+)-adenosine triphosphatase (ATPase) and glucose-6-phosphatase (reversed by 40-87%). Similarly, thioacetamide-induced inhibitions of the activities of Na(+)-K(+)-ATPase, Ca(++)-ATPase, Mg(++)-ATPase, succinate dehydrogenase and elevations in the activities of alkaline phosphatase, gamma-glutamyl transpeptidase, and acid ribonuclease were also significantly reversed. A significant reversal of the toxicants-induced decrease in [14C]-leucine incorporation was also observed. These results indicate that picroliv can also reverse D-galactosamine- or thioacetamide-induced hepatic damage in rats.

Animals↗

PubMed1992

Picroliv and its components kutkoside and picroside I protect liver against galactosamine-induced damage in rats.

D-Galactosamine (800 mg/kg, intraperitoneally) caused significant decrease in the activities of 5'-nucleotidase, glucose-6-phosphatase and cytochrome P450 and increase in activities of gamma-glutamyl transpeptidase, succinate dehydrogenase, acid phosphatase and acid ribonuclease in liver after 24 hr. The levels of RNA, protein and glycogen decreased while total lipids, phospholipids, cholesterol and lipid peroxides increased. It also increased the serum levels of transaminases, alkaline phosphatase and bilirubin while protein concentration decreased significantly. Oral administration of Picroliv (12 mg/kg/day for 7 days), a standardised iridoid glycoside fraction of Picrorhiza kurroa, significantly prevented the biochemical changes in liver and serum of galactosamine-toxicated rats. Kutkoside (12 mg/kg/day for 7 days) also protected against changes in most of the hepatic and serum constituents studied. Another iridoid glycoside from Picroliv, Picroside I, at the same dose level could only prevent toxicant-induced changes in acid phosphatase, phospholipids and lipid peroxides in liver and alkaline phosphatase in serum. Mixture of Picroside I and Kutkoside in the ratio of 1:1.5 at 12 mg/kg dose elicited lesser response than Picroliv.

5'-Nucleotidase↗

PubMed1992

Effects of picroliv, the active principle of Picrorhiza kurroa, on biochemical changes in rat liver poisoned by Amanita phalloides.

The efficacy of Picroliv, a standardized iridoid glycoside fraction of Picrorhiza kurroa, was studied against the Amanita phalloides-induced biochemical changes in rat liver. A phalloides (50 mg.kg-1) caused significant increases in the activities of hepatic 5'-nucleotidase, gamma-glutamyl transpeptidase, acid ribonuclease, and succinate dehydrogenase, but a decrease in glucose-6-phosphatase. The level of cytochrome P-450 in microsomal fraction and content of glycogen in liver showed significant depletions. Picroliv (25 mg.kg-1.d-1 x 10 d) provided significant restorations of all the biochemical changes poisoned by A phalloides except cytochrome P-450 and glycogen. These results demonstrated the protective effect of Picroliv against A phalloides-induced hepatotoxicity in rats.

Amanita↗

PubMed1991

Picroliv protects against monocrotaline-induced hepatic damage in rats.

Monocrotaline, a pyrrolizidine alkaloid, caused changes in most of the biochemical parameters in rats 12 days after a single dose of 120 mg/kg. These included significantly increased activities of hepatic succinate dehydrogenase, acid ribonuclease, acid phosphatase, gammaglutamyl transpeptidase and 5'-nucleotidase and decreased in the activities of glucose-6-phosphatase and cytochrome P450. The levels of DNA, RNA and glycogen in liver and albumin and protein in serum decreased while serum bilirubin increased. The histopathological changes in liver were characterized by diffused hepatocyte alterations in the form of ballooning, granular cytoplasm, indistinct cell outlines, nuclear changes, focal necrosis, and vascular damage. When picroliv, a standardized iridoid glycoside fraction of Picrorhiza kurroa, was administered orally in a dose of 25 mg/kg simultaneously with monocrotaline, alterations in most of the biochemical parameters along with the histopathological changes in liver caused by monocrotaline were prevented.

Animals↗

PubMed1991

Picroliv affords protection against thioacetamide-induced hepatic damage in rats.

Thioacetamide (100 mg/kg), when administered to normal rats, caused a significant increase in the activities of 5'-nucleotidase and gamma-glutamyl transpeptidase and a decrease in the activities of glucose 6-phosphatase and succinate dehydrogenase enzymes in the liver. DNA, RNA, and proteins were increased while the cytochrome P450 in the microsomal fraction and the glycogen content in the liver were decreased significantly. Elevations in the activities of GOT, GPT, and alkaline phosphatase and bilirubin content in serum were also observed. Picroliv, a standardised glycoside fraction of Picrorhiza kurroa, in doses of 12.5 and 25 mg/kg prevented most of the biochemical changes induced by thioacetamide in liver and serum. The hepatoprotective activity of Picroliv was comparable with that of silymarin, a known hepatoprotective agent obtained from seeds of Silybum marianum.

Animals↗