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Biomedical subjects

M K Demetrikopoulos

Publications and source records attributed to M K Demetrikopoulos.

10 recordsLinked to original sources
PubMed2000

Neuropeptides in drug research.

Neuropeptides have been a subject of considerable interest in the pharmaceutical industry over the last 20 years or more. Many drug discovery teams have contributed to our understanding of neuropeptide biology but no significant drugs that act selectively upon neuropeptide receptors have yet emerged from the clinic. There are, however, a plethora of clinically useful drugs that act at other classes of neurotransmitter and neuromodulator receptors, many of them discovered over the last 20 years. Nevertheless, we think that the future for the discovery of novel drugs acting at neuropeptide receptors looks bright for two reasons: (1) there has been a substantial increase in our understanding of the function of neuropeptides; and (2) high-throughput screening (HTS) against neuropeptide receptors has now begun to yield many interesting drug-like molecules, rather than peptides, that have the potential to become clinically useful drugs. The objective of this review is to summarise our current understanding of specific areas of neuropeptide biology and pharmacology in the CNS as well as the PNS. We will also speculate on where we think the new generation of neuropeptide agonists and antagonists could emerge from the clinic.

Animals↗
PubMed2000

Blood level of B and CD4+ lymphocytes measured before induction of an experimental tumor in rats predicts tumor progression and survival.

After an initial series of experiments indicated that early responses of B lymphocytes were important in controlling tumor metastases in two rat models of cancer (N. Quan et al., Cancer Res., 59: 1080-1089, 1999), the present study assessed whether differences in the number of B lymphocytes that are normally present in different individual rats before any tumor development could predict tumor growth, metastases, and length of survival when tumor challenge subsequently occurred. Repeated baseline measures of several circulating lymphocyte subtypes (i.e., natural killer, B, CD4+, CD8+ lymphocytes) were made in individual inbred WAG rats before any introduction of tumor cells, and stable baselines for these subtypes were found. Animals were then injected with 2 x 10(6) CC531 tumor cells (a syngeneic tumor) into the leg, and the size of the resulting primary tumor measured. Primary tumors were surgically removed 6-7 weeks after tumor-cell injection, and animals then followed until death from metastases. In two experiments, the size of the primary tumor as well as the length of time that animals survived correlated with the pretumor percentage of certain lymphocyte subtypes in peripheral blood before tumor-cell injection. Baseline percentage of B lymphocytes was significantly negatively correlated with the size of the primary tumor and was positively correlated with the duration of survival. Baseline percentage of CD4+ lymphocytes showed the opposite relationship, being positively correlated with tumor size and negatively correlated with survival time, although these correlations were lower than those for B lymphocytes. Percent B lymphocytes in circulation also declined during tumor development. In summary, a high percentage of endogenous peripheral blood B lymphocytes predicted growth of smaller primary tumors and longer survival after experimental tumor induction in a rat model, further suggesting that B lymphocytes are involved in protection against development of certain tumors.

Adenocarcinoma↗
PubMed1999

Evidence for involvement of B lymphocytes in the surveillance of lung metastasis in the rat.

These studies examined the composition of lymphocytes within the lung after the introduction of tumor cells that metastasize to the lung in rats. i.v. delivery of MADB106 tumor cells into syngeneic Fischer 344 rats caused dose- and time-dependent development of lung tumors, with surface metastases evident 7 days after injection and markedly increased 11 days after injection. The total number of lymphocytes recovered from the lung was increased 11 days after injection but not 7 days after injection. When lymphocytes from the lung, spleen, and blood were subjected to fluorescence-activated cell sorting analysis, the most conspicuous change was an increase in the percentage of CD45RA+ cells (i.e., B lymphocytes in the rat) in the lung, with no changes seen in the percentage of natural killer (NKR-P1+), CD4+, or CD8+ cells in the lung. Analysis of the time course showed that B lymphocytes increased in the lung soon after i.v. tumor injection, with an initial peak seen 6 h after injection. Rapid influx of B lymphocytes into lung after i.v. tumor cell injection was also observed in another syngeneic tumor model, i.e., after injection of CC531 cells into WAG rats. To determine whether the influx of B lymphocytes into the lung might participate in tumor surveillance, a high dose of antibody (100 microg) to rat B lymphocytes was given to immunoneutralize these cells; this produced an increase in lung tumors in both models. Finally, Fischer 344 rats were given a s.c. injection of MADB106 tumor cells that made them resistant to lung tumors when given a later i.v. injection of these tumor cells. These animals were found to have an elevated level of B lymphocytes residing in the lung associated with the resistance to lung tumor. These findings suggest that early responses of B lymphocytes are important in protection against tumor development in two rat models of cancer.

Adenocarcinoma↗
PubMed1998

Galanin: a significant role in depression?

This paper describes a hypothesis that attempts to account for how changes in noradrenergic systems in the brain can affect depression-related behaviors and symptoms. It is hypothesized that increased activity of the locus coeruleus (LC) neurons, the principal norepinephrine (NE)-containing cells in the brain, causes release of galanin (GAL) in the ventral tegmentum (VTA) from LC axon terminals in which GAL is colocalized with NE. It is proposed that GAL release in VTA inhibits the activity of dopaminergic cell bodies in this region whose axons project to forebrain, thereby resulting in two of the principal symptoms seen in depression, decreased motor activation and decreased appreciation of pleasurable stimuli (anhedonia). The genesis of this hypothesis, which derives from studies using an animal model of depression, is described as well as recent data consistent with the hypothesis. The formulation proposed suggests that GAL antagonists may be of therapeutic benefit in the treatment of depression.

Animals↗
PubMed1998

Immune function in healthy adolescents.

In the present study, we examine immunological functioning in normal healthy African-American and Latino/Latina adolescents recruited from an inner-city high school and an inner-city clinic. A battery of tests was performed with enumerative and functional measures which encompassed both innate and adaptive immunity. We found immune differences related to age, gender, and race on both the enumerative and the functional immune measures. This data expands the available body of information concerning normal immunity in healthy adolescents.

Adolescent↗
PubMed1997

Phagocytosis and killing of Staphylococcus aureus: effects of stress and depression in children.

While a large body of literature depicting relationships between depression or stress and immunity exists, few such studies have dealt with children, and none investigated myeloid cell-derived immunity. We investigated both phagocytosis and bactericidal activity against Staphylococcus aureus in children with major depressive disorder (MDD). We found that both MDD and stress influence the bactericidal but not the phagocytic activity of polymorphonuclear leukocytes. The data support the existence of psychobiologic effects in children and suggest possible mechanisms by which depression and stress may affect health.

Blood Bactericidal Activity↗
PubMed1994

Electrical stimulation of the dorsal midbrain periaqueductal gray suppresses peripheral blood natural killer cell activity.

This study examined the effects of dorsal midbrain periaqueductal gray (PAG) stimulation on both splenic and peripheral blood natural killer (NK) cell function as well as the proliferative response of lymphocytes to phytohemagglutinin mitogen. Male Sprague-Dawley rats were implanted with bipolar electrodes in the dorsal PAG. Following recovery, bipolar electrical stimulation eliciting a flight response was delivered at the rate of one/min for 30 min to freely moving rats. While dorsal PAG stimulation did not alter mitogen response or splenic NK activity, stimulation of this region of the PAG produced a marked decrease in peripheral blood NK response. In order to begin to explore a possible mechanism regulating suppression of peripheral blood NK activity, naltrexone (10 mg/kg) was administered prior to dorsal PAG stimulation. The results of this experiment replicated the findings that demonstrated suppression of peripheral blood NK following dorsal PAG stimulation. Naltrexone did not effect PAG induced suppression of peripheral blood NK. These findings point to the importance of the dorsal aspect of the PAG in the regulation of peripheral blood NK activity and further suggest that this phenomenon may not be opioid mediated.

Animals↗
PubMed1990

Effect of serotonergic drugs on negative contrast in consummatory behavior.

The effect of acute and chronic administration of the 5-HT1A agonist buspirone on successive negative contrast was investigated in Experiments 1-6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1-5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.

Animals↗
PubMed1987

Effect of clonidine on consummatory negative contrast and on novelty-induced stress.

In Experiments 1 and 1a rats were shifted from 32% to 4% sucrose solutions. The resultant negative contrast effect in consummatory behavior was not alleviated by clonidine (3.12, 6.25, 12.5, 25.0 and 50.0 micrograms/kg). The lower dose of the drug had no effect on behavior, the higher doses reduced consumption in shifted and unshifted rats in a dose dependent fashion. In Experiment 2 clonidine (6.25, 12.5 micrograms/kg) raised plasma glucose levels in a dose dependent fashion when the animals were exposed to a novel environment. These results are at variance with those obtained with chlordiazepoxide (and other anxiolytics in the case of contrast effects) and suggest limits on the degree to which clonidine can be considered to function as an anxiolytic.

Animals↗