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Kevin F Foley

Publications and source records attributed to Kevin F Foley.

9 recordsLinked to original sources
PubMed2006

IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells.

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [(3)H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE(2) (10 microM), IFN-gamma (500 ng/ml), TNF-alpha (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 microM). [(3)H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [(3)H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-alpha and IFN-gamma elicited significant decreases in SERT function. Neither TNF-alpha nor IFN-gamma were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-alpha and IFN-gamma could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.

Caco-2 Cells↗
PubMed2006

Bupropion: pharmacology and therapeutic applications.

A total of 17 years after its introduction, bupropion remains a safe and effective antidepressant, suitable for first-line use. Bupropion undergoes metabolic transformation to an active metabolite, 4-hydroxybupropion, through hepatic cytochrome P450-2B6 (CYP2B6) and has inhibitory effects on cytochrome P450-2D6 (CYP2D6), thus raising concern for clinically-relevant drug interactions. Common side effects are nervousness and insomnia. Nausea appears slightly less common than with the SSRI drugs and sexual dysfunction is probably the least of any antidepressant. Bupropion is relatively safe in overdose with seizures being the predominant concern. The mechanism of action of bupropion is still uncertain but may be related to inhibition of presynaptic dopamine and norepinephrine reuptake transporters. The activity of vesicular monoamine transporter-2, the transporter pumping dopamine, norepinephrine and serotonin from the cytosol into presynaptic vesicles, is increased by bupropion and may be a component of its mechanism of action. Bupropion is approved for use in major depression and seasonal affective disorder and has demonstrated comparable efficacy to other antidepressants in clinical trials. Bupropion is also useful in augmenting a partial response to selective serotonin reuptake inhibitor antidepressants, although bupropion should not be combined with monoamine oxidase inhibitors. It may be less likely to provoke mania than antidepressants with prominent serotonergic effects. Bupropion is effective in helping people quit tobacco smoking. Anecdotal reports indicate bupropion may lower inflammatory mediators such as tumor necrosis factor-alpha, may lower fatigue in cancer and may help reduce concentration problems.

Antidepressive Agents, Second-Generation↗
PubMed2005

Culture conditions influence uptake and intracellular localization of the membrane permeable cGMP-dependent protein kinase inhibitor DT-2.

The membrane-permeable peptide DT-2 which utilizes the HIV-Tat membrane translocation sequence is known to inhibit cGMP-dependent protein kinase (PKG) effectively in vitro and in various cell lines and tissue preparations. However, the uptake characteristics of DT-2 have not been studied in detail. We investigated the intracellular uptake and localization of fluorescein-labeled DT-2 (fDT-2) in cultured C6-glial cells and vascular smooth muscle cells (VSMCs) as well as VSMCs in intact arteries. To avoid fixation-induced fluorescence, live unfixed cells and arteries were incubated with fDT-2 and examined using conventional and confocal fluorescence microscopy. In non-differentiated cultured VSMCs, uptake appeared vesicular with nuclear exclusion, consistent with an endocytotic internalization mechanism. Inhibition of endocytosis by phenylarsine oxide (PAO), low temperature or disruption of actin polymerization by cytochalasin-D or lantrunculin-A showed a residual non-endocytotic fDT-2 translocation with diffuse cytosolic and nuclear uptake. Similarly, differentiated contractile VSMCs within the medial layer of intact cerebral arteries also showed a distinctively different, more diffuse cytosolic uptake and time dependent nuclear localization. To verify the morphology dependency of fDT-2 uptake, VSMCs were reconstituted in fibrillar collagen matrices. The cells adopted a differentiated morphology and fDT-2 translocation was similar to cells in intact arteries. These results demonstrate that VSMCs cells utilize distinct cellular uptake mechanisms depending on their phenotype.

Animals↗
PubMed2005

Inhibition of cGMP-dependent protein kinase reverses phenotypic modulation of vascular smooth muscle cells.

We have previously shown that type I cGMP-dependent protein kinase (PKG) can alter the phenotype of cultured vascular smooth muscle cells (VSMCs). Although the expression of contractile proteins in VSMCs has been shown to be modulated with the induction of PKG, experiments in which PKG inhibition brings about reduced expression of contractile markers have not been performed. To more thoroughly examine the role of PKG in the expression of contractile proteins, recombinant adenovirus containing the PKG coding sequence (AD-PKG) was used to induce gene expression and morphologic changes in adult rat aortic VSMCs. Cells expressing PKG, but not control adenovirus-infected cells, began to express a specific marker protein for the contractile phenotype, smooth muscle myosin heavy chain (SMMHC), within 48 hours of PKG induction. The morphology of the AD-PKG-infected cells began to change from a fibroblastic phenotype to a spindle-shaped phenotype within 72 hours after PKG induction. The specific cell-permeable PKG inhibitory peptide DT-2, but not control peptides, reversed the biochemical and morphologic changes associated with PKG expression. These results suggest that PKG expression and activity in cultured VSMCs is capable of altering the VSMC phenotype. These data also verify the intracellular action of DT-2 and reveal uptake and dynamic properties of this PKG-inhibiting peptide.

Adenoviridae↗
PubMed2003

Methcathinone is a substrate for the serotonin uptake transporter.

We previously reported that the psychostimulant drug methcathinone inhibits serotonin accumulation via the plasma membrane serotonin uptake transporter. By analogy to known substrates for the serotonin transporter, we hypothesized that methcathinone is also a substrate for this transporter and that inhibition of serotonin uptake by methcathinone occurs in part through competition for substrate recognition sites within the transporter. To test the hypothesis we preloaded human platelets with [3H]5-HT then superfused the platelets with either methcathinone or with the known serotonin uptake transporter substrate para-methylthioamphetamine. Under superfusion conditions, transporter substrates will evoke an increase in released [3H]5-HT through a carrier-mediated exchange process. For direct assessment of methcathinone transport via the serotonin uptake transporter, we tested whether [3H]methcathinone would be accumulated by cells stably expressing the cloned human serotonin uptake transporter (293SERT cells). Supporting the hypothesis, superfusion of [3H]5-HT-containing platelets with methcathinone or with para-methylthioamphetamine produced a large increase in tritium efflux. The efflux declined when the drugs were removed. When increasing concentrations of [3H]methcathinone were incubated with 293SERT cells under conditions used to assess serotonin transport, saturable, single-site accumulation of radiolabel was observed. The uptake of [3H]methcathinone was temperature, inhibitor, and sodium-sensitive, and was not observed in wild-type HEK 293 cells. Non-linear regression analysis of specific [3H]methcathinone uptake produced values for KM and Vmax of 244+/-51 nM and 202+/-25 fmol/min./mg protein, respectively. These data support the notion that the reported serotonergic neurotoxicity of methcathinone may arise through accumulation of the drug within serotonergic neurones.

Blood Platelets↗
PubMed2002

Inhibition of transport function and desipramine binding at the human noradrenaline transporter by N-ethylmaleimide and protection by substrate analogs.

N-ethylmaleimide (NEM) inhibits [(3)H]desipramine binding and [(3)H]noradrenaline uptake at the rat noradrenaline transporter (rNET) by covalently modifying cysteine residues. We report here that NEM also inhibits [(3)H]desipramine binding and [(3)H]noradrenaline uptake at the cloned human noradrenaline transporter (hNET) stably expressed in C6 glial cells. The IC(50) for NEM inhibition of [(3)H]noradrenaline uptake was 43.6+/-5.5 microM. We tested several compounds for their abilities to inhibit [(3)H]noradrenaline uptake via the hNET and for their abilities to protect against NEM inactivation of [(3)H]desipramine binding. We found that the substrate analogs bupropion, 3-bromomethcathinone, and 4-bromomethcathinone all inhibit uptake at the hNET with IC(50) values of 1370+/-140, 158+/-20, and 453+/-30 nM, respectively. These compounds as well as methamphetamine, methcathinone, and desipramine also protected the hNET from NEM inactivation of [(3)H]desipramine binding. The ability of substrate analogs and desipramine to protect the [(3)H]desipramine binding site is consistent with the hypothesis that the desipramine binding site and the substrate binding site are mutually exclusive. It also supports the use of structure-activity relationships derived from substrate analogs in the rational design of hNET uptake inhibitors. The hNET contains 10 cysteine residues whereas the rNET contains 12 cysteine residues. Since the hNET and the rNET are both inhibited by NEM, and because the NEM inhibition is protectable by desipramine and substrate analogs, we conclude that the two additional cysteine residues (C28 and C447) present in the rNET are not likely to be involved in desipramine binding or uptake function.

Animals↗
PubMedDate not supplied

Review of evidence that posttransplantation psychiatric treatment commonly affects prolactin levels and thereby influences graft fate.

Delirium, depression and other psychiatric difficulties are commonly encountered by posttransplantation patients, and antipsychotic medicines are frequently used to treat these difficulties. This article reviews previous research data concerning the immunological effects of these medicines, with particular focus on the consequences of prolactin elevation. Unproven but of concern is that these effects may influence graft fate. Older antipsychotic medicines such as haloperidol and chlorpromazine have a high likelihood of elevating prolactin. Prolactin is an immunologically active molecule generally promoting bone marrow function. This may be of benefit post-stem-cell transplant, helping engraftment, but could further rejection of solid-organ transplants. Elevated prolactin is implicated in the facilitation of graft-versus-host disease. Aripiprazole is the antipsychotic medicine least likely to increase prolactin (and may actually decrease prolactin); risperidone, the most likely to increase prolactin. Olanzapine, quetiapine and ziprazadone are antipsychotic medicines with a lower likelihood of elevating prolactin. Older ("neuroleptic") antipsychotics, such as chlorpromazine, droperidol and haloperidol, perphenazine and many others, are likely to elevate serum prolactin. Among antidepressants, most serotonin reuptake inhibitors, with the exception of sertraline, can slightly elevate prolactin. The atypical (i.e., alone in their class) antidepressants bupropion and mirtazapine are prolactin neutral. The immunological consequences of psychiatric medicines should be considered when treating transplant patients for delirium, depression and thought disorders; in addition, if elevation of prolactin is thought to be of immunological importance during psychiatric treatment, then it should be monitored and treated. The dopamine agonists used to treat Parkinson's disease--bromocriptine, pergolide, pramipexole, ropinerole--usually reverse antipsychotic-induced prolactin increases without compromising psychiatric effectiveness.

Antipsychotic Agents↗