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Biomedical subjects

H K Manji

Publications and source records attributed to H K Manji.

81 records · Page 5Linked to original sources
PubMed1991

The mechanisms of action of lithium. II. Effects on adenylate cyclase activity and beta-adrenergic receptor binding in normal subjects.

As part of a study of the effects of lithium carbonate on neurochemical function in man, platelet and lymphocyte adenylate cyclase activity and lymphocyte beta-adrenergic receptor binding characteristics were determined before and after 2 weeks of lithium treatment in 10 normal volunteers. Lithium had differential effects on platelet and lymphocyte adenylate cyclase activity. In platelets, basal and stimulated (guanyl imidodiphosphate [Gpp[NH]p] or cesium fluoride) adenylate cyclase activity was significantly augmented by lithium treatment. By contrast, in lymphocytes, Gpp(NH)p- and cesium fluoride-stimulated adenylate cyclase activity was unaffected, while basal activity was decreased modestly after lithium. These results are consistent with preclinical studies that suggest that lithium's effects on adenylate cyclase activity are specific with respect to tissue and brain region and that lithium may interfere with guanine nucleotide binding (G) protein function. Lithium treatment significantly increased the ratio of low- to high-affinity dissociation constants for agonist displacement of antagonist binding to lymphocyte beta-adrenergic receptors (thought to reflect coupling between the beta-adrenergic receptor and stimulatory G protein). Lithium had significant effects on measures associated with signal transduction that might be contrasted to its more subtle effects on neuronal function (norepinephrine release) and neuroendocrine systems (responses to serotoninergic challenge) in these same subjects (reported in a companion article). Lithium's primary site of action may be on signal transduction mechanisms. These effects subsequently may be manifested in changes in neurotransmitter function that may be important to lithium's mood-stabilizing actions.

Adenylyl Cyclases↗
PubMed1991

Down-regulation of beta receptors by desipramine in vitro involves PKC/phospholipase A2.

Chronic treatment with a number of antidepressants results in a down-regulation and/or a desensitization of rat cortical beta-adrenergic receptors (beta ARs). Although these effects generally have been attributed to elevations in intrasynaptic norepinephrine via presynaptic mechanisms, the recent demonstration of similar changes in beta ARs following in vitro incubation of cultured cells with desipramine (DMI) suggests that direct, postsynaptic mechanisms may also be involved. To study these mechanisms, we incubated rat C6 glioma cells with 10 microM DMI for 1 or 5 days. DMI produced a significant reduction in beta AR density following chronic (but not acute) treatment (BMAX control = 1325 +/- 78 fmol/mg; DMI = 1179 +/- 96; p less than .05). Interestingly, the beta AR down-regulation was accompanied by an increase in KL/KH ratio (ratio of dissociation constants for the low- and high-affinity states of the receptor), suggesting that these drugs may stabilize the high-affinity complex. DMI treatment attenuated the cyclic adenosine monophosphate (cAMP) response to 1 microM isoproterenol (control = 540 +/- 82 pmol/mg/15 min; DMI = 335 +/- 64; p less than .05), but not to agents acting distal to the receptor (cholera toxin or forskolin). Coincubation of C6 cells with either the phospholipase A2 (PLA2) inhibitor mepacrine or the protein kinase C (PKC) inhibitor H7, during chronic treatment with DMI, blocked the down-regulation of beta ARs. Incubation of C6 cells with phorbol esters (PKC activators) also down-regulated beta ARs, effects that were nonadditive with those of DMI. Incubation with H7 alone resulted in an up-regulation of beta ARs, consistent with a tonic regulatory effect of PKC on beta ARs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies.

Considerable evidence suggests that signal transduction pathways are targets of lithium (Li) action. A number of investigators have reported that Li attenuates both adenylate cyclase (AC) activity and phosphoinositide (PI) turnover in rodents and in humans, thus "dampening" these systems. We have studied selected components of these second-messenger systems in a series of clinical and preclinical investigations. To overcome confounding effects of alterations in mood state, we examined AC activity and G-protein ribosylation in peripheral blood cells from 10 healthy volunteers, prior to and following 14 days of Li administration. Basal and postreceptor [cesium fluoride (CsF) or Gpp(NH)p] stimulated AC activity were unaffected in lymphocytes. In contrast, both basal and stimulated AC activity in platelets were significantly augmented, compatible with an attenuation of Gi function. Ribosylation of platelet Gs by cholera toxin was unchanged, whereas that of Gi by pertussis toxin (PT) was increased. Given that undissociated G protein is the preferred substrate for PT, our results suggest that Li interferes with subunit dissociation and the subsequent activation of Gi. To determine if Li has similar effects on Gi in the central nervous system, we measured extracellular (EC) cyclic adenosine monophosphate (cAMP) in rat brain by in vivo microdialysis, revealing a dose-dependent increase in cAMP by norepinephrine (NE) antagonized by propranolol. Chronic (4-week) Li doubled basal EC cAMP, while decreasing the fractional response to 100 microM NE. Thus, using in vivo microdialysis, we observed the reported reduction in NE-stimulated AC activity, but only as a function of elevated basal cAMP. Increased basal AC activity has been observed following chronic Li in both humans and rat tissues but generally has not been considered relevant. The PI generating system is another proposed major target for Li that we have studied using an in vitro cell culture model of peripheral blood cells. Chronic (6-day) exposure of neutrophil-like HL60 cells to 1 mM LiCl did not affect agonist fMet-Leu-Phe (fMLP) induced PI turnover. In contrast, Li attenuated both agonist and phorbol ester stimulated Na+/H+ exchange, suggesting reduced protein kinase C (PKC) function. Western blot analysis revealed altered levels of PKC in both membrane and cytosolic fractions. The functional consequences of these complex effects on the two major signal transduction pathways and their interactions in the intact living organism remain to be elucidated.

Adult↗
PubMed1990

Chronic Li+ attenuates agonist- and phorbol ester-mediated Na+/H+ antiporter activity in HL-60 cells.

The effects of Li+ on signal transduction in dibutyryl cAMP-differentiated HL-60 cells were studied. Upon differentiation, these human promyelocytic leukemia cells express a chemotactic formyl peptide receptor, which is coupled through a guanine nucleotide-binding protein to phospholipase C. Stimulation with fMet-Leu-Phe results in changes in intracellular pH which are thought to be mediated by protein kinase C regulation of Na+/H+ antiporter function. Acute LiCl treatment (10 mM) was without any effect on Na+/H+ activity. However, pretreatment of HL-60 cells with 1 or 10 mM LiCl for at least 5 days resulted in a marked attenuation of fMet-Leu-Phe effects on Na+/H+ activity. In undifferentiated HL-60 cells, which lack fMet-Leu-Phe receptors, intracellular acidification induced by the proton ionophore nigericin generates an alkalinization response. Chronic (but not acute) Li+ treatment also resulted in an inhibition of the nigericin-mediated response. Furthermore, stimulation of the Na+/H+ antiporter by the phorbol ester, phorbol-12-myristate-13-acetate, was also markedly attenuated by chronic LiCl treatment, suggesting an impairment of protein kinase C activity. In contrast, fMet-Leu-Phe-induced increases in intracellular Ca2+ and phospho-inositide breakdown were unchanged in cells treated with Li+ for 5 days. These results indicate that chronic but not acute Li+ treatment alters intracellular pH regulation possibly at a site distal to the fMet-Leu-Phe receptor.

Calcium↗
PubMed1990

Antidepressants, metabolites, and apparent drug resistance.

Antidepressant drugs are extensively metabolized prior to elimination from the body. These metabolites usually have biological and chemical properties different from those of the parent drug. This article explores the pharmacodynamic consequences of such metabolism as possibly contributing to failure to respond to or tolerate a drug. Differential side effects, especially of tricyclic antidepressant metabolites, are considered. Next, shifts in effects of presumed serotonin uptake inhibitors are described. Problems involving active metabolites of more novel compounds such as bupropion, amoxapine and trazodone range from possible reversal of response to prohibitive side effects. Finally, principles are deduced for identifying those cases in which metabolic considerations are most likely to be relevant to observed drug resistance.

Amoxapine↗
PubMedDate not supplied

Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants.

OBJECTIVE: To determine whether the currently available evidence supports the hypothesis that antidepressants and mood stabilizers may bring about some of their long-term therapeutic effects by regulating signal transduction pathways and gene expression in the central nervous system. METHODS: To address this question, we reviewed the evidence showing that chronic administration of antidepressants and mood stabilizers involves alterations in signaling pathways and gene expression in the central nervous system. RESULTS: A large body of data has shown that lithium and valproate exert effects on the protein kinase C signaling pathway and the activator protein 1 family of transcription factors; in contrast, antidepressants affect the cyclic adenosine monophosphate pathway and may bring about their therapeutic effects by modulating cyclic adenosine monophosphate-regulated gene expression in the central nervous system. CONCLUSIONS: Given the key roles of these signaling cascades in the amplification and integration of signals in the central nervous system, the findings have clear implications not only for research into the etiology and pathophysiology of the severe mood disorders but also for the development of novel and innovative treatment strategies.

Antidepressive Agents↗