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Biomedical subjects

H K Manji

Publications and source records attributed to H K Manji.

At least 19 recordsLinked to original sources
PubMed2004

Protein kinase C overactivity impairs prefrontal cortical regulation of working memory.

The prefrontal cortex is a higher brain region that regulates thought, behavior, and emotion using representational knowledge, operations often referred to as working memory. We tested the influence of protein kinase C (PKC) intracellular signaling on prefrontal cortical cognitive function and showed that high levels of PKC activity in prefrontal cortex, as seen for example during stress exposure, markedly impair behavioral and electrophysiological measures of working memory. These data suggest that excessive PKC activation can disrupt prefrontal cortical regulation of behavior and thought, possibly contributing to signs of prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder.

Adrenergic alpha-Agonists↗
PubMed2004

Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers.

Bipolar disorder afflicts approximately 1-3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.

Antimanic Agents↗
PubMed2004

Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology.

Bipolar affective disorder (manic-depressive illness) is a common, severe, chronic, and often life-threatening illness, associated with significant comorbidity. The recognition of the significant morbidity and mortality of patients with bipolar disorder, as well as the growing appreciation that a high percentage of patients respond poorly to existing treatments, has made the task of discovering new therapeutic agents, that are both efficacious and have few side effects increasingly more important. Most recent agents introduced into the pharmacopeia for the treatment of bipolar disorder have been anticonvulsants and atypical antipsychotics. We propose that novel treatments developed specifically for bipolar disorder will arise from (1) understanding more precisely the molecular mechanisms of treatments that are clearly efficacious or (2) developing medications based on the knowledge obtained of the underlying pathophysiology of bipolar disorder. Knowledge with regard to the underlying pathophysiology of bipolar disorder is increasing at a rapid pace, including alterations in intracellular signaling cascades as well as impairments of cellular plasticity and resilience in critical neuronal circuits. We propose that therapeutics designed to enhance cellular plasticity and resilience and that counter maladaptive stress-responsive systems may have considerable utility for the treatment of bipolar disorder. Therapeutic strategies designed to address cellular resilience and plasticity include the regulation of neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput and mitochondrial function. While the task of developing novel medications for bipolar disorder is truly daunting, these and similar approaches will ultimately lead to better medications for the millions who suffer from this devastating illness.

Antimanic Agents↗
PubMed2003

Possible involvement of the ERK signaling cascade in bipolar disorder: behavioral leads from the study of mutant mice.

Despite the devastating impact that bipolar disorder has on the lives of millions worldwide, little is known for certain about its etiology or pathophysiology. Whereas research has traditionally focused on biogenic amines, it is becoming increasingly more apparent that intracellular pathways are involved in the etiology and treatment of the disease and that a true understanding of the pathophysiology of bipolar disorder must address its neurobiology at different physiological levels, that is, molecular, cellular, systems and behavioral levels. There is now considerable biochemical evidence that the antimanic agents lithium and valproate robustly activate the ERK signaling cascade in therapeutically relevant paradigms. This raises the possibility that this pathway may play a role in the antimanic effects of these agents. The present paper reviews behavioral studies that may shed light on the involvement of the ERK pathway in affective-like behaviors in animals. The available literature suggests that genetic manipulations of the brain-derived neurotrophic factor (BDNF)-ERK kinase pathway produces a variety of changes in affective-like behaviors, with most changes consistent with manic-like behavior. Thus, overall, mice with targeted mutation of the BDNF gene exhibited increased spontaneous locomotion and increased response to acute amphetamine, altered response to chronic cocaine, increased aggression, increase in risk-taking behavior, as demonstrated by time spent in the center of an open field, and changes in eating patterns. Although it has to be acknowledged that the currently available behavioral data from the BDNF-ERK pathway mutants is less than ideal to offer real substantiation relating this pathway to bipolar disorder, the data still supports the possibility that this pathway modulates manic-like behavior in animals, and perhaps mania in humans.

Animals↗
PubMed2002

PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers.

The complexity of the unique biology of bipolar disorder--which includes the predisposition to episodic, and often progressive, mood disturbance--and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our ability to identify the underlying pathophysiology of this fascinating neuropsychiatric disorder. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of bipolar disorder. In particular, a converging body of preclinical data has shown that chronic lithium and valproate, at therapeutically relevant concentrations, regulate the protein kinase C signaling cascade. This has led to the investigation of the antimanic efficacy of tamoxifen (at doses sufficient to inhibit protein kinase C), with very encouraging preliminary results. A growing body of data also suggests that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of bipolar disorder. It is thus noteworthy that mood stabilizers, such as lithium and valproate, indirectly regulate a number of factors involved in cell survival pathways--including cAMP response element binding protein, brain derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases--and may thus bring about some of their delayed long-term beneficial effects via under-appreciated neurotrophic effects. The development of novel treatments, which more directly target molecules involved in critical central nervous system cell survival and cell death pathways, has the potential to enhance neuroplasticity and cellular resilience, thereby modulating the long-term course and trajectory of these devastating illnesses.

Anticonvulsants↗
PubMed2001

The effects of lithium on ex vivo cytokine production.

BACKGROUND: Studies suggest that lithium may have profound immunomodulatory effects in animal models as well as in humans. METHODS: In this study, whole blood cultures from normal control subjects were established for 5 days and the effects of lithium on cytokine production were investigated. Because many of lithium's actions have been postulated to be modulated through phosphoinositide (PI), protein kinase C (PKC) and cyclic adenosine monophosphate (c-AMP) signaling pathways, the effects of myo-inositol and prostaglandin E(2), alone or in combination with lithium, were also investigated. RESULTS: We found that lithium caused an increase in interleukin-4 and interleukin-10 levels, traditionally classified as T-helper lymphocyte type-2 cytokines, and a decrease in interleukin-2 and interferon-gamma levels, traditionally classified as T-helper lymphocyte type-1 (TH-1) cytokines. This shift cannot be fully explained by lithium's actions on the PI, PKC, or c-AMP messenger systems. CONCLUSIONS: Monocytes exposed to lithium in the presence of a mitogen for 5 days produced a shift toward the production of TH-2 cytokines and away from the production of TH-1 cytokines. The study suggests that lithium may have complex time-dependent effects on immune function.

Adult↗
PubMed2001

The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth.

The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of AP-1 transcription factors, as well as the expression of genes regulated by AP-1, in cultured cells and brain regions involved in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation, neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK pathway activator and produces neurotrophic effects.

Base Sequence↗
PubMed2001

Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability.

Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT-PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers - the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and/or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.

Animals↗
PubMed2001

The cellular neurobiology of depression.

Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.

Antidepressive Agents↗
PubMed2001

Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers.

Background New research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication. Aim To elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilisers. Method Results from integrated clinical and laboratory studies are reviewed. Results Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein 1 family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2. Conclusions The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilisers. Additionally, mood stabilisers may exert underappreciated neuroprotective effects.

Journal Article↗
PubMed2001

Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers.

BACKGROUND: New research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication. AIM: To elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilizers. METHOD: Results from integrated clinical and laboratory studies are reviewed. RESULTS: Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein I family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2. CONCLUSIONS: The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilizers. Additionally, mood stabilizers may exert underappreciated neuroprotective effects.

Antimanic Agents↗
PubMed2001

Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics.

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.

Animals↗
PubMed2000

Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness.

Recent neuroimaging studies have demonstrated regional central nervous system volume reductions in mood disorders, findings that are complemented by postmortem observations of cell atrophy and loss. It is thus noteworthy that lithium and valproate have recently been demonstrated to robustly increase the expression of the cytoprotective protein bcl-2 in the central nervous system. Chronic lithium not only exerts neuroprotective effects in several preclinical paradigms but also enhances hippocampal neurogenesis. Valproate robustly promotes neurite outgrowth and activates the ERK mitogen-activated protein kinase pathway, a signaling pathway utilized by many endogenous neurotrophic factors. Consistent with its preclinical neurotrophic/neuroprotective effects, chronic lithium treatment of patients with manic-depressive illness increases brain N-acetylaspartate (a putative marker of neuronal viability and function) levels, an effect that is localized almost exclusively to gray matter. To determine if lithium was producing neuropil increases, quantitative three-dimensional magnetic resonance imaging studies were undertaken, which revealed that chronic lithium significantly increases total gray matter volume in the human brain of patients with manic-depressive illness. Together, these results suggest that a reconceptualization about the optimal long-term treatment of recurrent mood disorders is warranted. Optimal long-term treatment for these severe illnesses may only be achieved by the early use of agents with neurotrophic/neuroprotective effects, irrespective of the primary, symptomatic treatment.

Affect↗
PubMed2000

Lithium-induced increase in human brain grey matter.

Rodent studies have shown that lithium exerts neurotrophic or neuroprotective effects. We used three-dimensional magnetic resonance imaging and brain segmentation to study pharmacologically-induced increases in grey matter volume with chronic lithium use in patients with bipolar mood disorder. Grey-matter volume increased after 4 weeks of treatment. The increases in grey matter probably occurred because of neurotrophic effects.

Adolescent↗
PubMed2000

Lithium treatment in ovo: effects on embryonic heart rate, natural death of ciliary ganglion neurons, and brain expression of a highly conserved chicken homolog of human MTG8/ETO.

Understanding the action of the mood stabilizer lithium is dependent on availability of experimental models where lithium treatment at clinically relevant concentrations induces marked phenotypic and genotypic changes. Here we report on such changes in the chicken embryo. Lithium chloride (0.6 mM), applied in ovo 60 h after incubation, markedly delayed the heart rate increase observed from ED2.5 to ED5, and induced the brain expression of a new chicken gene cETO from ED7 to ED15. At the same time the overall developmental dynamics and embryo survival, or the expression of chicken gephyrin were not significantly affected. Furthermore, lithium treatment (0.3 mM, 48 h after incubation) abolished the difference in neuronal number between ED12 ciliary ganglia developing in the presence or absence of postganglionic target muscles. We show that cETO is a close homologue of the human transcription factor MTG8/ETO; named after its location on chromosome 8, and participation in chromosomal translocation 8;21 in myeloid leukemia. The mRNA and protein levels of ETO and gephyrin had a parallel course in chicken brain development suggesting that the expression of both genes is regulated mainly at the level of gene transcription. However, the patterns of expression were markedly different. ETO peaked at ED7 and decreased five-fold at ED15. In contrast, gephyrin levels increased five-fold from ED7 to ED15. We propose that the induction of ETO expression, in concert with lithium-induced upregulation of other genes, such as PEBP2beta and bcl-2, is participating in the neuroprotective effect of chronic lithium treatment.

Amino Acid Sequence↗
PubMed2000

Signaling: cellular insights into the pathophysiology of bipolar disorder.

Clinical studies over the years have provided evidence that monoamine signaling and hypothalamic-pituitary-adrenal axis disruption are integral to the pathophysiology of bipolar disorder. A full understanding of the pathophysiology from a molecular to a systems level must await the identification of the susceptibility and protective genes driving the underlying neurobiology of bipolar disorder. Furthermore, the complexity of the unique biology of this affective disorder, which includes the predisposition to episodic and often progressive mood disturbance, and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our progress to date. Imaging studies in patient populations have provided evidence of a role for anterior cingulate, amygdala, and prefrontal cortex in the pathophysiology of bipolar disorder. More recent research strategies designed to uncover the molecular mechanisms underlying our pharmacologic treatments and their interaction in the regulation of signal transduction as well as more advanced brain imaging studies remain promising approaches. This experimental strategy provides data derived from the physiologic response of the system in affected individuals and addresses the critical dynamic interaction with pharmacologic agents that effectively modify the clinical expression of the pathophysiology.

Antipsychotic Agents↗
PubMed2000

Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study.

This study examined the hypothesis that lithium inhibits the PI signaling pathway in humans during in vivo administration by concurrently measuring PKC isozymes and platelet membrane phosphoinositides in lithium-treated patients and healthy individuals. The platelet membrane and cytosolic levels of PKC alpha, beta I, beta II, delta, and epsilon were measured using Western blotting. The relative platelet membrane contents of phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP(2)) were measured with two-dimensional thin-layer chromatography. Nine euthymic lithium-treated bipolar subjects and 11 healthy control subjects were studied. Compared to control subjects, lithium-treated bipolar patients had significantly lower levels of cytosolic PKC alpha isozyme (t-test=-3.24, d.f.=17, P=0.01) and PIP(2) platelet membrane levels (t-test=-2.51, d.f.=18, P=0.02), and a trend toward reduced levels of cytosolic PKC beta II isozyme (t=-2.17, d.f.=17, P=0.05). There was no significant correlation between PIP(2) and any of the PKC isozymes. These preliminary findings suggest that chronic lithium treatment may decrease the levels of both cytosolic PKC alpha isozyme and membrane PIP(2) in platelets of bipolar disorder patients.

Adult↗