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Robert K. Mcnamara - One of the best experts on this subject based on the ideXlab platform.
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Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?
The Journal of Clinical Psychiatry, 1996Co-Authors: Robert H. Lenox, Robert K. McnamaraAbstract:Background : Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs Valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of Valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. Method : HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium Valproate 1 mM, carbamazepine 100 μM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium Valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 μM, or sodium Valproate I mM in the absence or presence of inositol 40 μM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. Results: We report that chronic exposure of HN33 cells to either lithium or Valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to Valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and Valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by Valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. Conclusion : These data provide evidence that, like lithium, chronic exposure to Valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by Valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and Valproate may share this property.
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Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?
The Journal of clinical psychiatry, 1996Co-Authors: Robert H. Lenox, Robert K. Mcnamara, J M Watterson, D. G. WatsonAbstract:Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs Valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of Valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium Valproate 1 mM, carbamazepine 100 microM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium Valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 microM, or sodium Valproate 1 mM in the absence or presence of inositol 40 microM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. We report that chronic exposure of HN33 cells to either lithium or Valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to Valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and Valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by Valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. These data provide evidence that, like lithium, chronic exposure to Valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by Valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and Valproate may share this property.
Robert H. Lenox - One of the best experts on this subject based on the ideXlab platform.
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Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?
The Journal of Clinical Psychiatry, 1996Co-Authors: Robert H. Lenox, Robert K. McnamaraAbstract:Background : Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs Valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of Valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. Method : HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium Valproate 1 mM, carbamazepine 100 μM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium Valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 μM, or sodium Valproate I mM in the absence or presence of inositol 40 μM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. Results: We report that chronic exposure of HN33 cells to either lithium or Valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to Valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and Valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by Valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. Conclusion : These data provide evidence that, like lithium, chronic exposure to Valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by Valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and Valproate may share this property.
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Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?
The Journal of clinical psychiatry, 1996Co-Authors: Robert H. Lenox, Robert K. Mcnamara, J M Watterson, D. G. WatsonAbstract:Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs Valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of Valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium Valproate 1 mM, carbamazepine 100 microM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium Valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 microM, or sodium Valproate 1 mM in the absence or presence of inositol 40 microM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. We report that chronic exposure of HN33 cells to either lithium or Valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to Valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and Valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by Valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. These data provide evidence that, like lithium, chronic exposure to Valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by Valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and Valproate may share this property.
D. G. Watson - One of the best experts on this subject based on the ideXlab platform.
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Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?
The Journal of clinical psychiatry, 1996Co-Authors: Robert H. Lenox, Robert K. Mcnamara, J M Watterson, D. G. WatsonAbstract:Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs Valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of Valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium Valproate 1 mM, carbamazepine 100 microM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium Valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 microM, or sodium Valproate 1 mM in the absence or presence of inositol 40 microM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. We report that chronic exposure of HN33 cells to either lithium or Valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to Valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and Valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by Valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. These data provide evidence that, like lithium, chronic exposure to Valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by Valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and Valproate may share this property.
J M Medina - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of neonatal brain fuel utilization by Valproate and E-Δ2-Valproate is not a consequence of the stimulation of the γ-aminobutyric acid shunt
Life sciences, 1994Co-Authors: Juan P Bolanos, J M MedinaAbstract:Abstract Stimulation of the γ-aminobutyric acid (GABA) shunt by Valproate and its major metabolite, E-Δ 2 -Valproate, has been proposed to decrease brain energy metabolism. In order to elucidate this hypothesis, the effect of these drugs on substrate utilization in neonatal rat brain slices was studied. The overall rate of lactate utilization was dose-dependently inhibited by both drugs. Valproate and E-Δ 2 -Valproate inhibited both sterol and fatty acid syntheses from 3-hydroxybutyrate. The rate of glucose utilization was not affected by Valproate nor E-Δ 2 -Valproate. The inhibition of the GABA aminotransferase by aminooxyacetate decreased lipogenesis from lactate, 3-hydroxybutyrate and glucose. The inhibitor of the mitochondrial pyruvate carrier, α-cyano-4-hydroxycinnamate, strongly decreased the rate of lactate, 3-hydroxybutyrate and glucose utilization, suggesting that the inhibition of pyruvate mitochondrial carrier is not the mode of action of these drugs. It is suggested that inhibition of plasma membrane monocarboxylate carrier by Valproate and E-Δ 2 -Valproate, but not the activation of the GABA shunt, is responsible for the inhibition of the brain fuel utilization.
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Evidence of stimulation of the gamma-aminobutyric acid shunt by Valproate and E-delta 2-Valproate in neonatal rat brain.
Molecular pharmacology, 1993Co-Authors: J P Bolaños, J M MedinaAbstract:The effect of Valproate and its more active metabolite E-delta 2-Valproate on the rate of glucose oxidation through different metabolic pathways in neonatal rat brain slices was studied. The presence of Valproate or E-delta 2-Valproate did not change the rate of [3,4-14C]glucose or [6-14C]glucose incorporation into CO2, suggesting that glucose oxidation through the pyruvate dehydrogenase-catalyzed reaction and through the tricarboxylic acid cycle was not affected by these drugs. However, both drugs significantly enhanced the rate of [2-14C]glucose oxidation, supporting the notion that the activity of the gamma-aminobutyric acid (GABA) shunt is specifically stimulated by Valproate and, to a greater extent, by E-delta 2-Valproate. The presence of methionine sulfoximine or gamma-hydroxybutyrate did not change the GABA shunt activity. Brain glutamate decarboxylase activity was significantly increased after incubation of the brain slices in the presence of Valproate. Consequently, our results suggest that the mechanism of action of Valproate is related to the increase in the levels of the inhibitory neurotransmitter GABA caused by the enhancement of flux through the glutamate decarboxylase-catalyzed reaction.
Matteo Bologna - One of the best experts on this subject based on the ideXlab platform.
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Clinical and Kinematic Features of Valproate-Induced Tremor and Differences with Essential Tremor
The Cerebellum, 2020Co-Authors: Giulia Paparella, Luca Angelini, Alessandro De Biase, Antonio Cannavacciuolo, Donato Colella, Carlo Di Bonaventura, Anna Teresa Giallonardo, Alfredo Berardelli, Matteo BolognaAbstract:Tremor is a common movement disorder that can be induced by medications, including Valproate, which is used for the treatment of epilepsy. However, the clinical and neurophysiological features of Valproate-induced tremor are still under-investigated. We performed a clinical and kinematic assessment of Valproate-induced tremor by considering tremor body distribution and activation conditions. We investigated possible correlations between demographic and clinical data and kinematic features. Valproate-induced tremor results were also compared with those collected in a large sample of patients with essential tremor. Sixteen Valproate-induced tremor patients and 93 essential tremor patients were enrolled. All participants underwent a standardised neurological examination and video recording. Patients also underwent an objective assessment of postural, kinetic and rest tremor of the upper limbs and head tremor through kinematic analysis. Nonparametric tests were used for statistical comparisons between the two groups. Clinical evaluation showed a higher occurrence of rest tremor as well as head or voice, and lower limb involvement in patients with Valproate-induced tremor. Kinematic analysis showed a substantial variability in the tremor features of patients with Valproate-induced tremor. Compared to essential tremor, we found a higher occurrence of rest tremor of the upper limbs and the involvement of more body segments in Valproate-induced tremor patients. Valproate-induced tremor has distinctive clinical and kinematic features, which may suggest that Valproate interferes with the cerebellar functions.