| 1 | J. Med. Chem. 2000 Dec 43: 4893-909 |
|---|---|
| PMID | 11123999 |
| Title | Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. |
| Abstract | (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | World J. Biol. Psychiatry 2004 Apr 5: 100-6 |
| PMID | 15179669 |
| Title | Antipsychotic drugs influence transport of the beta-adrenergic antagonist [3H]-dihydroalprenolol into neuronal and blood cells. |
| Abstract | The amine hypothesis suggests that the cause of schizophrenic or depressive psychosis is dysfunction of noradrenergic or serotonergic neurotransmission. We investigated pharmacological properties of [3H]-dihydroalprenolol (DHA) transport into C6, IMR32, native lymphocytes, B-lymphoblastoids and MOLT-3 cells. DHA transport was inhibited by a heterogeneous group of structurally related compounds exhibiting an amine group and various aromatic ring structures. It was verified on cells of neuronal/glial and blood cell origin but in detail on B-lymphoblastoids. The latter once showed strongest inhibition of DHA transport using tricyclic antidepressants (amitriptyline: IC50 = 2.86 microM, imipramine: IC50 = 3.33 microM) and haloperidol (IC50 = 3.98 microM) as a neuroleptic. Antipsychotics like clozapine (IC50 = 11 microM), olanzapine (IC50 = 15 microM), spiperone (IC50 = 66 microM) and EMD 49980 (ICso > 100 microM) were less effective. In contrast to cells of blood origin, a stimulation of DHA transport by antipsychotics was not detectable using neuronal cells. As antipsychotics showed a distinct inhibition and, concerning cells of blood origin, a stimulation of transport after pre-incubation, further investigations seem to be of interest in respect to its involvement in the cellular uptake of drugs and therefore its impact on the quality of therapy of psychiatric patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Dec 32: 1793-7 |
| PMID | 18721842 |
| Title | Effects of haloperidol and risperidone on the expression of heat shock protein 70 in MK-801-treated rat C6 glioma cells. |
| Abstract | Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists such as dizocilpine (MK-801) produce schizophrenia-like psychosis in humans and induce the expression of heat shock protein 70 (HSP70) in rats. The present study examines the effects of antipsychotic drugs, haloperidol and risperidone, on the expression of HSP70 produced by MK-801 in rat C6 glioma cells. After pretreating with haloperidol and risperidone for 1 h, 6 h, 24 h and 72 h, respectively, C6 glioma cells were cultivated again in MK-801 for 6 h, and then, the extent of HSP70 expression was measured by immunoblotting using anti-HSP70 monoclonal antibody. The expression of HSP70 induced by MK-801 significantly decreased as the duration of haloperidol pretreatment was extended (p=0.002). Risperidone also increasingly attenuated the expression of HSP70 produced by MK-801 as the duration of pretreatment grew longer (p=0.003). The present findings show that haloperidol and risperidone decrease the HSP70 expression in MK-801-treated rat C6 glioma cells. These results suggest that HSP70 and NMDA receptors may play a significant role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Eur. J. Nucl. Med. Mol. Imaging 2009 Jul 36: 1167-75 |
| PMID | 19247652 |
| Title | Steroid hormones affect binding of the sigma ligand 11C-SA4503 in tumour cells and tumour-bearing rats. |
| Abstract | Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist (11)C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. (11)C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of (11)C-SA4503 to C6 cells was increased (approximately 50%) upon removal and decreased (approximately 60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC(50) progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of (11)C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of (11)C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | J. Psychopharmacol. (Oxford) 2010 Jul 24: 1055-67 |
| PMID | 19329549 |
| Title | The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. |
| Abstract | D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia. The effect of risperidone, a benzisoxazole derivative, atypical antischizophrenic drug, on the activity of human DAO was tested using an in-vitro oxygraph system and rat C6, stable C6 transformant cells overexpressing mouse DAO (designated as C6/DAO) and pig kidney epithelial cells (LLC-PK(1)). Risperidone has a hyperbolic mixed-type inhibition, designated as 'partial uncompetitive inhibition effect', with K(i) value of 41 microM on human DAO. Risperidone exhibited a protective effect from D-amino acid induced cell death in both C6/DAO and LLC-PK(1) cells with 10% increase in viability. These data indicate the involvement of DAO activity in D-serine metabolism and also suggest a new mechanism of action to risperidone as antischizophrenic drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Neuroscience 2010 Jun 167: 1025-31 |
| PMID | 20226844 |
| Title | Haloperidol and clozapine decrease S100B release from glial cells. |
| Abstract | Recent meta-analyses showed consistently elevated levels of S100B in serum and cerebrospinal fluid of schizophrenic patients. This finding has been attributed to glial pathology because S100B is produced by astrocytes and oligodendrocytes. However, S100B may be likewise associated with schizophrenia-related disturbances in glial cell as well as adipocyte energy supply and glucose metabolism. The influence of antipsychotic drugs on S100B levels remains unclear, and some studies have suggested that treatment with these drugs may actually contribute to the elevated S100B levels observed in schizophrenic patients. In this study, we explored the effects of the typical antipsychotic haloperidol and the atypical prototype drug clozapine on the release of S100B by astrocytic C6 cells and oligodendrocytic OLN-93 cells. Because of the association between schizophrenia and disturbances in energy metabolism, we assessed the effects of these drugs under basal condition (BC) compared to serum and glucose deprivation (SGD). We found that treatment of C6 and OLN-93 cells with haloperidol and clozapine reduced the release of S100B from C6 and OLN-93 cells under BC and SGD in vitro at a tissue concentration corresponding to the assumed therapeutic dose range of these drugs. These data suggest that elevated levels of S100B in bodily fluids of schizophrenic patients are normalized rather than increased by the effects of antipsychotic drugs on glial cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neuroscience 2010 Jun 167: 1025-31 |
| PMID | 20226844 |
| Title | Haloperidol and clozapine decrease S100B release from glial cells. |
| Abstract | Recent meta-analyses showed consistently elevated levels of S100B in serum and cerebrospinal fluid of schizophrenic patients. This finding has been attributed to glial pathology because S100B is produced by astrocytes and oligodendrocytes. However, S100B may be likewise associated with schizophrenia-related disturbances in glial cell as well as adipocyte energy supply and glucose metabolism. The influence of antipsychotic drugs on S100B levels remains unclear, and some studies have suggested that treatment with these drugs may actually contribute to the elevated S100B levels observed in schizophrenic patients. In this study, we explored the effects of the typical antipsychotic haloperidol and the atypical prototype drug clozapine on the release of S100B by astrocytic C6 cells and oligodendrocytic OLN-93 cells. Because of the association between schizophrenia and disturbances in energy metabolism, we assessed the effects of these drugs under basal condition (BC) compared to serum and glucose deprivation (SGD). We found that treatment of C6 and OLN-93 cells with haloperidol and clozapine reduced the release of S100B from C6 and OLN-93 cells under BC and SGD in vitro at a tissue concentration corresponding to the assumed therapeutic dose range of these drugs. These data suggest that elevated levels of S100B in bodily fluids of schizophrenic patients are normalized rather than increased by the effects of antipsychotic drugs on glial cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | J. Neurosci. Res. 2010 Jun 88: 1829-40 |
| PMID | 20091774 |
| Title | D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO). |
| Abstract | D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in alpha,beta-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which "simulate" the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [(3)H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [(3)H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jul 35: 1291-6 |
| PMID | 21513766 |
| Title | In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants. |
| Abstract | Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jul 35: 1291-6 |
| PMID | 21513766 |
| Title | In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants. |
| Abstract | Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jan 40: 1-11 |
| PMID | 22960606 |
| Title | Two-dimensional gel electrophoresis revealed antipsychotic drugs induced protein expression modulations in C6 glioma cells. |
| Abstract | The efficacy and side effects of long-term administration of antipsychotic drugs (APDs) may be attributed to drug-induced change in protein expression in brain cells. Glial cells are non-neuronal cells that can provide nutrients and physiological support to neuronal cells. Glial cells are believed to participate in neurotransmission, neurons' early development, and guiding migration of neurons. Accumulated clinical data also indicate relationships between disturbance of glial cells' function and various psychotic diseases including schizophrenia. We used two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry protein identification to analyze differentially expressed proteins in haloperidol-, risperidone-, and clozapine-treated C6 glioma cells. We found that the expression of pericentrin, glial fibrillary acidic protein, Rho GDP-dissociation inhibitor 1, anionic trypsin-1, peroxiredoxin-1, and parvalbumin were regulated by each of the three APDs. Western blot analysis supported the findings. Real-time quantitative PCR detected changed transcriptions of those proteins. Protein and gene expression of N-cadherin in C6 cells were affected by haloperidol and clozapine but not risperidone. In addition, regulatory effects of clozapine on the glyceraldehyde 3-phosphate dehydrogenase gene were observed in C6 cells. This may be the first study to uncover how APD-modulated genes may cause protein expression changes and affect ARHGDIA-mediated regulation of Rho GTPase family proteins in glial cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Int J Psychophysiol 2013 Jul 89: 63-71 |
| PMID | 23707337 |
| Title | Interhemispheric EEG coherence is reduced in auditory cortical regions in schizophrenia patients with auditory hallucinations. |
| Abstract | Central auditory processing has been reported to be impaired in schizophrenia patients who experience auditory hallucinations, and interhemispheric transfer in auditory circuits may be compromised. In this study, we used EEG spectral coherence to examine interhemispheric connectivity between cortical areas known to be important in the processing of auditory information. Coherence was compared across three subject groups: schizophrenia patients with a recent history of auditory hallucinations (AH), schizophrenia patients who did not experience auditory hallucinations (nonAH), and healthy controls (HC). Subjects listened to pure tone and word stimuli while EEG was recorded continuously. Upper alpha and upper beta band coherence was calculated from six pairs of electrodes located over homologous auditory areas in the left and right cerebral hemispheres. Significant between-group differences were found on four electrode pairs (C3-C4, C5-C6, Ft7-Ft8 and Cp5-Cp6) in the upper alpha band. Relative to both the HC and nonAH groups, coherence was lower in the AH patients, consistent with the hypothesis that interhemispheric connectivity is reduced in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jun 43: 14-22 |
| PMID | 23246638 |
| Title | Interleukin-6-induced S100B secretion is inhibited by haloperidol and risperidone. |
| Abstract | Although inflammation may be a physiological defense process, imbalanced neuroinflammation has been associated with the pathophysiology of brain disorders, including major depression and schizophrenia. Activated glia releases a variety of pro-inflammatory cytokines that contribute to neuronal dysfunction. Elevated levels of S100B, a glia derived protein, have been observed in the serum and CSF of schizophrenic patients suggesting a glial role in the disease. We evaluated whether S100B secretion (in C6 glioma cells and hippocampal slices in Wistar rats) could be directly modulated by the main inflammatory cytokines (IL-1?, TNF-?, IL-6 and IL-8) altered in schizophrenia, as well as the possible involvement of mitogen-activated protein kinase (MAPK) pathways in these responses. We also investigated the effects of typical and atypical antipsychotic drugs on glial cytokine-induced S100B release. Our results suggest that S100B secretion is increased by pro-inflammatory cytokines via MAPK and that oxidative stress may be a component of this modulation. These results reinforce the idea that the S100B protein is involved in the inflammatory response observed in many brain diseases, including schizophrenia. Moreover the antipsychotics, haloperidol and risperidone, were able to inhibit the secretion of S100B following IL-6 stimulation in C6 glioma cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jun 43: 14-22 |
| PMID | 23246638 |
| Title | Interleukin-6-induced S100B secretion is inhibited by haloperidol and risperidone. |
| Abstract | Although inflammation may be a physiological defense process, imbalanced neuroinflammation has been associated with the pathophysiology of brain disorders, including major depression and schizophrenia. Activated glia releases a variety of pro-inflammatory cytokines that contribute to neuronal dysfunction. Elevated levels of S100B, a glia derived protein, have been observed in the serum and CSF of schizophrenic patients suggesting a glial role in the disease. We evaluated whether S100B secretion (in C6 glioma cells and hippocampal slices in Wistar rats) could be directly modulated by the main inflammatory cytokines (IL-1?, TNF-?, IL-6 and IL-8) altered in schizophrenia, as well as the possible involvement of mitogen-activated protein kinase (MAPK) pathways in these responses. We also investigated the effects of typical and atypical antipsychotic drugs on glial cytokine-induced S100B release. Our results suggest that S100B secretion is increased by pro-inflammatory cytokines via MAPK and that oxidative stress may be a component of this modulation. These results reinforce the idea that the S100B protein is involved in the inflammatory response observed in many brain diseases, including schizophrenia. Moreover the antipsychotics, haloperidol and risperidone, were able to inhibit the secretion of S100B following IL-6 stimulation in C6 glioma cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Korean J. Physiol. Pharmacol. 2015 Jul 19: 365-72 |
| PMID | 26170741 |
| Title | Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies. |
| Abstract | Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor (NF)-?B, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Int. J. Biochem. Cell Biol. 2016 Jan 70: 82-91 |
| PMID | 26592196 |
| Title | Chlorpromazine inhibits mitochondrial apoptotic pathway via increasing expression of tissue factor. |
| Abstract | Chlorpromazine (CPZ) is a widely used antipsychotic drug with antagonistic effect on dopamine receptors. Accumulating evidence has shown that CPZ plays a neuroprotective role in various models of toxicity and apoptosis. However, the underlying mechanism contributing to this protective effect remains unclear. Here, we evaluate the effect of CPZ on mitochondrial apoptotic pathway in the neuron system. Higher levels of B-cell lymphoma-2 (Bcl-2) and tissue factor (TF) but lower apoptotic rate were found in hippocampus of CPZ-treated schizophrenic patients compared with non-antipsychotic treated controls. Additionally, both short-term and long-term treatment of CPZ in rats could up-regulate the levels of Bcl-2 and TF with no cytotoxic effects. In the in vitro experiment, expression of Bcl-2 was up-regulated in the C6 glioma cells transfected with pEGFP-N1-TF recombinant plasmid. Furthermore, in another independent rat model of apoptosis, compared with the group administrated with alcohol only, the brains of the CPZ-pretreated rats showed lower expression of cleaved caspase-3, cytochrome c and Bax, but higher expression of Bcl-2 and TF. Our data demonstrate that CPZ exerts its neuronal protective effects through inhibiting the activation of mitochondrial apoptotic pathway by up-regulating TF expression, thus providing new insight into CPZ function and application. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |