| 1 | Neuroscience 2001 -1 107: 535-50 |
|---|---|
| PMID | 11720778 |
| Title | Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. |
| Abstract | Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased BAX and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Pharmacopsychiatry 2003 Jan 36: 37-41 |
| PMID | 12649775 |
| Title | Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis - a case report. |
| Abstract | A 45-year-old female suffering from severe chronic schizophrenia of the paranoid type did not respond to typical antipsychotics. Five weeks after starting therapy with clozapine, she developed a clozapine-induced agranulocytosis (CA). Discontinuation of clozapine and treatment with granulocyte colony-stimulating factor (G-CSF) led to normalization of blood neutrophil counts within three weeks. This report suggests enhanced apoptosis of blood neutrophils during the acute phase of CA resulting from enhanced expression of the pro-apoptotic proteins BAX and Bik and from a decrease of the anti-apoptotic BCl-X(L) mRNA. The time course of decline and recovery of neutrophilic cells, as well as the release pattern of endogenous G-CSF, resembles those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimics that of cytotoxic progenitor cell mobilization, e. g., after cytostatic drug administration. Our findings argue against the hypothesis that clozapine-mediated inhibition of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) release is involved in CA development. Because clozapine-induced cell death mainly affects the neutrophil lineage, the elucidation of the exact mechanism of CA may open new perspectives for the treatment of psychiatric and possibly hematological disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Pharmacol. Exp. Ther. 2003 Jan 304: 266-71 |
| PMID | 12490600 |
| Title | Blockade of phencyclidine-induced cortical apoptosis and deficits in prepulse inhibition by M40403, a superoxide dismutase mimetic. |
| Abstract | Repetitive administration of phencyclidine (PCP) in the perinatal period results in cortical apoptosis and a long-lasting deficit in sensorimotor gating. Because these changes are olanzapine-sensitive, we have suggested that the effects of perinatal PCP could be used to model certain aspects of schizophrenia. Studies of PCP and N-methyl-D-aspartate-induced cell death suggested that superoxide could play a role in the pathway leading to death after PCP administration. The purpose of the current study was to determine whether the in vivo administration of M40403, a superoxide dismutase mimetic, could prevent PCP-induced cortical apoptosis and/or deficits in prepulse inhibition. Perinatal rat pups were administered 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11 with or without treatment with 10 mg/kg M40403. Pups were either killed on PN 12 for analysis of various apoptotic markers or they were assessed for prepulse inhibition on PN 24 to 26. Treatment with M40403 2 and 24 h after each PCP treatment prevented PCP-induced increases in two measures of apoptosis in the dorsolateral frontal cortex and in the olfactory cortex. PCP-induced proapoptotic changes in BAX and Bcl-X(L) were also prevented by M40403 treatment. This regimen did not prevent the deficit in prepulse inhibition caused by PCP treatment, but when the treatment regimen was extended through PN 23, M40403 completely prevented the PCP-induced deficit in prepulse inhibition. These data suggest that perinatal PCP treatment leads to long-lasting changes in the pathway(s), leading to cell death and behavioral deficits, and that the superoxide radical plays a critical role in the underlying mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Am J Psychiatry 2004 Jan 161: 109-15 |
| PMID | 14702258 |
| Title | Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. |
| Abstract | Neuroimaging findings have identified lower cortical gray matter volume in schizophrenia. Apoptosis (programmed cell death) has been proposed as a contributing pathophysiological mechanism. Levels of antiapoptotic Bcl-2 protein are low in the temporal cortex of schizophrenia patients. Bcl-2 interacts with the proapoptotic BAX protein at an upstream checkpoint to regulate the activation of apoptosis by caspase-3 and other proteolytic caspase proteins. A high BAX/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity. It was hypothesized that the BAX/Bcl-2 ratio, but not caspase-3, would be high in the temporal cortex of patients with chronic schizophrenia. BAX, Bcl-2, and caspase-3 proteins were measured by semiquantitative Western blot in Brodmann's area 21 (middle temporal gyrus) of postmortem tissue from patients with schizophrenia (N=15), bipolar disorder (N=15), or major depression (N=15) and nonpsychiatric comparison subjects (N=15). The BAX/Bcl-2 ratio was 50% higher in the schizophrenia patients than the nonpsychiatric comparison subjects. The level of caspase-3 (inactive zymogen and activated subunits) was not significantly different. The higher BAX/Bcl-2 ratio suggests that cortical cells are vulnerable to apoptosis in chronic schizophrenia. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase. Furthermore, the results appear to distinguish the pathophysiology of schizophrenia from most classic neurodegenerative disorders, in which postmortem caspase-3 levels are high. Further studies are needed to investigate the implications of abnormal apoptotic proteins in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J Clin Psychopharmacol 2005 Oct 25: 419-26 |
| PMID | 16160616 |
| Title | Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. |
| Abstract | The present study examined cellular effects of the atypical antipsychotic drug clozapine on blood cells of treated patients with and without clozapine-induced agranulocytosis (CA). Blood from one patient who commenced clozapine treatment was examined at weekly intervals for 128 days. Olanzapine-treated (n = 5) and polymedicated (n = 14) schizophrenic patients, as well as healthy subjects (n = 19) and septic shock patients (n = 8), were studied for comparison. We observed dramatically increased numbers of native neutrophils stained for superoxide anion production (P < or = 0.005, n = 10) and significantly elevated expression levels of the proapoptotic genes p53 (P < or = 0.020), BAX alpha (P < or = 0.001), and bik (P < or = 0.002) in all tested non-CA patients (n = 19) and CA patients (n = 4). In non-CA patients, the expression of these genes did not correlate to the percentage of apoptotic neutrophils (2.0% +/- 1.3%), but in CA patients about 37% of the neutrophils show morphologic signs of apoptosis (P < or = 0.001). Under G-CSF therapy of CA, the number of apoptotic neutrophils and the expression of the proapoptotic genes decreased significantly. In conclusion, high production of reactive oxygen species in neutrophils of clozapine-treated patients, together with increased expression of proapoptotic genes, suggests that neutrophils are predisposed to apoptosis in schizophrenic patients under clozapine therapy. The correlation between drug and proapoptotic markers was highest for clozapine and BAX alpha as well as superoxide anion radicals. This indicates oxidative mitochondrial stress in neutrophils of clozapine-treated patients which probably contributes to the induction of apoptosis and sudden loss of neutrophils and their precursors in CA patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Schizophr. Res. 2006 May 84: 20-8 |
| PMID | 16626937 |
| Title | Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines. |
| Abstract | The aim of this study was to investigate whether there is an increased susceptibility to apoptosis in cultured fibroblasts from patients with schizophrenia. Dermal fibroblasts were collected and cultured from three groups: patients with schizophrenia, patients with non-schizophrenic psychosis, and healthy comparison subjects. Susceptibility to apoptosis was measured at the level of degradation product (proportion of cells in the sub-G0 cell cycle fraction in which apoptotic bodies accumulate), pro-apoptotic effector (activated caspase-3), and molecular regulators (P53, BAX and Bcl-2). Cell lines were studied under both basal culture and cycloheximide (an apoptotic inducer) exposure conditions. Consistent with increased susceptibility to apoptosis, the proportion of sub-G0 cells under basal conditions was significantly larger in the schizophrenia group, compared to the non-schizophrenic psychosis group. However when apoptosis was stimulated with cycloheximide, the schizophrenia group showed an attenuated caspase-3 response. The pattern of correlations between regulators, caspase-3 and the proportion of sub-G0 cells was different in the schizophrenia group, consistent with group-specific apoptotic pathway dysregulation. The study demonstrated anomalous apoptotic mechanisms in schizophrenia, which appear not to affect non-schizophrenia psychosis patients. The detection of these anomalies in fibroblasts suggests that altered apoptosis may be observable in all somatic cell types in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Schizophr. Res. 2006 May 84: 20-8 |
| PMID | 16626937 |
| Title | Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines. |
| Abstract | The aim of this study was to investigate whether there is an increased susceptibility to apoptosis in cultured fibroblasts from patients with schizophrenia. Dermal fibroblasts were collected and cultured from three groups: patients with schizophrenia, patients with non-schizophrenic psychosis, and healthy comparison subjects. Susceptibility to apoptosis was measured at the level of degradation product (proportion of cells in the sub-G0 cell cycle fraction in which apoptotic bodies accumulate), pro-apoptotic effector (activated caspase-3), and molecular regulators (P53, BAX and Bcl-2). Cell lines were studied under both basal culture and cycloheximide (an apoptotic inducer) exposure conditions. Consistent with increased susceptibility to apoptosis, the proportion of sub-G0 cells under basal conditions was significantly larger in the schizophrenia group, compared to the non-schizophrenic psychosis group. However when apoptosis was stimulated with cycloheximide, the schizophrenia group showed an attenuated caspase-3 response. The pattern of correlations between regulators, caspase-3 and the proportion of sub-G0 cells was different in the schizophrenia group, consistent with group-specific apoptotic pathway dysregulation. The study demonstrated anomalous apoptotic mechanisms in schizophrenia, which appear not to affect non-schizophrenia psychosis patients. The detection of these anomalies in fibroblasts suggests that altered apoptosis may be observable in all somatic cell types in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Behav. Brain Res. 2006 Apr 168: 236-42 |
| PMID | 16360889 |
| Title | The effects of chronic administration of quetiapine on the phencyclidine-induced reference memory impairment and decrease of Bcl-XL/Bax ratio in the posterior cingulate cortex in rats. |
| Abstract | Quetiapine, a new atypical antipsychotic drug, effectively alleviates positive and negative symptoms, as well as cognitive impairment that may be caused by neurodegeneration, in schizophrenia patients. Earlier in vivo and in vitro studies have demonstrated that quetiapine may be a neuroprotectant. The present study was designed to examine the beneficial effects of quetiapine on the possible cognitive impairment and changes of brain apoptotic regulation proteins induced by phencyclidine (PCP) in rats. Rats were treated with quetiapine (10 mg/kg/day; intraperitoneal (i.p.)) or vehicle for 16 days. On day 14, 1 h after the administration of quetiapine, the rats were given PCP (50 mg/kg; subcutaneous (s.c.)) or vehicle. Then quetiapine was administrated for an additional 2 days. One day after the last quetiapine injection (3 days after the PCP injection), the rats were trained on a spatial memory task in a radial arm maze. After the behavioural test, the rats were decapitated for Western blot analysis. PCP induced reference memory impairment, and a decrease of the ratio of an anti-apoptotic Bcl-2 family member (Bcl-XL) to a pro-apoptotic analogue (BAX) in the posterior cingulate cortex. Chronic administration of quetiapine counteracted the PCP-induced reference memory impairment and decrease of Bcl-XL/BAX ratio in the posterior cingulate cortex. These results suggest that quetiapine may have ameliorating effects on the cognitive impairment and brain apoptotic processes induced by PCP. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Neuropsychopharmacology 2007 Jan 32: 95-102 |
| PMID | 16641945 |
| Title | Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. |
| Abstract | In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic BAX, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of BAX and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Int. J. Neuropsychopharmacol. 2007 Jun 10: 359-68 |
| PMID | 16780607 |
| Title | The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex. |
| Abstract | Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, BAX, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Neurosci. Lett. 2009 Sep 463: 60-3 |
| PMID | 19632297 |
| Title | No association between the Bcl2-interacting killer (BIK) gene and schizophrenia. |
| Abstract | The Bcl2-interacting killer (BIK) gene interacts with cellular and viral survival-promoting proteins, such as Bcl-2, to enhance apoptosis. The BIK protein promotes cell death in a manner analogous to Bcl-2-related death-promoting proteins, BAX and Bak. There have been lower Bcl-2 levels and increased BAX/Bcl-2 ratio in the temporal cortex of patients with schizophrenia compared with those in controls. Because the death-promoting activity of BIK was suppressed in the presence of the cellular and viral survival-promoting proteins, the BIK protein is suggested as a likely target for antiapoptotic proteins. The purpose of this study is to investigate the association between genetic variants in the BIK gene and schizophrenia in a large Japanese population (1181 patients with schizophrenia and 1243 healthy controls). We found nominal evidence for association of alleles, rs926328 (chi2=4.44, p=0.035, odds ratio=1.13) and rs2235316 (chi2=4.41, p=0.036, odds ratio=1.13), with schizophrenia. However, these associations were no longer positive after correction for multiple testing (rs926328: corrected p=0.105, rs2235316: corrected p=0.108). We conclude that BIK might not play a major role in the susceptibility of schizophrenia in Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Int. J. Neuropsychopharmacol. 2009 Jul 12: 805-22 |
| PMID | 19149911 |
| Title | Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. |
| Abstract | Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/BAX ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Neurosci. Res. 2011 Apr 69: 283-90 |
| PMID | 21238512 |
| Title | Protective effects of atypical antipsychotic drugs against MPP(+)-induced oxidative stress in PC12 cells. |
| Abstract | Recent studies have suggested that some atypical antipsychotic drugs may have protective properties against oxidative stress. To confirm these findings, we investigated the protective effects of atypical antipsychotic drugs such as olanzapine, aripiprazole, and ziprasidone on oxidative stress induced by the N-methyl-4-phenylpyridinium (MPP(+)) ion in PC12 cells. Haloperidol, a typical antipsychotic drug, was used for comparison. We determined the antioxidant effects of atypical antipsychotic drugs using a number of measures, including cell viability, the formation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and BAX levels. MPP(+) treatment induced significant loss of cell viability, the formation of ROS, reduction of SOD activity, and up-regulation of BAX expression. However, olanzapine, aripiprazole and ziprasidone reversed these effects caused by MPP(+) treatment, but ziprasidone did not influence cell viability. In contrast, haloperidol did not affect all these effects. Moreover, haloperidol strongly increased the expression of BAX under MPP(+)-free conditions. Olanzapine, aripiprazole, and ziprasidone, but not haloperidol, may exert antioxidant effects through modulating ROS levels, SOD activity, and BAX expression to provide protective effects against MPP(+)-induced oxidative stress in PC12 cells. These results suggest that some atypical antipsychotic drugs have a useful therapeutic effect by reducing oxidative stress in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | J Psychiatr Res 2014 Jan 48: 94-101 |
| PMID | 24128664 |
| Title | Increased susceptibility to apoptosis in cultured fibroblasts from antipsychotic-naïve first-episode schizophrenia patients. |
| Abstract | Altered apoptosis has been proposed as a potential mechanism involved in the abnormal neurodevelopment and neurodegenerative processes associated with schizophrenia. The aim of this study was to investigate in primary fibroblast cultures whether antipsychotic-naïve patients with first-episode schizophrenia have greater apoptotic susceptibility than healthy controls. Cell growth, cell viability and various apoptotic hallmarks (caspase-3 activity, translocation of phosphatidylserine, chromatin condensation and gene expression of AKT1, BAX, BCL2, CASP3, GSK3B and P53) were measured in fibroblast cultures obtained from skin biopsies of patients (n = 11) and healthy controls (n = 8), both in basal conditions and after inducing apoptosis with staurosporine. Compared to controls, cultured fibroblasts from patients showed higher caspase-3 activity and lower BCL2 expression. When exposed to staurosporine, fibroblasts from patients also showed higher caspase-3 activity; a higher percentage of cells with translocated phosphatidylserine and condensed chromatin; and higher p53 expression compared to fibroblasts from controls. No differences in cell viability or cell growth were detected. These results strongly support the hypothesis that first-episode schizophrenia patients may have increased susceptibility to apoptosis, which may be involved in the onset and progression of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | J Exerc Rehabil 2014 Aug 10: 218-24 |
| PMID | 25210696 |
| Title | Treadmill exercise inhibits hippocampal apoptosis through enhancing N-methyl-D-aspartate receptor expression in the MK-801-induced schizophrenic mice. |
| Abstract | schizophrenia is a severe mental disorder characterized by abnormal mental functioning and disruptive behaviors. Abnormal expression of N-methyl-D-aspartate (NMDA) receptor, one of the glutamate receptor subtypes, has also been suggested to contribute to the symptoms of schizophrenia. The effect of treadmill exercise on schizophrenia-induced apoptosis in relation with NMDA receptor has not been evaluated. In the present study, we investigated the effect of treadmill exercise on neuronal apoptosis in the hippocampus using MK-801-induced schizophrenic mice. MK-801 was intraperitoneally injected once a day for 2 weeks. The mice in the exercise groups were forced to run on a treadmill exercise for 60 min, once a day for 2 weeks. In the present results, repeated injection of the NMDA receptor antagonist MK-801 reduced expression of NMDA receptor in hippocampal CA2-3 regions. MK-801 injection increased casapse-3 expression and enhanced cytochrome c release in the hippocampus. The ratio of BAX to Bcl-2 was higher in the MK-801-induced schizophrenia mice than the normal mice. In contrast, treadmill exercise enhanced NMDA receptor expression, suppressed caspae-3 activation and cytochrome c release, and inhibited the ratio of BAX to Bcl-2. Based on present finding, we concluded that NMDA receptor hypofunctioning induced neuronal apoptosis in MK-801-induced schizophrenic mice. Treadmill exercise suppressed neuronal apoptosis through enhancing NMDA receptor expression in schizophrenic mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | J Exerc Rehabil 2014 Aug 10: 218-24 |
| PMID | 25210696 |
| Title | Treadmill exercise inhibits hippocampal apoptosis through enhancing N-methyl-D-aspartate receptor expression in the MK-801-induced schizophrenic mice. |
| Abstract | schizophrenia is a severe mental disorder characterized by abnormal mental functioning and disruptive behaviors. Abnormal expression of N-methyl-D-aspartate (NMDA) receptor, one of the glutamate receptor subtypes, has also been suggested to contribute to the symptoms of schizophrenia. The effect of treadmill exercise on schizophrenia-induced apoptosis in relation with NMDA receptor has not been evaluated. In the present study, we investigated the effect of treadmill exercise on neuronal apoptosis in the hippocampus using MK-801-induced schizophrenic mice. MK-801 was intraperitoneally injected once a day for 2 weeks. The mice in the exercise groups were forced to run on a treadmill exercise for 60 min, once a day for 2 weeks. In the present results, repeated injection of the NMDA receptor antagonist MK-801 reduced expression of NMDA receptor in hippocampal CA2-3 regions. MK-801 injection increased casapse-3 expression and enhanced cytochrome c release in the hippocampus. The ratio of BAX to Bcl-2 was higher in the MK-801-induced schizophrenia mice than the normal mice. In contrast, treadmill exercise enhanced NMDA receptor expression, suppressed caspae-3 activation and cytochrome c release, and inhibited the ratio of BAX to Bcl-2. Based on present finding, we concluded that NMDA receptor hypofunctioning induced neuronal apoptosis in MK-801-induced schizophrenic mice. Treadmill exercise suppressed neuronal apoptosis through enhancing NMDA receptor expression in schizophrenic mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Curr Mol Pharmacol 2016 Jan -1: -1 |
| PMID | 26758954 |
| Title | Role of hexokinase and VDAC in neurological disorders. |
| Abstract | Several neurological diseases such as bipolar disorders and schizophrenia are linked to impaired brain energy metabolism. A key feature of brain bioenergetics is hexokinase (HK) binding to the outer mitochondrial membrane through the voltage dependent anion channel (VDAC). This has metabolic consequences, with phosphorylation of glucose by mitochondrially bound hexokinase being closely coupled to production of substrate ATP by intramitochondrial oxidative phosphorylation. Additionally, binding of HK to mitochondria inhibits BAX-induced cytochrome c release and apoptosis. Moreover VDAC1 expression level is elevated in cerebellum of patients with Down ´s syndrome, while in Alzheimer ´s disease, VDAC1 levels are decreased in frontal cortex and VDAC2 elevated in temporal cortex. Thus, understanding the roles of VDAC and HK, either separate or interacting in brain, provides new opportunities and challenges to elucidate pathophysiological mechanisms for future therapeutic strategies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Brain Res. 2016 May -1: -1 |
| PMID | 27208492 |
| Title | Na(+), K(+)-ATPase dysfunction causes cerebrovascular endothelial cell degeneration in rat prefrontal cortex slice cultures. |
| Abstract | Cerebrovascular endothelial cell dysfunction resulting in imbalance of cerebral blood flow contributes to the onset of psychiatric disorders such as depression, schizophrenia and bipolar disorder. Although decrease in Na(+), K(+)-ATPase activity has been reported in the patients with schizophrenia and bipolar disorder, the contribution of Na(+), K(+)-ATPase to endothelial cell dysfunction remains poorly understood. Here, by using rat neonatal prefrontal cortex slice cultures, we demonstrated that pharmacological inhibition of Na(+), K(+)-ATPase by ouabain induced endothelial cell injury. Treatment with ouabain significantly decreased immunoreactive area of rat endothelial cell antigen-1 (RECA-1), a marker of endothelial cells, in a time-dependent manner. Ouabain also decreased Bcl-2/BAX ratio and phosphorylation level of glycogen synthase kinase 3? (GSK3?) (Ser9), which were prevented by lithium carbonate. On the other hand, ouabain-induced endothelial cell injury was exacerbated by concomitant treatment with LY294002, an inhibitor of phosphoinositide 3- (PI3-) kinase. We also found that xestospongin C, an inhibitor of inositol triphosphate (IP3) receptor, but not SEA0400, an inhibitor of Na(+), Ca(2+) exchanger (NCX), protected endothelial cells from cytotoxicity of ouabain. These results suggest that cerebrovascular endothelial cell degeneration induced by Na(+), K(+)-ATPase inhibition resulting in Ca(2+) release from endoplasmic reticulum (ER) and activation of GSK3? signaling underlies pathogenesis of these psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | 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 |