Evidence for neuroprotective effects of antipsychotic drugs: implications for the pathophysiology and treatment of schizophrenia.
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Animals↗
Biomedical subjects
Xin-Min Li
Publications and source records attributed to Xin-Min Li.
Lactosylceramide: lateral interactions with cholesterol.
Lactosylceramide (LacCer) is a key intermediate in glycosphingolipid metabolism and is highly enriched in detergent-resistant biomembrane fractions associated with microdomains, i.e., rafts and caveolae. Here, the lateral interactions of cholesterol with LacCers containing various homogeneous saturated (8:0, 16:0, 18:0, 24:0) or monounsaturated acyl chains (18:1, 24:1) have been characterized using a Langmuir-type film balance. Cholesterol-induced changes in lateral packing were assessed by measuring changes in average molecular area, i.e., area condensations, and in lateral elasticity, i.e., surface compressional moduli (C S(-1)) with emphasis on high surface pressures (> or = 30 mN/m) that mimic biomembrane conditions. Cholesterol most dramatically affected the lateral packing elasticity of LacCers with long saturated acyl chains at sterol mole fractions > or = 0.3, consistent with liquid-ordered (LO) phase formation. The lateral elasticity within the LacCer-cholesterol LO-phase was much lower than that observed within pure LacCer condensed, i.e., gel, phase. The magnitude of the cholesterol-induced reduction in lateral elasticity was strongly mitigated by cis monounsaturation in the LacCer acyl chain. At identical high sterol mole fractions, higher lateral elasticity was observed within LacCer-cholesterol mixtures compared with galactosylceramide-cholesterol and sphingomyelin-cholesterol mixtures. The results show how changes to sphingolipid headgroup and acyl chain structure contribute to the modulation of lateral packing elasticity in sphingolipid-cholesterol LO-phases.
Antigens, CD↗
The effects of chronic administration of quetiapine on the methamphetamine-induced recognition memory impairment and dopaminergic terminal deficit in rats.
Previous studies have suggested that quetiapine, a new atypical antipsychotic drug, may have beneficial effects on cognitive impairment and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the therapeutic effects of chronic administration of quetiapine on methamphetamine (METH)-induced recognition memory impairment and dopaminergic terminal neurotoxicity in rats. Rats were pretreated with METH (5 mg/kg; s.c.) four times at 2-h intervals while their body temperature was monitored. Fifteen minutes after the last METH injection, rats were administered quetiapine (10 mg/kg/day; i.p.) for 28 days. One day after the last quetiapine injection, rats were trained and tested on an object recognition task on days 29 and 30. Finally, on day 31, rats were sacrificed for immunohistochemistry, 1 day after the object recognition task. METH induced hyperthermia, recognition memory impairment and a decrease of tyrosine hydroxylase immunoreactivity in the caudate putamen (CPu) of striatum. Quetiapine attenuated the METH-induced hyperthermia. Furthermore, chronic post-treatment of quetiapine reversed the METH-induced memory impairment and dopaminergic terminal deficit. These findings suggest that quetiapine may have therapeutic effects in the treatment of cognitive impairment and neurodegeneration induced by METH.
Animals↗
Haloperidol and atypical antipsychotics share a same action of decreasing P75(NTR) mRNA levels in PC12 cells.
P75(NTR) is a common neurotrophin receptor which binds all neurotrophins with similar affinities and has been shown to be capable of mediating programmed cell death. In this study, we investigated effects of the antipsychotic drugs (APDs) haloperidol, clozapine, quetiapine, and risperidone on p75(NTR) mRNA levels in PC12 cells. Haloperidol is a prototype of typical APDs, and the other three drugs are atypical APDs, which are effective in reducing negative symptoms and cognitive deficits of schizophrenia, cause less side effects, and are more tolerable compared to haloperidol. PC12 cells were cultured with various concentrations of haloperidol, clozapine, quetiapine, or risperidone, in their media. After culture for 48h, the cell viabilities and p75(NTR) mRNA levels were measured. It was shown that both haloperidol and the atypical APDs used in this study deceased p75(NTR) mRNA levels in PC12 cells in a dose dependent manner, while not affecting cell viabilities. In further experiments, doses that produced significant/greatest effects were chosen and provided in the culture media for various periods. Decreases in p75(NTR) mRNA levels were observed in cultures treated for 12h with quetiapine, 24h with clozapine or risperidone, or for 48h with haloperidol. These results suggest that both haloperidol and atypical APDs have the same action of decreasing p75(NTR) mRNA levels in PC12 cells. Although the underlying molecular mechanism of this action remains to be elucidated, this finding is particularly relevant given the neurodevelopmental deficits associated with schizophrenia and important roles of p75(NTR) in mediating cell death.
Animals↗
Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus.
Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsychotics and antidepressants, compared to responses to either type of drugs alone. Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14 days); (3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia.
Animals↗
Antipsychotic drugs cause glial cell line-derived neurotrophic factor secretion from C6 glioma cells.
OBJECTIVE: Atypical antipsychotic drugs have been shown to protect PC12 cells from cell death induced by a variety of stimuli in culture. Recently, it has been postulated that trophic factors, such as brain-derived neurotrophic factor (BDNF), play a role in preventing cell death. It has been shown that antipsychotic drugs attenuate the decrease in rat hippocampal BDNF that results from immobilization-induced stress. We aimed to determine whether the neuroprotective effects of antipsychotic drugs could be mediated through glial cell line-derived neurotrophic factor (GDNF). METHODS: We investigated the effects of the atypical antipsychotic drugs quetiapine and clozapine and the typical antipsychotic haloperidol on the secretion of GDNF from rat C6 glioma cells. RESULTS: All 3 drugs increased the amount of GDNF secreted from C6 glioma cells into the medium after 48-hour culture. The intracellular content of GDNF was not altered by treatment with any of the antipsychotic drugs. None of the antipsychotic drugs decreased cell number. CONCLUSION: This study suggests that stimulation of GDNF release from glial cells by antipsychotic drugs might underlie some of their neuroprotective properties in situ.
Animals↗
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.
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.
Analysis of Variance↗
Quetiapine and venlafaxine synergically regulate heme oxygenase-2 protein expression in the hippocampus of stressed rats.
HO-2 is a constitutive isoform of heme oxygenase (HO), a microsomal enzyme that catalyzes the cleavage of the heme ring to form ferrous iron, carbon monoxide, and biliverdin. In contrast to HO-1, which is inducible, HO-2 is not responsive to stimuli tested to date except for prolonged exposure to the adrenal glucocorticoids (GCs). Previous studies have shown that high GC concentrations or stress damage or kill hippocampal neurons. In the present study, it was found that chronic restraint stress decreased HO-2 protein levels in hippocampal neurons, as demonstrated by immunohistochemistry and Western blot analysis. Moreover, our results showed that the combination of 2.5mg/kg of venlafaxine and 5mg/kg of quetiapine effectively prevented the HO-2 protein decrease in hippocampal neurons of stressed rats, whereas either of the drugs alone did not show any effect. At higher dose levels, both quetiapine (10mg/kg) and venlafaxine (5mg/kg) produced significant effects comparable to that of their combination. Quetiapine is an atypical antipsychotic and venlafaxine an antidepressant. In previous studies, these two drugs have been shown to prevent or protect against the stress-induced decrease in hippocampal neurogenesis and BDNF expression. These data suggest that both quetiapine and venlafaxine share the hippocampus as their common target by enhancing hippocampal resilience, which may be impaired in patients with schizophrenia or depression.
Animals↗
Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress.
Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippocampi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippocampal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippocampus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated cAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippocampal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippocampal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippocampus are implicated.
Animals↗
Olanzapine and quetiapine protect PC12 cells from beta-amyloid peptide(25-35)-induced oxidative stress and the ensuing apoptosis.
We previously found that the atypical antipsychotic drugs (APDs) clozapine, olanzapine, quetiapine, and risperidone reduce PC12 cell death induced by hydrogen peroxide, N-methyl-4-phenylpyridinium ion, or beta-amyloid peptide (Abeta(25-35)). Such neurotoxic substances have in common the capability of causing oxidative stress. Atypical APDs have been used in treating schizophrenia and in treating psychotic symptoms of patients with Alzheimer's disease (AD), in which Abeta is involved by causing oxidative stress. Therefore, we hypothesized that atypical APDs might alleviate oxidative stress in PC12 cells, thus protecting them from apoptosis. PC12 cells were seeded in plates or chambers for 24 hr and cultured for another 24 hr with olanzapine or quetiapine in the medium, and then the cells were cultured in the new medium containing Abeta(25-35) and/or olanzapine, quetiapine, but not serum, for various periods. It was shown that cultures treated with olanzapine + Abeta(25-35), or quetiapine + Abeta(25-35), had significantly higher cell viabilities and lower rates of apoptosis compared with the cultures exposed only to Abeta(25-35). In addition, the drugs blocked the activation of caspase-3 caused by Abeta(25-35). Furthermore, olanzapine and quetiapine prevented Abeta(25-35)-induced overproduction of intracellular reactive oxygen species, Abeta(25-35)-induced decrease in mitochondrial membrane potential, and Abeta(25-35)-induced changes in activities of the key antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. In consideration of the wealth of evidence linking oxidative stress to the pathophysiology of schizophrenia and AD, these findings give us a new insight into the therapeutic actions of atypical antipsychotics in patients with the disorders.
Amyloid beta-Peptides↗
Olanzapine attenuates the okadaic acid-induced spatial memory impairment and hippocampal cell death in rats.
It is hypothesized that olanzapine, an atypical antipsychotic drug, has beneficial effects on cognitive impairment and neuropathological changes in treating neurodegenerative diseases. In the present study, we investigated the effects of chronic administration of olanzapine on the spatial memory impairment and hippocampal cell death induced by the direct injection of okadaic acid (OA), a potent neurotoxin, into the rat hippocampus. After being pretreated with olanzapine (0.5 or 2 mg/kg/day, i.p.) for 2 weeks, the rats were unilaterally microinjected with OA (100 ng) into the hippocampus, and then were continuously administrated with olanzapine for an additional week The rats were trained on a spatial memory task in an eight-arm radial maze before OA administration, and tested on the same task 18 h after the last olanzapine injection. After the behavioral test, the rats were killed for Nissl staining and terminal deoxynucleutidyl transferase-mediated biotinylated UTP nick end labeling staining. OA significantly induced spatial memory impairment, and caused pyramidal cell loss in the CAI and apoptotic cell death in the hippocampus. Olanzapine significantly attenuated OA-induced spatial memory impairment and the OA-induced neuropathological changes in the hippocampus. These findings suggest that olanzapine may have therapeutic effects in treatment of cognitive impairment and neuropathological changes of schizophrenia and other neurodegenerative diseases.
Analysis of Variance↗
Amitriptyline and fluoxetine protect PC12 cells from cell death induced by hydrogen peroxide.
OBJECTIVE: To investigate the potential protective effects of amitriptyline and fluoxetine in a catecholamine cell model. METHODS: Cultured rat pheochromocytoma (PC12) cells were pretreated with amitriptyline or fluoxetine for 24 or 48 hours and were then subjected to neurotoxic insult (200 micromol/L hydrogen peroxide). Cell viability was determined by measurement of the reduction product of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). The enzyme activity of superoxide dismutase (SOD) was determined by a commercial SOD assay kit. RESULTS: The decrease in cell viability induced by hydrogen peroxide was attenuated in PC12 cells pretreated with 100 micromol/L amitriptyline for 24 hours or with 50 micromol/L amitriptyline or 50 micromol/L fluoxetine for 48 hours. Pretreatment with either amitriptyline or fluoxetine was associated with increased SOD activity in PC12 cells. Inhibition of SOD activity with diethyldithiocarbamic acid reduced the cytoprotective action of fluoxetine. CONCLUSIONS: These data suggest that the neuroprotective actions of some antidepressants include the upregulation of SOD activity.
Amitriptyline↗
Foreign body in the heart.
As an emergency, a foreign body in the heart should generally be removed as early as possible by surgical or non-surgical procedures in order to avoid any complications. Early treatment typically results in a better prognosis.
Journal Article↗
Chronic administration of quetiapine alleviates the anxiety-like behavioural changes induced by a neurotoxic regimen of dl-amphetamine in rats.
We have demonstrated that the atypical antipsychotic drugs prevent cell death in PC12 cells induced by various cytotoxins and have protective effects on methamphetamine-induced neurotoxcity in rats. The present study was designed to examine the possible effects of chronic administration of quetiapine, an atypical antipsychotic drug, on the anxiety-like behavioural consequences of a neurotoxic regimen of dl-amphetamine. Rats were treated with quetiapine (10 mg/kg/day; i.p.) for 33 days. During days 15-19 of this period, the animals were given dl-amphetamine (20 mg/kg/day; s.c.) 1 h after the administration of quetiapine. The repeated administration of dl-amphetamine resulted in a decrease of tyrosine hydroxylase (TH) immunostaining in the caudate putamen, hyperthermia, and anxiety-like behavioural changes. The behavioural changes were indicated by a significant increase in the time spent in the light box in the light/dark box test, an increase in the ratios of ambulation distance inside the inner circle over the total ambulation distance and rearings inside the inner circle over the total rearings in the open field test, and an increase in the time spent in open arms in the elevated plus-maze test. Chronic administration of quetiapine significantly attenuated the dl-amphetamine-induced hyperthermia, and the anxiety-like behavioural changes in the light/dark box and in the open field tests. These results suggest that quetiapine can normalize the dl-amphetamine-induced anxiety-like behavioural changes, and might be helpful in the treatment for amphetamine-induced emotional changes.
Amphetamine↗
Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine.
In the present study, we used a repeated restraint stress animal model to observe the changes in the expression of brain-derived neurotrophic factor (BDNF) and B cell lymphoma protein-2 (Bcl-2) in hippocampal neurons of rats, monitored the time course of the expression over 3 weeks post-stress period, and examined the effects of the chronic administration of olanzapine on the time course. Olanzapine is an atypical antipsychotic drug that has been shown to be neuroprotective in previous in vitro studies. We found: (1) the repeated restraint stress decreases the levels of expression of BDNF and Bcl-2 in hippocampal neurons; (2) the stress-induced decreases spontaneously recover to their pre-stress levels in 3 weeks after the last stress exposure; (3) administration of olanzapine for 1 week returns the expression of Bcl-2 to its pre-stress level, and the administration for 3 weeks causes an excessive expression of BDNF in hippocampal neurons. In the context of the lower levels of BDNF and Bcl-2, and structural brain abnormalities observed in patients with schizophrenia, our findings suggest that BDNF and Bcl-2 may be involved in the pathophysiology of schizophrenia and in the therapeutic action of atypical antipsychotic drugs.
Animals↗
Neuroprotective effects of olanzapine on methamphetamine-induced neurotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl-2 decrease in rats.
It is hypothesized that atypical antipsychotic drugs have neuroprotective effects which may be one of the mechanisms in treatment of schizophrenia. We investigated the neuroprotective effects of olanzapine (OLA), an atypical antipsychotic drug, on methamphetamine (METH)-induced neurotoxicity in rats. After pretreatment with OLA (2 mg/kg/day) by intraperitoneal injection for 2 weeks, rats were administered METH (7.5 mg/kg, four times at 2-h intervals) by subcutaneous injection while their body temperature was monitored. The rats were sacrificed 24 h after the last injection of METH for immunohistochemistry. METH-induced 24 h mortality was effectively reduced and METH-induced decrease of tyrosine hydroxylase immunoreactivity in caudate putamen (CPu) was significantly attenuated by OLA chronic pretreatment. Furthermore, we showed that the above neuroprotective potential of OLA might be associated with its attenuating effects on METH-induced hyperthermia and with its preventative actions on METH-induced decrease of Bcl-2, an anti-apoptotic gene product, in the CPu. Our results suggest that OLA may be a neuroprotective agent and that its neuroprotective potential may contribute to its therapeutic effects in treatment of schizophrenia.
Analysis of Variance↗
Human glycolipid transfer protein: probing conformation using fluorescence spectroscopy.
Glycolipid transfer protein (GLTP) is a soluble 24 kDa protein that selectively accelerates the intermembrane transfer of glycolipids in vitro. Little is known about the GLTP structure and dynamics. Here, we report the cloning of human GLTP and characterize the environment of the three tryptophans (Trps) of the protein using fluorescence spectroscopy. Excitation at 295 nm yielded an emission maximum (lambda(max)) near 347 nm, indicating a relatively polar average environment for emitting Trps. Quenching with acrylamide at physiological ionic strength or with potassium iodide resulted in linear Stern-Volmer plots, suggesting accessibility of emitting Trps to soluble quenchers. Insights into reversible conformational changes accompanying changes in GLTP activity were provided by addition and rapid dilution of urea while monitoring changes in Trp or 1-anilinonaphthalene-8-sulfonic acid fluorescence. Incubation of GLTP with glycolipid liposomes caused a blue shift in the Trp emission maximum but diminished the fluorescence intensity. The blue-shifted emission maximum, centered near 335 nm, persisted after separation of glycolipid liposomes from GLTP, consistent with formation of a GLTP-glycolipid complex at a glycolipid-liganding site containing Trp. The results provide the first insights into human GLTP structural dynamics by fluorescence spectroscopy, including global conformational changes that accompany GLTP folding into an active conformational state as well as more subtle conformational changes that play a role in GLTP-mediated transfer of glycolipids between membranes, and establish a foundation for future studies of membrane rafts using GLTP.
Amino Acid Sequence↗
Antipsychotic drugs clozapine and olanzapine upregulate bcl-2 mRNA and protein in rat frontal cortex and hippocampus.
To investigate whether atypical antipsychotic drugs exert an effect on the neuroprotective protein Bcl-2, rats were chronically treated with clozapine or olanzapine for 28 days. The expression of bcl-2 mRNA and Bcl-2 protein was determined, respectively, by in situ hybridization in tissue sections and Western blot on tissue samples from rat frontal cortex and hippocampus. The bcl-2 mRNA positive cells were increased in these regions after drug treatments, and quantitative analysis revealed that the upregulation of bcl-2 mRNA and Bcl-2 protein is significantly greater than in vehicle control (p<0.05 or p<0.01). It is demonstrated that neuroprotective protein Bcl-2 is involved in the action of atypical antipsychotic drugs, and might represent a neuroprotective mechanism of these drugs.
Animals↗