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1.
Neuroscience ; 156(4): 1005-16, 2008 Oct 28.
Article in English | MEDLINE | ID: mdl-18801413

ABSTRACT

Learning potential and memory capacity are factors that strongly predict the level of rehabilitation and the long-term functional outcome in patients with schizophrenia. Unfortunately, however, the effects of antipsychotic drugs (i.e. the primary treatments for schizophrenia) on these components of cognition are unclear, particularly when they are administered chronically (i.e. a standard clinical practice). In this rodent study we evaluated the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the first generation antipsychotic chlorpromazine (10.0 mg/kg/day), or the second generation antipsychotic olanzapine (10.0 mg/kg/day) on the repeated acquisition of a water maze task (i.e. a method of assessing spatial learning potential in a repeated testing format). We assessed locomotor function (in an open field) and employed a radial arm maze (RAM) task to assess antipsychotic effects (5.0 and 10.0 mg/kg/day doses) on spatial working memory during the treatment period between 15 days and 2 months. Finally, we conducted experiments using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to evaluate the therapeutic relevance of our method of drug delivery (oral administration in drinking water). In the water maze experiments, both antipsychotics were associated with impairments in acquisition in the earlier test sessions that could eventually be overcome with repeated testing while olanzapine also impaired retention in probe trials. Both antipsychotics were also associated with impairments in delayed non-match-to-position trials in the RAM and some impairments of motor function (especially in the case of olanzapine) as indicated by slightly reduced swim speeds in the water maze and decreased activity in some components of the open field assessment. Finally, LC-MS/MS studies indicated that the method of antipsychotic administration generated clinically relevant plasma levels in the rat. These animal data indicate that chronic oral treatment with chlorpromazine or olanzapine can impair the performance of tasks designed to assess specific components of cognition that are affected in schizophrenia.


Subject(s)
Antipsychotic Agents/administration & dosage , Benzodiazepines/administration & dosage , Chlorpromazine/administration & dosage , Maze Learning/drug effects , Memory, Short-Term/drug effects , Space Perception/drug effects , Administration, Oral , Analysis of Variance , Animals , Antipsychotic Agents/blood , Area Under Curve , Behavior, Animal/drug effects , Benzodiazepines/blood , Chlorpromazine/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Exploratory Behavior/drug effects , Hand Strength/physiology , Male , Maze Learning/physiology , Motor Activity/drug effects , Olanzapine , Rats , Rats, Wistar , Reaction Time/drug effects
2.
Neuroscience ; 150(2): 413-24, 2007 Dec 05.
Article in English | MEDLINE | ID: mdl-17942237

ABSTRACT

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition.


Subject(s)
Antipsychotic Agents/adverse effects , Brain/drug effects , Cognition Disorders/chemically induced , Memory Disorders/chemically induced , Nerve Growth Factor/antagonists & inhibitors , Neurons/drug effects , Acetylcholine/metabolism , Administration, Oral , Animals , Basal Nucleus of Meynert/drug effects , Basal Nucleus of Meynert/metabolism , Basal Nucleus of Meynert/physiopathology , Brain/metabolism , Brain/physiopathology , Cholinergic Fibers/drug effects , Cholinergic Fibers/metabolism , Cognition Disorders/metabolism , Cognition Disorders/physiopathology , Down-Regulation/drug effects , Down-Regulation/physiology , Drug Administration Schedule , Haloperidol/pharmacology , Learning Disabilities/chemically induced , Learning Disabilities/metabolism , Learning Disabilities/physiopathology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Nerve Growth Factor/metabolism , Neurons/metabolism , Rats , Rats, Wistar , Receptor, trkA/drug effects , Receptor, trkA/metabolism , Risperidone/pharmacology , Space Perception/drug effects , Space Perception/physiology , Time
3.
Neuroscience ; 146(3): 1316-32, 2007 May 25.
Article in English | MEDLINE | ID: mdl-17434684

ABSTRACT

First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.


Subject(s)
Antipsychotic Agents/pharmacology , Haloperidol/pharmacology , Memory/drug effects , Neurons/drug effects , Parasympathetic Nervous System/drug effects , Psychomotor Performance/drug effects , Receptors, Nerve Growth Factor/biosynthesis , Risperidone/pharmacology , Animals , Enzyme-Linked Immunosorbent Assay , Hand Strength/physiology , Hippocampus/drug effects , Male , Maze Learning/drug effects , Membrane Transport Proteins/metabolism , Motor Activity/drug effects , Parasympathetic Nervous System/cytology , Postural Balance/drug effects , Rats , Rats, Wistar , Receptor, Nerve Growth Factor/biosynthesis , Receptor, trkA/metabolism , Recognition, Psychology/drug effects , Vesicular Acetylcholine Transport Proteins/metabolism
4.
Neuroscience ; 140(4): 1277-87, 2006 Jul 21.
Article in English | MEDLINE | ID: mdl-16626873

ABSTRACT

Several postmortem and neuroimaging studies suggest that central nicotinic and muscarinic acetylcholine receptors are important in both the pathophysiology and pharmacotherapy of schizophrenia. However, while antipsychotic drugs are routinely used in the therapeutics of schizophrenia, little is known about their effects on the densities of these receptors when they are administered for extended periods of time (a common practice in the clinical setting). In the present study in rats, the residual effects of prior chronic exposure to representative first generation antipsychotics and second generation antipsychotics on the densities of high affinity nicotinic acetylcholine receptors and muscarinic acetylcholine receptor in the brain were investigated. Test subjects were treated with the first generation antipsychotics, haloperidol (2.0 mg/kg/day) or chlorpromazine (10.0 mg/kg/day) or the second generation antipsychotics, risperidone (2.5 mg/kg/day) or olanzapine (10.0 mg/kg/day) in drinking water for periods of 90 or 180 days, given a drug-free washout period (i.e. returned to normal drinking water) for two weeks and then killed. Quantitative receptor autoradiography was subsequently performed using 16 mum sagittal slices of whole brain incubated with [3H]-epibatidine, [3H]-pirenzepine or [3H]-AFDX-384 to measure high affinity nicotinic acetylcholine receptors, M1 and M2 muscarinic acetylcholine receptors, respectively. The most notable experimental result was a moderate, but significant (P<0.01) increase in [3H]-AFDX-384 binding sites in a number of brain regions (including cortex, hippocampus, subiculum, substantia innominata, and thalamus) associated with prior exposure to olanzapine for 90, but not 180 days. Olanzapine was also associated with a significantly higher density of [3H]-pirenzepine binding sites in cortex lamina I after 90 days of prior drug exposure. These data indicate that chronic treatment with a commonly used second generation antipsychotic, olanzapine is associated with modest increases in M2 muscarinic acetylcholine receptors in memory-related brain regions that may eventually abate with longer periods of chronic drug exposure.


Subject(s)
Antipsychotic Agents/administration & dosage , Brain/drug effects , Brain/metabolism , Receptors, Muscarinic/metabolism , Receptors, Nicotinic/metabolism , Animals , Male , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Wistar
5.
Neuroscience ; 136(2): 519-29, 2005.
Article in English | MEDLINE | ID: mdl-16216423

ABSTRACT

A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.


Subject(s)
Antipsychotic Agents/pharmacology , Brain Chemistry/drug effects , Receptors, Nicotinic/drug effects , Acoustic Stimulation , Animals , Antipsychotic Agents/blood , Autoradiography , Bungarotoxins/pharmacokinetics , Densitometry , Male , Rats , Rats, Wistar , Reflex, Startle/drug effects , Time Factors , alpha7 Nicotinic Acetylcholine Receptor
6.
Article in English | MEDLINE | ID: mdl-14623492

ABSTRACT

A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of patients with or without medication. The current study investigated the relationship between these biochemical measures in first-episode psychotic patients (N=16) at baseline and after 6 months of antipsychotic treatment (N=5 each with risperidone and olanzapine) and compared them to matched normal subjects. The indices of oxidative stress included: antioxidant enzymes; superoxide dismutase, glutathione peroxidase and catalase; and the oxidative injury as the levels of plasma lipid peroxides. The key membrane EPUFA's been; linolenic acid, arachidonic acid, nervonic acid, docosapentaenoic acid and docosahexaenoic acid. Furthermore, the changes in these biochemical measures were correlated with clinical symptomatology. Data indicated that, at baseline, reduced levels of antioxidant enzymes were associated with increased plasma lipid peroxides and reduced membrane EPUFAs, particularly omega-3 fatty acids. Furthermore, these biochemical measures normalized after 6 months of antipsychotic treatment. Parallel-improved psychopathology indicated that membrane EPUFA status might be partly affected by oxidative damage, which together may contribute to the pathophysiology and thereby, psychopathology of schizophrenia. These data also support the augmentation of antipsychotic treatment by supplementation with a combination of antioxidants and omega-3 fatty acids.


Subject(s)
Antipsychotic Agents/therapeutic use , Erythrocyte Membrane/metabolism , Fatty Acids, Essential/blood , Psychotic Disorders/blood , Adult , Alkanes/blood , Antioxidants/therapeutic use , Drug Therapy, Combination , Erythrocyte Membrane/drug effects , Erythrocytes/enzymology , Fatty Acids, Omega-3/therapeutic use , Fatty Acids, Unsaturated/blood , Humans , Lipid Peroxides/blood , Oxidative Stress
7.
J Neurochem ; 86(5): 1089-100, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12911617

ABSTRACT

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.


Subject(s)
Antipsychotic Agents/pharmacology , Apolipoproteins/metabolism , Brain/drug effects , Brain/metabolism , Pirenzepine/analogs & derivatives , Animals , Apolipoproteins/drug effects , Apolipoproteins D , Benzodiazepines , Brain/cytology , Haloperidol/antagonists & inhibitors , Haloperidol/pharmacology , Male , Neuronal Plasticity/drug effects , Neurons/cytology , Neurons/drug effects , Olanzapine , Pirenzepine/pharmacology , Rats , Rats, Wistar , Risperidone/pharmacology
8.
Psychopharmacology (Berl) ; 164(4): 360-8, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12457265

ABSTRACT

RATIONALE: In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways - an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use. OBJECTIVES: The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats. METHODS: After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining. RESULTS: In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle. CONCLUSIONS: The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present.


Subject(s)
Brain/drug effects , Haloperidol/pharmacology , Maze Learning/drug effects , Mental Recall/drug effects , Orientation/drug effects , Pirenzepine/analogs & derivatives , Pirenzepine/pharmacology , Receptors, Cholinergic/drug effects , Animals , Benzodiazepines , Brain/pathology , Choline O-Acetyltransferase/metabolism , Cholinergic Fibers/drug effects , Drug Administration Schedule , Escape Reaction/drug effects , Male , Microscopy, Fluorescence , Olanzapine , Rats , Rats, Wistar , Reaction Time/drug effects
9.
Article in English | MEDLINE | ID: mdl-11370992

ABSTRACT

1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.


Subject(s)
Antioxidants/therapeutic use , Fatty Acids, Omega-3/therapeutic use , Oxidative Stress/physiology , Schizophrenia/diet therapy , Animals , Dietary Supplements , Fatty Acids, Omega-3/metabolism , Humans , Schizophrenia/metabolism
10.
J Assoc Physicians India ; 48(9): 871-6, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11198784

ABSTRACT

OBJECTIVES: To evaluate the benefit of a dietary fiber preparation (Fibernat) in patients with chronic ischemic heart disease (IHD). METHODS: From January 1997 to March 1998, 114 consecutive patients with chronic IHD were enrolled in this prospective double blind randomized placebo controlled trial. The fiber (F) and placebo (P) groups were comparable at baseline. All patients were given advice regarding dietary and lifestyle modifications. Concomitant drug therapy was not altered. The drug (consisting of soluble and insoluble fibers obtained from fenugreek, guar gum and wheat bran) and placebo were administered for six months (10 grams twice daily). RESULTS: The following parameters improved in both groups: HDL cholesterol (32 to 39 mg/dl, p < 0.0009 in F and 33 to 38, p < 0.007 in P), total: HDL cholesterol ratio (6.7 to 5.6, p < 0.0007 in F and from 7.0 to 6.0, p < 0.01 in P) and weight (64.0 to 63.0 kg, p < 0.002 in F and 60.3 to 59.5, p < 0.002 in P). The Apolipoprotein B increased (101 to 129 mg/dl, p < 0.00001 in F and 98 to 127, p < 0.0008 in P). The following parameters improved only in group F: LDL cholesterol (146 to 134, p < 0.027), Apolipoprotein A-1 (105 to 139, p < 0.001), body mass index (24.9 to 24.5, p < 0.03) and waist circumference (37.2 to 36.7, p < 0.03). Total cholesterol, VLDL cholesterol, triglycerides, hip circumference, W:H ratio, exercise time and blood sugar were unchanged in both groups. CONCLUSIONS: Fibernat is well tolerated, safe and had favorable effects on LDL cholesterol, Apolipoprotein A-1, body mass index and waist circumference.


Subject(s)
Dietary Fiber/therapeutic use , Myocardial Ischemia/diet therapy , Adult , Aged , Aged, 80 and over , Apolipoprotein A-I/blood , Apolipoproteins B/blood , Body Constitution , Body Mass Index , Cation Exchange Resins , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Chronic Disease , Dietary Fiber/adverse effects , Double-Blind Method , Female , Humans , India , Male , Middle Aged , Myocardial Ischemia/blood , Prospective Studies
11.
J Postgrad Med ; 45(4): 110-3, 1999.
Article in English | MEDLINE | ID: mdl-10734348

ABSTRACT

The anthropometry, lipid profile and dietary characteristics of 114 patients with chronic ischaemic heart disease (IHD) were evaluated. There were 91 (80%) men and the mean age was 56 +/- 9 years. The body mass index was near normal (24.4 +/- 3.4), but the waist: hip ratio was high (0.94 +/- 0.06) suggesting central obesity. This was well in accordance of the step II recommendations of the NCEP guidelines as regards their caloric intake and its break-up in terms of carbohydrate, protein and fat (including saturated, mono-unsaturated and poly-unsaturated fatty acids) content. Their daily cholesterol intake (31 +/- 32 mg/day, range 4-180) was very low. The total cholesterol (212 +/- 37 mg%) was marginally elevated, HDL cholesterol (33 +/- 7.5 mg%) was low, LDL cholesterol (148 +/- 39 mg%) was high and the total: HDL ratio (6.8 +/- 2.0) was significantly abnormal. The serum triglyceride level (154 +/- 68 mg%) was on the higher side of normal. These observations give further credence to the recently evolving view that there are different and hitherto unrecognised risk factors of IHD in Indians, who seem to have the highest incidence of IHD amongst all ethnic groups of the world despite consuming a diet low in fat and cholesterol content.


Subject(s)
Myocardial Ischemia , Adult , Aged , Aged, 80 and over , Anthropometry , Female , Humans , Lipoproteins/blood , Male , Middle Aged , Myocardial Ischemia/blood
12.
Biol Psychiatry ; 43(9): 674-9, 1998 May 01.
Article in English | MEDLINE | ID: mdl-9583001

ABSTRACT

BACKGROUND: Impaired antioxidant defense and increased lipid peroxidation has been reported in chronic schizophrenic patients. Recently, we have reported an impaired antioxidant defense in never medicated first-episode schizophrenic and schizophreniform patients. We report now a concomitant increase in plasma lipid peroxides. METHODS: The plasma lipid peroxides [thiobarbituric acid reactive substances (TBARS)] were analyzed by chemical and high performance liquid chromatography procedures in 26 patients admitted for a first episode of schizophrenic (N = 17) or schizophreniform psychosis (N = 9) and 16 normal control subjects. The patients had a duration of 4.5 days (SD 2.8) of psychosis at the time of the study. RESULTS: Plasma TBARS levels were significantly higher in the patients than in normal controls (P < .002). TBARS levels were above the normal range in 16 of the 26 patients. Higher TBARS levels were associated with a greater severity of negative symptoms and lower red blood cell activity of the glutathione peroxidase. CONCLUSIONS: The findings indicate ongoing oxidative injury at the very onset of psychosis. If valid, this would indicate the need for adjunctive antioxidant treatment from the beginning of the course of nonaffective psychoses. This might prevent a deteriorating course and development of the deficit syndrome.


Subject(s)
Lipid Peroxides/blood , Psychotic Disorders/blood , Adult , Female , Glutathione Peroxidase/blood , Humans , Lipid Peroxidation , Male , Malondialdehyde/blood , Psychiatric Status Rating Scales , Schizoid Personality Disorder/blood , Schizophrenia/blood , Thiobarbituric Acid Reactive Substances/analysis
13.
J Psychiatr Res ; 30(6): 421-39, 1996.
Article in English | MEDLINE | ID: mdl-9023786

ABSTRACT

Cultured skin fibroblasts, among other non-neuronal cells (e.g. platelets, lymphocytes, red blood cells), provide an advantageous system for investigating dynamic molecular regulatory processes underlying abnormal cell growth, metabolism, and receptor-mediated signal transduction, without the confounding effects of disease state and its treatment in a variety of brain disorders, including schizophrenia, and are useful for studies of systemic biochemical defects with predominant consequences for brain function. These cells are also useful for studying aspects of neurotransmitter functions because the cells express enzymes involved in their metabolism, as well as their receptors with complete machinery for signal transduction. These processes also function predictably with receptors that are transfected in fibroblasts. This review will focus on the use of cultured skin of which have also been studied in post-mortem brains. These mechanisms might involve DNA processing and mitogenesis, cell-cell adhesion molecules, actions of growth factors, oxidative damage, and membrane phospholipid derived second messengers. This review will further discuss the implications of these processes to clinical and structural brain abnormalities. An understanding of these biochemical processes might help establish therapeutic implications and identify the risk for illness through experimental strategies such as epidemiology, family pedigree and high risk populations. Finally, despite some methodological limitations, skin fibroblasts are relatively easy to grow and maintain as primary cultures or as immortalized cell lines for long periods of time for use in investigating newly identified biochemical abnormalities.


Subject(s)
Cell Division/genetics , Energy Metabolism/genetics , Schizophrenia/genetics , Signal Transduction/genetics , Cell Division/physiology , Cell Line, Transformed , Cells, Cultured , Energy Metabolism/physiology , Fibroblasts , Humans , Neurotransmitter Agents/physiology , Schizophrenia/physiopathology , Signal Transduction/physiology , Transfection/genetics
14.
Prostaglandins Leukot Essent Fatty Acids ; 55(1-2): 45-54, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8888122

ABSTRACT

There is increasing evidence that oxidative injury contributes to pathophysiology of schizophrenia, indicated by the increased lipid peroxidation products in plasma and CSF, and altered levels of both enzymatic and non-enzymatic antioxidants in chronic and drug-naive first-episode schizophrenic patients. The increased plasma lipid peroxidation is also supported by concomitant lower levels of esterified polyunsaturated essential fatty acids of red blood cell plasma membrane phospholipids. Because membrane phospholipids play a critical role in neuronal signal transduction, oxidative damage of these lipids may contribute to the proposed altered neurotransmitter receptor-mediated signal transduction and thereby alter information processing in schizophrenia. Adjunctive treatment with antioxidants (e.g. vitamins E and C, beta-carotene and quinones) at the initial stages of illness may prevent further oxidative injury and thereby ameliorate and prevent further possible deterioration of associated neurological and behavioral deficits in schizophrenia.


Subject(s)
Antioxidants/therapeutic use , Membrane Lipids/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Schizophrenia/drug therapy , Cell Membrane/metabolism , Schizophrenia/metabolism
15.
Prostaglandins Leukot Essent Fatty Acids ; 55(1-2): 65-70, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8888125

ABSTRACT

Based on the lower levels of long-chain polyunsaturated analogs of essential fatty acids (EPUFAs) in plasma membrane phospholipids of red blood cells, brain and cultured skin fibroblasts from schizophrenic patients, a defective utilization (uptake, conversion to EPUFAs and incorporation into membrane phospholipids) of precursor EFAs has been suggested. Utilization of radiolabeled linoleic (LA, 18:2(n-6)) and alpha-linolenic (ALA, 18:3(n-3)) acids was studied in cultured skin fibroblasts from patients with established schizophrenia and at the first episode of psychosis, and normal controls. Uptake and incorporation of both the EFAs were similar in fibroblasts from both groups of patients studied compared with normal controls. However, although the utilization of LA into arachidonic acid (AA, 20:4n-6) was similar in patients and controls, the utilization of eicosapentaenoic acid (EPA, 20:5(n-3)) into docosahexaenoic acid (DHA, 22:6(n-3)) was significantly lower in first-episode psychotic patients (patients, 96.33 +/- 27.16 versus normals, 161.66 +/- 26.33 nmoles per mg total protein; P = < 0.001). This data indicates that the level of delta 6- as well as delta 5-desaturase may be normal. However, the levels of delta 4-desaturase may be lower in fibroblasts from schizophrenic patients even at the first episode of psychosis.


Subject(s)
Fatty Acids, Essential/metabolism , Fibroblasts/metabolism , Schizophrenia/metabolism , Adult , Arachidonic Acid/metabolism , Carbon Radioisotopes , Case-Control Studies , Cells, Cultured , Eicosapentaenoic Acid/analysis , Eicosapentaenoic Acid/metabolism , Fatty Acids, Essential/analysis , Humans , Linoleic Acids/analysis , Linoleic Acids/metabolism , Linolenic Acids/analysis , Linolenic Acids/metabolism , Membrane Lipids/metabolism , Middle Aged , Schizophrenia/pathology
16.
Prostaglandins Leukot Essent Fatty Acids ; 55(1-2): 101-7, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8888131

ABSTRACT

The neurodevelopmental hypothesis of schizophrenia implicates abnormal or disrupted neural growth during embryogenesis. It is postulated here that stress-inducing agents acting upon a compromised cellular system resulting from abnormal plasma membrane lipids could effect the neuronal abnormalities observed in schizophrenia. The heat stress response is induced by exposure to hyperthermia as well as a variety of other agents. The response to these agents includes the cessation of most transcriptional and translational activities, accompanied by the induction of a highly specific set of proteins. A concomitant reduction in metabolic activity including cell cycle delays is also observed. Much of the enormous literature on the heat stress response concentrates on protein and DNA interactions, especially with regard to transcriptional control. However, a variety of lipids are intrinsically involved in the heat stress response. This paper will provide a brief introduction to the heat shock proteins and will explore the roles that lipids play in the heat shock response.


Subject(s)
Heat-Shock Response/physiology , Lipid Metabolism , Schizophrenia/metabolism , Heat-Shock Proteins/metabolism , Humans , Nervous System/embryology , Nervous System Malformations , Temperature , Time Factors
17.
Psychiatry Res ; 63(2-3): 133-42, 1996 Jul 31.
Article in English | MEDLINE | ID: mdl-8878309

ABSTRACT

Recent studies have found lower red cell plasma membrane contents and composition of the long chain polyunsaturated essential fatty acid derivatives, particularly arachidonic acid and docosahexaenoic acid, in a subgroup of chronic schizophrenic patients. These fatty acids are particularly enriched in the brain. Red blood cell levels of fatty acids are influenced by diet, medications, and other factors. Cell plasma membrane compositions of arachidonic and docosahexaenoic acids were therefore examined in cultured skin fibroblasts from 12 schizophrenic patients, 8 of whom were drug-naive and in a first episode of psychosis, 6 bipolar patients, and 8 normal control subjects. Docosahexaenoic acid as well as total n-3 essential fatty acid contents were significantly lower in cell lines from schizophrenic patients than in cell lines from bipolar patients and normal subjects, with no difference between the latter two groups. Arachidonic acid levels did not differ across the groups. The essential fatty acid profile observed is consistent with deficient delta-4 desaturase activity in schizophrenic patients.


Subject(s)
Arachidonic Acid/blood , Bipolar Disorder/blood , Cell Membrane/physiology , Docosahexaenoic Acids/blood , Fatty Acids, Essential/blood , Fibroblasts/physiology , Phospholipids/blood , Schizophrenia/blood , Adult , Cells, Cultured , Fatty Acid Desaturases/blood , Fatty Acids, Unsaturated/blood , Female , Humans , Male
18.
Schizophr Res ; 19(1): 1-17, 1996 Mar.
Article in English | MEDLINE | ID: mdl-9147491

ABSTRACT

There is increasing evidence that free radical-mediated CNS neuronal dysfunction is involved in the pathophysiology of schizophrenia. Free radicals (oxyradicals, such as superoxide, hydroxyl ions, and nitric oxide) cause cell injury when they are generated in excess or the antioxidant defense is impaired. Both of these processes seem to be affected in schizophrenia. Evidence of excessive oxyradical generation is premised on the assumption that there is increased catecholamine turnover, though there is little direct evidence to support such a view, which is further accentuated by neuroleptic treatment. However, antioxidant enzymes (superoxide dismutase, SOD; glutathione peroxidase, GSHPx; and catalase, CAT) which are constitutively expressed in all tissues, are found to be altered in erythrocytes of schizophrenic patients. Also, possible oxyradical-mediated injury to CNS is suggested by increased lipid peroxidation products in cerebrospinal fluid and plasma, and reduced membrane polyunsaturated fatty acids (PUFAs) in the brain and RBC plasma membranes. The brain is more vulnerable to oxyradical-mediated injury,because its membranes are preferentially enriched in oxyradical sensitive PUFAs, and damaged adult neurons cannot be replaced. In addition to their pathological role, oxyradicals have critical physiological functions in neuronal development, differentiation, and signal transduction, all of which may be altered in some cases of schizophrenia. It may be possible to define cellular injury processes, investigate underlying dynamic regulatory molecular processes, and find ways to prevent these injury processes using peripheral cell models, e.g., red blood cells, lymphocytes and cultured skin fibroblasts. Information on the clinical implications of these processes are valuable for developing new and innovative therapeutic strategies for schizophrenia.


Subject(s)
Antioxidants/metabolism , Brain/metabolism , Schizophrenia/metabolism , Cell Membrane/metabolism , Free Radicals/metabolism , Humans , Lipid Peroxidation
19.
Schizophr Res ; 19(1): 19-26, 1996 Mar.
Article in English | MEDLINE | ID: mdl-9147492

ABSTRACT

Previous studies found peripheral activities of antioxidant enzymes to be abnormal in schizophrenic patients. It is not understood whether this is integral to the disease process or a result of long-term treatment with neuroleptics. Red blood cell activities of three antioxidant enzymes--superoxide dismutase, glutathione peroxidase, and catalase--were therefore examined in 14 drug-naive, first episode patients with a diagnosis of schizophrenia or schizophreniform disorder and 10 normal subjects. The patients had an average duration of psychosis of 4.46 days (SD 2.5). Superoxide dismutase activity was significantly lower in patients than in normal controls, with no difference between the groups in activities of the other two enzymes. Lower superoxide dismutase activity was associated with deterioration of school functioning from childhood to early adolescence and a history of poorer school functioning during early adolescence. These findings indicate a compromised antioxidant defense at the onset of psychosis, and suggest that oxidative injury might contribute to adverse developmental events in the pathogenic cascade of schizophrenia.


Subject(s)
Antioxidants/metabolism , Brain/metabolism , Catalase/metabolism , Glutathione Peroxidase/metabolism , Psychotic Disorders/metabolism , Schizophrenia/metabolism , Superoxide Dismutase/metabolism , Adult , Female , Free Radicals/metabolism , Humans , Male , Schizophrenic Psychology
20.
Biol Psychiatry ; 38(4): 246-54, 1995 Aug 15.
Article in English | MEDLINE | ID: mdl-8547447

ABSTRACT

Effects of monosialoganglioside (GM1 ganglioside) cotreatment with haloperidol (HAL) were studied in rat on the haloperidol treatment-associated changes in cholinergic enzymes, choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) in three brain regions of interest: striatum, hippocampus, and cerebral cortex. Short-term (8 days) haloperidol treatment significantly increased the levels of both ChAT and AChE in all the three regions of brain, as compared with controls (for ChAT: p < .0001 for all comparisons, and for AChE: striatum: p < .0001; hippocampus: p < .0003; cortex: p < .05). Cotreatment with GM1 ganglioside further increased the ChAT activity relative to haloperidol treatment alone in all three regions (p < .05). The AChE activity was also significantly higher than controls in all three regions (p < .05 for all comparisons) and higher than haloperidol treatment only in hippocampus (p < .02). After chronic haloperidol treatment (45 days), ChAT activity in cortex had returned to control values in both HAL and HAL + GM1 groups, with no significant group differences remaining (p = .10). By contrast, relative to control values, HAL and HAL + GM1 groups both showed lower ChAT activity in the striatum, as well as in the hippocampus (p < .0001 for both), with significantly lower ChAT activity in the HAL than in the HAL + GM1 group for both areas (p = < .0001 for both). AChE activity showed a significant difference only between the HAL and HAL + GM1 groups in the cortex (p = .003), but no significant effects of group were seen on AChE activity in either striatum or hippocampus. These data suggest that the protective effects of GM1 ganglioside cotreatment on haloperidol-induced alterations in cholinergic systems can be relevant for protecting against the complications of neuroleptic-induced parkinsonism.


Subject(s)
Antipsychotic Agents/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Choline O-Acetyltransferase/metabolism , Corpus Striatum/enzymology , G(M1) Ganglioside/pharmacology , Haloperidol/pharmacology , Hippocampus/drug effects , Hippocampus/enzymology , Rats, Sprague-Dawley , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/analysis , Cerebral Cortex/chemistry , Corpus Striatum/chemistry , Corpus Striatum/drug effects , G(M1) Ganglioside/administration & dosage , G(M1) Ganglioside/analysis , Haloperidol/administration & dosage , Haloperidol/analysis , Hippocampus/chemistry , Male , Rats
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