ubiquinone and Schizophrenia

Topics: Humans; Mental Disorders; Mitochondria; Nervous System Diseases; Oxidative Stress; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Ubiquinone; Vitamins

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology with studying E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (chi-square (2, N = 10) = 20, p = 4.5400e-05), and spectral exponent between 30-50 Hz (chi-square (2, N = 16) = 13.88, p = 0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity (chi-square (3, N = 10) = 25.44, p = 1.2492e-05), spectral exponent between 1 and 20 Hz (chi-square (3, N = 16) = 43.5, p = 1.9273e-09) and 30-50 Hz (chi-square (3, N = 16) = 23.47, p = 3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis-NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses.

Topics: Acetylcarnitine; Brain; Case-Control Studies; Cell Line; Choline; Electron Transport Complex IV; Electrophysiology; Female; Humans; Induced Pluripotent Stem Cells; Male; Mitochondria; Organoids; Proof of Concept Study; Schizophrenia; Spectroscopy, Near-Infrared; Thioctic Acid; Ubiquinone

Oxidative stress has been reported to play a role in the psychopathology of schizophrenia, though only a few studies have investigated the relationship between early-onset schizophrenia and oxidative stress. The aim of the present study is to evaluate the level of oxidative stress and the presence of DNA damage in first-episode psychosis (FEP) in adolescents.. This study was conducted in the Department of Child Psychiatry of the Dicle University Hospital. It included 20 adolescent patients (age 11-17 years) with psychosis (acute psychosis, schizophreniform disorder, or schizophrenia) according to DSM-IV criteria who had received no previous psychiatric therapy (patient group) and 20 age/gender-matched healthy adolescents (control group). Structured psychiatric interviews [Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version (K-SADS-PL) and Positive and Negative Symptom Scale (PANSS)] were conducted on the patients, and the Clinical Global Impressions (CGI) scale was used to evaluate the severity of disease. Glutathione peroxidase (GPx), superoxide dismutase (SOD), coenzyme Q (CoQ), and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were determined using the ELISA method and commercial ELISA kits.. The mean age was 14.5 ± 1.6 years in the FEP group (male-to-female ratio: 8/12) and 14.4 ± 1.5 years in the control group (male-to-female ratio: 8/12). There were no differences between the patient and control groups in terms of SOD, GPx, or 8-OHdG values (p > 0.05).. This study on DNA damage and oxidative stress in FEP in adolescents had a small sample size, and our data suggest that oxidative stress is associated with a chronic disease course rather than being an early sign of early-onset schizophrenia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Child; Deoxyguanosine; Diagnostic and Statistical Manual of Mental Disorders; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Glutathione Peroxidase; Humans; Interview, Psychological; Male; Oxidative Stress; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Superoxide Dismutase; Ubiquinone

Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway was studied in neurological and psychiatric disorders. The concentration of trytophan, quinolinic acid, kynurenic acid, serotonin and 5-hydroxyindoleacetic acid was found to be higher in the plasma of patients with all these disorders; while that of tyrosine, dopamine, epinephrine and norepinephrine was lower. There was increase in free fatty acids and decrease in albumin (factors modulating tryptophan transport) in the plasma of these patients. Concentration of digoxin, a modulator of amino acid transport, and the activity of HMG CoA reductase, which synthesizes digoxin, were higher in these patients; while RBC membrane Na+-K+ ATPase activity showed a decrease. Concentration of plasma ubiquinone (part of which is synthesised from tyrosine) and magnesium was also lower in these patients. No morphine could be detected in the plasma of these patients except in MS. On the other hand, strychnine and nicotine were detectable. These results indicate hypercatabolism of tryptophan and hypocatabolism of tyrosine in these disorders, which could be a consequence of the modulating effect of hypothalamic digoxin on amino acid transport.

Topics: Adult; Biogenic Monoamines; Brain Diseases; Brain Neoplasms; Digoxin; Epilepsy, Generalized; Erythrocytes; Fatty Acids, Nonesterified; Female; Glioma; Glycine Agents; Humans; Hydroxymethylglutaryl CoA Reductases; Kynurenic Acid; Magnesium; Male; Microvascular Angina; Middle Aged; Morphine; Narcotics; Nicotine; Nicotinic Agonists; Parkinson Disease; Quinolinic Acid; Schizophrenia; Serum Albumin; Sodium-Potassium-Exchanging ATPase; Strychnine; Tryptophan; Tyrosine; Ubiquinone

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.

Topics: Central Nervous System Neoplasms; Digoxin; Epilepsy, Generalized; Free Radicals; Glioma; Humans; Lipid Peroxidation; Multiple Sclerosis; Nervous System Diseases; Parkinson Disease; Schizophrenia; Ubiquinone

The effects of the neuroleptic flupenthixol on the expression of the genes coding for the mitochondrial ubiquinone and cytochrome b5 reductases have been studied because of the importance of these enzymes in energy metabolism, oxidative stress and also because similar but oppositely directed changes have been previously observed in the cerebral cortex from schizophrenics. The neuroleptic flupenthixol reduces the expression in rats of the gene coding for NADH-cytochrome b5 reductase as measured by in situ hybridisation and its enzymic manifestation. Flupenthixol also reduces the enzymic activity of the mitochondrial NADH-ubiquinone reductase, and it has been previously shown that mRNA from the mitochondrially coded parts of the enzyme are reduced by the drug. Both the cis- and therapeutically less active trans-flupenthixol were found to produce these changes in rats. Post-mortem brain tissue from schizophrenics who have received neuroleptic medication have reduced levels of both reductases as measured enzymically, Lymphocyte samples from schizophrenics also have reduced levels of both reductases compared with normals. The superoxide anion O2- is the principle agent of oxidative stress and both the cytochrome b5 and the ubiquinone reductase enzymes were semi-purified from sheep liver and shown to produce appreciable amounts of superoxide. Superoxide production is reduced in brain homogenates from rats treated with flupenthixol. Its production is also reduced in brain tissue and lymphocytes from schizophrenics receiving neuroleptic medication. We conclude that neuroleptic medication reduces the expression of both the ubiquinone and cytochrome b5 reductase and among the effects of this reduction is a decrease in the production of neurotoxic superoxide.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Brain Chemistry; Cytochrome Reductases; Cytochrome-B(5) Reductase; Female; Flupenthixol; Gene Expression Regulation, Enzymologic; Humans; In Situ Hybridization; Lipid Peroxidation; Lymphocytes; Male; Middle Aged; Mitochondria; NAD; NAD(P)H Dehydrogenase (Quinone); Oligonucleotide Probes; Oxidative Stress; RNA, Messenger; Schizophrenia; Superoxides; Ubiquinone

The model presented here suggests that a defect in a selenium transport protein may be a necessary but not sufficient precondition for a sub-type of schizophrenia--a type of schizophrenia that has been characterized by negative symptoms, brain damage, and a lack of primarily paranoid ideation. A defective selenium transport protein and consequent low levels of selenium might adversely affect multiple enzyme systems. Selenium-enzyme interreactions are discussed and the effect of selenium on arachidonic acid and its metabolites, especially 12-HPETE, are examined in light of the presented model. If the proffered model is essentially correct, selenoprotein P, a hypothesized selenium transport protein, is a likely candidate for a protein involved in the etiology of a form of schizophrenia.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Carrier Proteins; Dopamine; Enzymes; Glutathione Peroxidase; Humans; Hydroxyeicosatetraenoic Acids; Models, Biological; Proteins; Rats; Schizophrenia; Schizophrenic Psychology; Selenium; Selenium-Binding Proteins; Selenoprotein P; Selenoproteins; Ubiquinone

Coenzyme Q10 in the plasma and erythrocytes were determined in ambulant schizophrenic patients. As a result, the erythrocyte level of coenzyme Q10 in these patients was significantly low compared with most of the control group.

Topics: Adult; Coenzymes; Erythrocytes; Female; Humans; Male; Schizophrenia; Ubiquinone