Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of studies have demonstrated alterations in the structure and function of the frontal cortex in some schizophrenic patients. The possible etiology and pathogenesis of these abnormalities are unknown, but genetic and developmental causes are frequently mentioned. Recent in vivo 31P NMR studies of the dorsal prefrontal cortex have been conducted in eleven neuroleptic naive, first episode schizophrenic patients and compared with normal controls of comparable age, educational level and parental educational level. The findings in the schizophrenic patients are different from those of normal IQ adult autistic patients of comparable age and Alzheimer's patients but similar to normal elderly controls. These studies show decreased frontal lobe utilization of adenosine triphosphate in the schizophrenic patients which suggests a hypoactive dorsal prefrontal cortex. In addition, indices of membrane phospholipid metabolism are altered in the schizophrenic patients. However, the findings in the schizophrenic patients are quite similar to those observed in normal elderly controls and to those that normally occur to a lesser degree during adolescence. The phospholipid alterations observed in the schizophrenic patients are compatible with either premature aging or altered timing and exaggeration of the regressive events which occur during normal brain development. The changes in high-energy phosphate metabolism observed in the schizophrenic patients may prove to be state dependent, but the changes in membrane phospholipid metabolism could be related to molecular changes that precede the onset of clinical symptoms and brain structural changes in schizophrenia. These findings suggest new avenues of thinking about the pathogenesis and treatment of schizophrenia.
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PMID:Molecular insights into schizophrenia. 152 18

The (F-18) fluorodeoxyglucose (FDG) technique to measure local cerebral metabolic rate for glucose (LCMRglu) is well accepted and widely used by many institutions around the world. A large number of studies has been carried out in normal volunteers and patients with a variety of CNS disorders. Several investigators have noted that no significant age-related changes in cerebral glucose use occur with normal aging. Some important and interesting findings have been revealed following sensory, motor, visual, and auditory stimulations. Functional imaging with FDG in certain neurologic disorders has dramatically improved our understanding of their underlying pathophysiologic phenomena. Some abnormalities detected on the positron emission tomography (PET) images have no corresponding changes on either x-ray computed tomograms (XCT) or magnetic resonance images (MRI). In patients with Alzheimer's disease, primary sensorimotor, visual, and cerebellar metabolic activity appears relatively preserved. In contrast, parietal, temporal, and to some degree, frontal glucose metabolism is significantly diminished even in the early stages of the disease. Patients with Huntington's disease and those at risk of developing this disorder have a typical pattern of diminished CMRglu in the caudate nuclei and putamen. In patients with stroke, PET images with FDG have demonstrated abnormal findings earlier than either XCT or MRI and with a wider topographic distribution. FDG scans have revealed interictal zones of decreased LCMRglu in approximately 70% of patients with partial epilepsy. The location of the area of hypometabolism corresponds to the site of the epileptic focus as determined by electroencephalography and microscopic examination of the resected tissue. Ictal scans during partial seizures demonstrate areas of hypermetabolism corresponding to the sites of seizure onset and spread. Several investigators have reported relative hypofrontal CMRglu in patients with schizophrenia. In our center, FDG scans from patients with schizophrenia were successfully differentiated from those obtained in normal controls. Finally, our preliminary data (using PET, XCT, and MRI) in patients with CNS disorders indicate that MRI provides excellent delineation of the structural abnormalities. It may prove to be superior to XCT in the evaluation of certain diseases such as cerebral ischemia and infarcts, head injury, tumors, and white matter lesions. Metabolic imaging with FDG provides functional information not obtainable with either MRI or NMR spectroscopy. Therefore, PET studies will play a complementary role to the anatomic imaging in the management of patients with CNS disorders.
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PMID:Positron emission tomography imaging of regional cerebral glucose metabolism. 293 38

A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.
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PMID:Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides. 394 14

Phospholipase A2 (PLA2) catalyzes the hydrolysis of membrane phospholipids to release cytotoxic products such as lysophosphatidylcholine. In schizophrenia increased PLA2 activity and an accelerated breakdown of membrane phospholipids have been reported. In neuronal do membranes PLA2 modulates dopamine (DA) release and DA receptor sensitivity. Using two different animal models we show inhibition of dopaminergic activity in vivo by intracerebral PLA2 application. (1) Unilateral stereotaxic injection of PLA2 into the substantia nigra pars compacta causes an apomorphine-induced ipsilateral rotational asymmetry. (2) Intracerebroventricular PLA2 application reduces apomorphine-induced locomotion. NMR spectroscopy studies show a disordered phospholipid metabolism in the prefrontal cortex (PFC) of schizophrenics. The hypofrontality hypothesis of schizophrenia postulates hypodopaminergic activity in the prefrontal cortex. We speculate that increased PLA2 activity in the PFC of schizophrenics might be related to both abnormalities and could thus contribute to hypofrontality in schizophrenia.
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PMID:Phospholipase A2 and the hypofrontality hypothesis of schizophrenia. 888 32

Ziprasidone is an antipsychotic agent indicated primarily for the treatment of schizophrenia. An intramuscular dosage form of ziprasidone was developed using beta-cyclodextrin sulfobutyl ether (SBECD) to solubilize the drug by complexation. Inclusion complexation of ziprasidone mesylate (ZM) with SBECD was studied by circular dichroism (CD) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, Monte Carlo simulations, phase-solubility studies, and counterion titration. The results of the studies indicate that ZM, of which the counterion is not fully dissociated from the drug, forms a 1:1 inclusion complex with SBECD with the benzisothiazole group positioned in the cavity. A mathematical model was developed to calculate stability constants of inclusion complexes for the ion pair (Z+M-:SBECD) and the dissociated ionic form (Z+:SBECD) of ZM; the values were 7892 and 957 M(-1), respectively. The model also allowed the dissociation constants of noncomplexed and complexed ZM to be calculated; the value of the former is 8-fold greater than the value of the latter. These results indicate that the inclusion complex formation of the ion pair is favored over that of the dissociated ionic form of ZM, and that the dissociation of ZM is suppressed by inclusion complexation with SBECD.
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PMID:Inclusion complexation of ziprasidone mesylate with beta-cyclodextrin sulfobutyl ether. 1018 67

Neurochemical brain imaging methods developed over the past 20 years offer significant promise for elucidating the biochemical underpinnings of schizophrenia. The two general methodologies used for these studies have been: 1) radiotracer imaging: PET (positron emission tomography) and SPECT (single photon emission computed tomography); and 2) NMR (nuclear magnetic resonance) imaging: fMRI (functional magnetic resonance imaging) and MRS (magnetic resonance spectroscopy). Despite conflicting findings, striatal D2 receptor density may be elevated in some, but not all patients. Elevated synthesis, and increased release of dopamine after amphetamine challenge have also been reported. Imaging of cortical 5-HT2A receptors suggests that this system is unaffected, in conflict with findings of postmortem studies. Although prior postmortem studies suggested an increase in cortical GABAA receptors, three SPECT studies have found no significant changes. MRS studies have shown decreased levels of NAA (N-acetyl-aspartate) moieties in hippocampus and frontal cortex of schizophrenic patients, which is consistent with the reported loss of neurons and neuropil in postmortem brains. In conclusion, developments in radiotracer and NMR imaging have provided promising leads to the biochemical abnormalities associated with schizophrenia. Future significant understanding is likely to occur with the development of new probes and enhanced instrument technology, when applied with an appreciation of the heterogeneity of the disorder and the need for careful clinical assessment of patients.
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PMID:Neurochemical brain imaging investigations of schizophrenia. 1047 14

Recent research suggests that deficient uptake or excessive breakdown of membrane phospholipids may be associated with schizophrenia. We review available clinical research on abnormalities in membrane fatty acid composition and metabolism in schizophrenia, and therapeutic trials of fatty acid in this disorder. All potentially relevant English-language articles were identified from the medical and psychiatric literature with the aid of computer searches using key words such as lipids, phospholipids, prostaglandins and schizophrenia. All studies which include human subjects are reviewed. Empirical studies related to membrane hypotheses of schizophrenia focus on: 1) assessment of prostaglandins (PG) and their essential fatty acid (EFA) precursors in the tissues of patients with schizophrenia; 2) evaluation of the niacin flush test as a possible diagnostic marker; 3) evaluation of phospholipase enzyme activity; 4) NMR spectroscopy studies of brain phospholipid metabolism; and 5) therapeutic trials of PG precursors for the treatment of schizophrenia. The most consistent clinical findings include red blood cell fatty acid membrane abnormalities, NMR spectroscopy evidence of increased phospholipid turnover and a therapeutic effect of omega-3 fatty acid supplementation of neuroleptic treatment in some schizophrenia patients. Studies of EFA metabolism have proved fruitful for generating and testing novel etiologic hypotheses and new therapeutic agents for schizophrenia. Greater attention to factors that influence tissue EFA levels such as diet, tobacco and alcohol are required to reconcile inconsistent findings. Treatment studies, although promising, require independent replication.
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PMID:Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. 1065 Apr 44

Phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) has gained much interest in schizophrenia research in recent years since it allows the non-invasive measurement of high-energy phosphates and phospholipids in vivo. However, until now only differences in metabolite concentrations between certain brain areas of schizophrenic patients and healthy controls have been examined. We investigated the influence of gender on the concentrations of different phosphorus compounds. For this purpose, well-defined volumes in the frontal lobe of 32 healthy controls and 51 schizophrenic in-patients were examined with an image selected in vivo spectroscopy (ISIS) sequence on a whole-body scanner at 1.5 T. Healthy females exhibited increased values of inorganic phosphate (P(i)) and decreased values of phosphocreatine (PCr) in comparison to their male counterparts. In schizophrenic patients such gender differences were not present. Thus, the results can be interpreted in the sense that frontal energy demanding processes are enhanced in female compared to male healthy volunteers; schizophrenia seems to reduce these gender differences.
NMR Biomed 1999 Dec
PMID:Frontal lobe in vivo (31)P-MRS reveals gender differences in healthy controls, not in schizophrenics. 1066 40

3-([4-(4-Chlorophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo-2, 3-beta-pyridine (L-745,870) is a dopamine D(4) selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.
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PMID:Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct. 1082 Jan 34

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound, pentameric ligand-gated ion channels associated with a variety of human disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and pain. Most known nAChRs contain an unusual eight-membered disulfide-containing cysteinyl-cysteine ring, ox-[Cys-Cys], as does the soluble acetylcholine binding protein (AChBP) found in the snail Lymnaea stagnalis. The cysteinyl-cysteine ring is located in a region implicated in ligand binding, and conformational changes involving this ring may be important for modulation of nAChR function. We have studied the preferred conformations of Ac-ox-[Cys-Cys]-NH2 by NMR in water and computationally by Monte Carlo simulations using the OPLS-AA force field and GB/SA water model. ox-[Cys-Cys] adopts four distinct low-energy conformers at slightly above 0 degrees C in water. Two populations are dependent on the peptide omega2 dihedral angle, with the trans amide favored over the cis amide by a ratio of ca. 60:40. Two ox-[Cys-Cys] conformers with a cis amide bond (C+ and C-) differ from each other primarily by variation of the chi3 dihedral angle, which defines the orientation of the helicity about the S-S bond (+/- 90 degrees ). Two trans amide conformers have the same S-S helicity (chi3 approximately -90 degrees ), but are distinguished by a backbone rotation about phi2 and psi1 (T- and T'-). The ratio of T-/T'-/C+/C- is 47:15:29:9. The orientation of the pendant moieties from the eight-membered ring is more compact for the major trans conformer (T-) than for the extended conformations adopted by T'-, C+, and C-. These conformational preferences are also observed in tetrapeptide and undecapeptide fragments of the human alpha7 subtype of the nAChR that contains the ox-[Cys-Cys] unit. Conformer T- is nearly identical to the conformation seen in the X-ray structure of ox-[Cys(187)-Cys(188)] found in the unliganded AChBP, and is a Type VIII beta-turn.
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PMID:Conformational analysis of the eight-membered ring of the oxidized cysteinyl-cysteine unit implicated in nicotinic acetylcholine receptor ligand recognition. 1174 32


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