Butyrate, but not propionate, reverses maternal diet-induced neurocognitive deficits in offspring.

BACKGROUND: Maternal diet plays a beneficial role in the health, including the neurodevelopment, of offspring. Insufficient fibre consumption among the general population has increased concern about neurocognitive diseases. However, the association between maternal low-fibre diet (MLFD) and neurocognitive function in offspring is still unclear. METHODS: Mice were fed diets containing diverse levels of fibre or administered short-chain fatty acids (SCFAs) during gestation. The neurocognitive functions of the offspring and synaptic plasticity-related protein levels were measured. Gene expression was disrupted by siRNA interference. Samples from pregnant women and paired umbilical cord blood (UCB) samples were analysed by the general linear model. RESULTS: We found that MLFD impaired cognitive function and synaptic plasticity in offspring and that the impairments were reversed by butyrate intake but not propionate intake. Mechanistic studies showed that histone deacetylase (HDAC)-4 is the most likely mediator of butyrate-dependent neurocognitive improvement. In addition, using human maternal serum and paired UCB samples, we demonstrated that SCFA levels in offspring were positively correlated with levels in the maternal serum. CONCLUSION: These results provide solid evidence that fibre in the maternal diet regulates neurocognitive functions in offspring through altering SCFA levels and supports the use of SCFA-dependent perinatal intervention for improving offspring health in the clinic.

Tissue Inhibitor of Metalloproteinase-2 Polymorphisms and Risk for HIV-Associated Neurocognitive Disorder.

The imbalance between MMPs and TIMPs is associated with the HIV dissemination tissue damage pathology neurodegenerative disorders, including HAND. Genetic variations in the TIMP gene may modulate the neurocognitive disorder in HIV patients. Hence, we evaluated the genetic variants of TIMP-2 (-418G/C, 303G/A) gene with the risk of HAND. Genotyping of TIMP-2 polymorphism was performed in 50 patients with HAND, 100 no HAND, and 154 healthy controls by PCR-RFLP. TIMP-2 -418GC and 303AA genotypes represented a predominant risk for HAND severity (OR = 1.55, P = 0.30; OR = 4.58, P = 0.24). The variant -418CC genotype, -418A allele, had exhibited a significant risk for the acquisition of HAND (OR = 12.55, P = 0.026; OR = 2.66, P = 0.004). TIMP-2 303GA, 303AA genotype, and 303A allele evinced a higher risk for HAND severity (OR = 1.82, P = 0.14; OR = 1.70, P = 0.63; and OR = 1.68, P = 0.12). In HIV patients, TIMP-2 -418CC genotype and -418C allele significantly occurred in comparison to healthy controls (OR = 10.10, P = 0.006; OR = 2.02, P = 0.009). In the intermediate and early HIV disease stage, TIMP-2 -418CC genotype was significantly increased compared with healthy controls (11.1% vs. 1.3%, OR = 14.63, P = 0.01; 16.9% vs. 1.3%, OR = 14.51, P = 0.002). In patients with HAND among tobacco and alcohol users, TIMP-2 -418CC genotype displayed a risk for HAND severity (OR = 3.96, P = 0.26; OR = 4.83, P = 0.19). On multivariate logistic regression, TIMP-2 303AA genotype, advanced stage, and gender had a risk for HAND severity (OR = 28.98, P = 0.02; OR = 2.35, P = 0.070; and OR = 2.36, P = 0.04). In conclusion, TIMP-2 -418G/C polymorphism independently, along with alcohol and tobacco, may have an impact on the acquisition of HAND and its severity. TIMP-2 303G/A polymorphism bare a risk for HAND severity.

Implications of efavirenz for neuropsychiatry: a review.

Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase.

Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders.

Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders.

Effect of matrix metalloproteinase-21 (572C/T) polymorphism on HIV-associated neurocognitive disorder.

Remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is a presumed reason for the development of HIV-associated neurocognitive disorders (HAND). The coding region polymorphism in MMP-21 572C/T gene may have a potential functional effect on ECM remodeling. Hence, we aimed to examine the association of MMP-21 polymorphism with the modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. Genotyping of MMP-21 572C/T polymorphism was performed by PCR-RFLP in total 150 HIV-infected individuals, 50 with HAND, 100 without HAND and 150 healthy controls. MMP-21 572TT genotype was predominantly higher in HAND patients compared with no HAND (OR = 1.63, p = 0.57). MMP-21 572T allele was associated with reduce risk for HAND severity (OR = 0.50, p = 0.04). Similarly, MMP-21 572TT genotype underrepresented in HIV-infected individuals compared to healthy controls (3.0% vs 6.7%, OR = 0.27, p = 0.08). MMP-21 572CT genotype and early HIV disease stage showed a higher risk for the advancement of HIV disease with marginal significance (OR = 1.89, p = 0.07). MMP-21 572CT genotype increased the risk for the modulation of HAND severity in tobacco users (OR = 1.98, p = 0.43). MMP-21 572CT genotype among tobacco and alcohol users showed elevated risk for the development of HAND in HIV-infected individuals (OR = 2.30, p = 0.15; OR = 1.86, p = 0.23). Similarly, MMP-21 572TT genotype enhanced the risk for the development of HAND in tobacco users (OR = 3.48, p = 0.40). In conclusion, the presence of coding region 572T allele may have protection for HAND severity. MMP-21 572C/T polymorphism and tobacco and alcohol usage may facilitate the development of HAND.

Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases.

Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na(+)/K(+) regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

Delusional misidentification and platelet monoamine oxidase.

Recently, reduced platelet monoamine oxidase (MAO) activity was demonstrated in two cases of paranoid schizophrenia exhibiting Capgras' syndrome. The present authors report platelet MAO studies in an additional patient with the Delusion of Doubles. In this case, one of delusional hyperidentification (false recognition), decreased platelet MAO activity compared with normal controls was detected. The patient, while not schizophrenic, showed platelet MAO activity comparable with that of a chronic schizophrenic control group. The possible significance of the findings are discussed.

Increased plasma phospholipase-A2 activity in schizophrenic patients: reduction after neuroleptic therapy.

Phospholipase-A2 (PLA2) is a key enzyme in the metabolism of phospholipids, and it may play an important role in neuronal function and neuronal plasticity. We determined the activity of PLA2 in the plasma of 20 drug-free schizophrenic patients, 6 nonschizophrenic psychiatric patients, and 21 healthy controls. Schizophrenic patients showed significantly higher plasma PLA2 activity than controls, and higher than our nonschizophrenic patients. Seventy percent of the schizophrenics had enzyme activity higher than the highest value from the control group. The increased plasma PLA2 activity in schizophrenics was reduced to the level of the controls after 3 weeks of neuroleptic treatment. These findings warrant further study for possible implications of this increased PLA2 activity in the etiopathology of schizophrenia.

Erythrocyte ITP pyrophosphohydrolase deficiency in a psychiatric population.

A higher incidence of erythrocyte ITP pyrophosphohydrolase deficiency was found among a psychiatric population when compared to a nonpsychiatric group of subjects. Although the incidence was highest among schizophrenics, particularly those diagnosed as paranoid, the majority of the patients did not show such deficiency. The parallelisms between ITP pyrophosphohydrolase and hypoxanthine-guanine phosphoribosyl transferase deficiencies, both characterized by the lack of availability of IMP, and correlated to behavioral disorders, suggest that irregularities of hypoxanthine nucleotides may be implicated in abnormal mental processes.

Prevalence of partial cerebroside sulfate sulfatase (arylsulfatase A) defect in adult psychiatric patients.

Metachromatic leukodystrophy (MLD) is a disease caused by a deficiency of the enzyme sulfatide sulfatase, also known as arylsulfatase A (ASA). We compared the activity of this enzyme in adult psychiatric patients and normal volunteers using nitrocatechol sulfate (ASA-NCS) and cerebroside sulfate (ASA-CS) as substrates. Our results showed that ASA-NCS activity in urine and leukocytes was significantly lower in psychiatric than in normal individuals, but that there were no differences between these two groups in the sulfatide excretion in urine or the ASA-CS activity in leukocytes. There was no correlation between enzyme activity in urine and in leukocytes, indicating that activity in urine does not truly reflect the levels of the enzyme in tissues. The correlation between ASA-NCS and ASA-CS activity in leukocytes was poor (0.51 for psychiatric patients and 0.59 for normals), suggesting that for a valid measure of the enzyme activity the assays should be carried out with CS as substrate. Results of our study also indicate that in 39 of the 145 psychiatric patients studied, the ASA-CS activity in leukocyte was less than 4 nmoles/mg protein/hr, which is below 50% of the normal means, whereas only one of the 30 normal subjects had a value this low. The presence of low levels of ASA-CS activity in a significantly large number of adult patients with varying psychiatric manifestations suggests that such patients may be asymptomatic carriers of the sulfatidase defect (heterozygotes for MLD), and that behavioral and functional disturbances in these patients may at least in part be related to sulfatidase deficiency. The significance of the ASA-NCS abnormality (reduction) in psychiatric patients is unclear.

The role of the one-carbon cycle in neuropsychiatric disease.

This paper reviews and correlates three separate recent findings that implicate the one-carbon cycle in neuropsychiatric disease: (i) the demonstration by kinetic studies that the Vmax of methionine adenosine transferase (MAT) is reduced in some schizophrenics and depressives and is increased in some manics, and that the activity of serine hydroxymethyltransferase (SHMT) is reduced in a further subpopulation of schizophrenics; (ii) the demonstration that S-adenosylmethionine (the product of MAT) is an effective clinical antidepressant; and (iii) the reports that L-methionine is an effective treatment for certain of the symptoms of Parkinson's disease. These clinical findings may be correlated with recent findings that transmethylation reactions (lipid and carboxymethylation) play an important role in synaptic events (coupling of receptors to adenylate cyclase and release of neurotransmitters).

Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher's disease.

A family is described in which adult-onset Gaucher's disease developed, followed years later by atypical psychotic disorders with neurologic and electroencephalographic abnormalities. A biochemical investigation of primary and secondary enzyme alterations in the index case was performed in an attempt to identify a pattern that might be specific to this clinical profile. The literature pertaining to CNS involvement in adult patients with Gaucher's disease is also reviewed. An etiologic link may exist between the inherited metabolic disorder and associated neuropsychiatric impairment. The biochemical basis of this hypothesized association remains unclear, however, and further enzymatic and pathologic investigations are warranted.

Comparative study of the proteinase inhibitor pattern in serum and cerebrospinal fluid.

After concentration the alpha 1-proteinase inhibitors (Pi) of cerebrospinal fluid (CSF) were separated by isoelectric focusing. The relative amounts of the different Pi components in the CSF were compared with those in the serum of the same donor. The Pi components were identified by crossed isoelectric focusing. Most of the serum Pi components could be detected in the CSF but their relative proportions in serum and CSF differed considerably. The typical serum Pi patterns observed for different phenotypes were not reflected in the CSF. In cases when CSF protein levels were abnormally high alterations of the CSF Pi pattern were observed, i.e. the proportions of at least some of the Pi components approached those in serum. It is concluded that CSF Pi components originate from the serum and that a highly selective blood-CSF barrier function results in a considerable alteration of the concentration pattern. It has been shown by crossed isoelectric focusing technique that at least two proteins acting as Pi in serum do not exert antiproteolytic activity in CSF. Consequently, in CSF these Pi components may have been chemically modified, resulting in an alteration of the acceptor sites but not of the isoelectric point of the inhibitor molecule.

Serum dopamine-beta-hydroxylase activity: clinical applications in child psychiatry.

Serum dopamine-beta-hydroxylase (DBH) activity was measured in 44 children with psychiatric disorders and 44 controls in order to determine significant variables affecting its potential use as a marker for specific molecular pathology in the neuropsychiatric disorders of childhood. The assay procedure was reliable and the serum enzyme activity for individuals appears to be stable. There is a very broad distribution of serum DBH activity in the population, and it is similar in males and females. The genetic determination of serum DBH activity was clear in this study, and the enzyme activity increased with age through childhood and adolescence. Thyroid hormone had no effect on serum DBH activity in euthyroid subjects. No difference in mean serum DBH activity emerged across diagnostic groups. When the findings were considered in relation to the results of other studies, it was concluded that the wide range of serum DBH activities in normal and patient populations, as well as developmental effects on the activity of the enzyme, make comparison of DBH activity among diagnostic groups in childhood difficult. Large subject groups, and a consideration of genetic and developmental effects, will clarify possible syndrome-related differences in enzyme activity.

Plasma glutamate decarboxylase activity in neuropsychiatry.

Plasma glutamate decarboxylase (GAD) activity was measured in patients with endogenous psychoses and neurologic diseases. Unmedicated schizophrenic patients showed no difference in plasma GAD levels compared to controls. Administration of neuroleptics together with anticholinergic agents increased plasma GAD activity in schizophrenic patients. Compared to controls, patients with major depression and bipolar illness showed significantly lower GAD activity. No effect of antidepressants and minor tranquilizers on plasma GAD activity was found. Relatively lower GAD activity was shown in neurotic patients. The enzyme activity in plasma of patients with Huntington's chorea (HC) was lower than control levels. The plasma GAD concentrations correlated with cerebrospinal fluid concentrations in five HC patients.

Platelet glutathione peroxidase and monoamine oxidase activity in schizophrenics with CT scan abnormalities: relation to psychosocial variables.

We have previously reported that the activity in platelets of the important antioxidant enzyme glutathione peroxidase (GPx) is inversely correlated with computed tomographic (CT) measures of brain atrophy in a population of patients with chronic schizophrenia, suggesting that low GPx may be a vulnerability factor in those schizophrenic patients with structural brain abnormalities. The significance of this finding has now been explored in a larger clinical population by examining the relation of GPx and CT parameters to psychosocial variables and to the activity of platelet monoamine oxidase (MAO), which has also been reported to be altered in certain schizophrenic populations. In the present study, low platelet GPx and high brain atrophy were found to be associated with DSM-III diagnoses of nonparanoid schizophrenia, a high degree of chronicity, and a predominance of negative symptoms. Contrary to some literature reports, atrophy also correlated with age and length of illness among the schizophrenic patients, although the contribution of these factors was less than that of low GPx, which was itself not age dependent. The ventricle-brain ratio (VBR) and atrophy were highly correlated in a control group of affective disorder patients, but not in the schizophrenic group, where large VBRs were found predominantly in the DSM-III undifferentiated subgroup. The low-GPx/high-atrophy schizophrenic patients had normal platelet MAO levels, and MAO was significantly lower only in the paranoid subgroup, consistent with reported observations. There was no evidence for a neuroleptic-induced effect on either enzyme.

Tetrahydrobiopterin metabolism in the Rett disease.

Tetrahydrobiopterin metabolism was studied in nine Swedish patients with the Rett disease. Normal values were found for the serum biopterin level, urine biopterins level and dihydropterine reductase activity. These findings suggest that a primary disturbance of tetrahydrobiopterin metabolism is unlikely.

Neurochemical aspects of the Rett syndrome.

Preliminary biochemical analyses on plasma, urine, cerebrospinal fluid (CSF) and post mortem brain areas in the rare Rett syndrome indicate no gross disturbance of neurotransmitter function in the periphery. The amino acid pattern, the plasma catecholamines, dopamine, noradrenaline and adrenaline, serotonin in plasma and platelets, and monoamine oxidase (MAO) B-activity in platelets were not different from controls. Urinary metabolites of biogenic amines tended to be increased in the Rett syndrome. Amino acid and noradrenaline concentrations were not changed in lumbar CSF. In a single case of the Rett syndrome, lower values for most amino acids were notable in post-mortem human brain areas and this finding was accompanied by a severe reduction of dopamine, noradrenaline and serotonin, while the metabolite, DOPAC, most times is increased, and HVA and 5-HIAA are decreased. MAO activities, determined in four brain areas, showed no major abnormalities. 3H-spiroperidol binding was significantly below normal in the putamen and 3H tryptamine binding sites in the occipital cortex showed increased binding numbers with no changes in Hill-coefficients. In conclusion, our preliminary data indicate no severe changes in the peripheral neurotransmitter synthesis and turnover, while first post-mortem data indicate severe reduction of biogenic amine synthesis with enhanced turnover and reduced dopaminergic D-2 receptor activity in the advanced stage of a single case of the Rett syndrome.

Adult metachromatic leukodystrophy. Arylsulphatase-A values in four generations of one family and some reflections about the genetics.

The authors describe an investigation of Adult Metachromatic Leukodystrophy in a Dutch family, of which two persons were affected. The studies of leukocyte arylsulphatase-A activity were made in 47 members of 4 generations of the same family. The propositus, a 30-year old man, showed a conspicious organic brain syndrome, that progressed in two years to a complete dementia. His leukocyte, liver and kidney arylsulphatase-A activities (ASA) were very low; leukocyte-ASA activity increased after aceto-salicylate. His brother had died at 34 years, after a progressive debelitating neuropsychiatric illness of eight years; postmortem metachromatic leukodystrophy was diagnosed. In all living family members, urine and leukocyte arylsulphatase-A activities were determined. The findings are discussed in relation to the genetics and pathogenesis of this adult form of metachromatic leukodystrophy. Allelic heterozygoty is proposed as inheritance model in this family. Suggestions for further research are made.

Creatine kinase and enolase: intracellular enzymes serving as markers of central nervous system damage in neuropsychiatric disorders.

A frequently used method to assess cellular dysfunction and damage in humans is to document the presence of uniquely intracellular proteins in extracellular spaces. Thus, increased plasma levels of transaminases generally reflect hepatocellular damage (Lieber 1978), increases in the cardiac fractions of creatine kinase (CK, or CPK for creatine phosphokinase) or lactate dehydrogenase (LDH) are diagnostic for myocardial infarction (Armstrong et al. 1979; 1982), and increases of skeletal muscle fractions of CK may indicate myopathy (Goto 1974; Ford 1984). Similarly, a number of enzymes and proteins serve as tumor markers in a variety of malignant cancer (e.g., Concannon et al. 1974; Foti et al. 1977).