CPZ
Carboxypeptidase Z precursor (EC 3.4.17.-) (CPZ)
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Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2-/- mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4 NG2 OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2-/- mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS.
MeSH Terms
- Aging
- Animals
- Astrocytes
- Cell Differentiation
- Cell Proliferation
- Central Nervous System
- Chemokine CXCL12
- Corpus Callosum
- Demyelinating Diseases
- Disease Models, Animal
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Multiple Sclerosis
- Myelin Sheath
- Oligodendroglia
- Receptors, Tumor Necrosis Factor, Type II
- Stem Cells
Normal aging has been linked to impairments in gating of irrelevant sensory information and neural markers of diminished cognitive processing. Whilst much of the research in this area has focussed on visual and auditory modalities it is unclear to what degree these findings apply to somatosensation. Therefore we investigated how age impacts early event-related potentials (ERPs) arising from relevant or irrelevant vibrotactile stimuli to the fingertips. Specifically, we hypothesised that older adults would demonstrate reduced attention-based modulation of tactile ERPs generated at early stages of cortical somatosensory processing. In accord with previous research we also expected to observe diminished P300 responses to attended targets and behavioural deficits. Participants received vibrotactile stimulation to the second and fifth digit on the left hand and reported target stimuli on one digit only (as instructed) with comparisons between two age groups: (1) Young adults (age range 20-39) and (2) Older adults (age range 62-89). ERP amplitudes for the P50, N70, P100, N140 and long latency positivity (LLP) were quantified for attended and non-attended trials at several electrodes (C4, CP4, CP3 and FC4). The P300 in response to attended target stimuli was measured at CPZ. There was no effect of attention on the P50 and N70 however the P100, N140 and LLP were modulated with attention. In both age groups the P100 and LLP were more positive during trials where the stimuli were attended to, whilst the N140 was enhanced for non-attended stimuli. Comparisons between groups revealed a reduction in P100 attention-based modulation for the older adults versus the young adults. This effect was due to a loss of suppression of the non-attended stimuli in older subjects. Moreover, the P300 was both slower and reduced in peak amplitude for older subjects in response to attended targets. Finally, older adults demonstrated impaired performance in terms of both reduced target detection accuracy and in reporting more false positives. Overall, present results reveal a deficit in suppressing irrelevant tactile information during an attention-demanding task which possibly relates to reduced markers of performance. Such a loss of inhibitory function is consistent with age-related change associated with a decline in executive control via prefrontal regions.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Analysis of Variance
- Attention
- Attention Deficit Disorder with Hyperactivity
- Brain Mapping
- Discrimination, Psychological
- Electroencephalography
- Event-Related Potentials, P300
- Female
- Fingers
- Functional Laterality
- Humans
- Male
- Middle Aged
- Physical Stimulation
- Sensory Gating
- Touch
- Young Adult
Although there is a great number of studies on the relationship between tardive dyskinesia and patient characteristics, too often their validity is impaired by the lack of operationalized criteria for the description of patients and signs. Reliable phenotyping is of utmost importance for linking clinical data with data from methods in neurobiology or molecular genetics. 241 patients with the DSM IV diagnosis "schizophrenia" or "schizoaffective disorder" were examined with the instruments SADS-L, OPCRIT, BPRS and PANSS. Motor phenomena were analyzed on 2 separate days within 3 months with the scales TDRS, AIMS, SAS, BAS. Tardive dyskinesia was diagnosed following the research criteria of Schooler and Kane. Lifetime medication with neuroleptics and anticholinergic drugs was assessed quantitatively. 97 out of 233 patients (= 41.6%) displayed persistent tardive dyskinesia. In univariate analysis, significant associations were found between tardive dyskinesia and the following independent variables (higher values means greater risk): Age (p = 0.0001), years from onset of the disorder (p = 0.001), total length of stay in hospital (p = 0.001), PANSS (single scales and sum score) (p = 0.0001), total amount of neuroleptics expressed as CPZ equivalents (p = 0.004). Logistic regression analysis showed that only the variables "age" and "negative symptoms" expressed as score on the PANSS negative subscale showed an association with tardive dyskinesia that could not be explained by covariation with other variables. The same results were found when, instead of the dichotomous variable "tardive dyskinesia yes/no" the associations with the TDRS score were analyzed. Future research should aim to approach the neurobiological correlates of "age" and "negative symptoms" in relationship to tardive dyskinesia.
MeSH Terms
- Adult
- Aging
- Antipsychotic Agents
- Dyskinesia, Drug-Induced
- Female
- Humans
- Male
- Psychiatric Status Rating Scales
- Regression Analysis
- Risk Factors
- Schizophrenia
- Schizophrenic Psychology
Chlorpromazine (CPZ) therapeutic drug monitoring is beset by inconclusive and controversial evidence on the positive correlation of plasma CPZ concentration and psychiatric improvement. Failure to establish meaningful correlation between plasma concentration and clinical benefit may be explained by chemical assay problems; differences in the pharmacokinetic plasma CPZ and metabolite profile due to age, acuteness or chronicity of the disease; drug interactions; and duration of neuroleptic treatment. At the other end, measurement of clinical effects in psychiatry suffers such drawbacks as less distinct and specific clinical end points, the patient's subjectiveness of symptoms and the investigator's subjectiveness on clinical scoring, and the ethical consideration of placebo use. Our data showed the following:L (1) Plasma levels of CPZ parent compound correlated better with improvement in thought disorders and paranoid delusion than with total Brief Psychiatric Rating Scale; there were no correlations with depression and withdrawal retardation. (2) Chronically treated patients achieved significantly lower plasma CPZ compared to acutely treated patients on oral CPZ dose but not those treated with an intramuscular dose. (3) Children, in comparison to adults, require higher doses to achieve similar plasma CPZ levels and have a lower response threshold, both for clinical improvement and toxicity. (4) The plasma concentration of CPZ can be diminished by concomitant use of anticholinergics. (5) A drug "holiday" increases peak plasma concentration of CPZ and may benefit the nonresponders.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Biological Availability
- Child
- Chlorpromazine
- Chronic Disease
- Drug Interactions
- Female
- Humans
- Male
- Middle Aged
- Parasympatholytics
- Psychotic Disorders
Efforts to find a correlation between serum levels of chlorpromazine (CPZ) and clinical effect have been rather unsuccessful, which could be due to fluctuations of CPZ and CPZ metabolite levels during treatment, the complicated metabolism of CPZ, or to varying degrees of protein binding. Using a mass fragmentographic analysis technique the variations of CPZ and two active metabolites nor1-CPZ and 7-OH-CPZ were studied in ten schizophrenic patients during the day at steady state and after withdrawal. There was a significant correlation between the area under curve (AUC) for CPZ in serum during 24-h treatment and serum concentration at different fixed times of the day. The half-life (T 1/2) for CPZ was found to be 8-33 h. 7-OH-CPZ and nor1-CPZ disappeared at about the same rate as the parent compound. The concentration of both metabolites was less than 10 ng/ml after 36 h. CPZ was administered to 43 schizophrenic patients in one of three fixed doses (200, 400, or 600 mg) according to a double-blind design. Plasma and cerebrospinal fluid (CSF) samples were analysed before and after both 2 and 4 weeks' treatment. The levels of the metabolites were considerably lower as compared to CPZ levels. The same levels were found after 2 and 4 weeks' treatment. There were no sex differences. The levels of CPZ and metabolites presented a weak positive correlation to daily dose but not to dose calculated by mg/kg body weight. Older patients tended to have higher CPZ and metabolite levels. The dose effects were very similar in plasma and CSF and there was a highly significant correlation between CPZ levels in serum and CSF. CSF/plasma ratio for CPZ seems to be an individual factor possibly related to variations in protein-binding in plasma and CSF.
MeSH Terms
- Adult
- Aging
- Chlorpromazine
- Female
- Humans
- Male
- Middle Aged
- Psychotic Disorders
- Sex Factors
- Time Factors
During the period February 1980-March 1982, clinical evaluation was carried out on 23,855 cases given cefmetazole (CMZ) in 3,916 medical treatment centres in Japan. The drug was found to have superior efficacy and to be of value for all age groups, ranging from infants and small children to the elderly, in infections due to Gram-positive cocci, Gram-negative bacilli and anaerobic bacteria sensitive to this drug. Experiments were also conducted to elucidate the mechanism of development of the disulfiram-like reaction found in cephems with a methyltetrazolylthiomethyl group at the 3 position, i.e., cefmetozole (CMZ), cefoperazone (CPZ) and latamoxef (LMOX). These experiments provided clear evidence that the reaction is due to a rise in the blood concentration of acetaldehyde, as a result of inhibition of acetaldehyde dehydrogenase activity caused by these cephems. The extent of increase in the blood concentration of AcH is proportional to the urinary excretion rate of mercaptomethyltetrazole (Me-TZ), being in the order CPZ greater than LMOX greater than CMZ. This order is believed to be due to the extent of distribution in bile by various antibiotics and to their stability in the tissue fluids.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Aldehyde Oxidoreductases
- Animals
- Azoles
- Bacterial Infections
- Cefmetazole
- Cefoperazone
- Cephamycins
- Child
- Child, Preschool
- Chromatography, High Pressure Liquid
- Dogs
- Drug Evaluation
- Ethanol
- Humans
- In Vitro Techniques
- Infant
- Japan
- Macaca fascicularis
- Male
- Middle Aged
- Moxalactam
- Rats
- Rats, Inbred Strains
- Respiratory Tract Infections
- Structure-Activity Relationship
- Tetrazoles