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Transforming Growth Factors β1 and β2 in the Cerebrospinal Fluid of Chronic Schizophrenic Patients
Abstract
Transforming growth factor betas (TGFβs) are potent immunosuppressive molecules released in the brain after injury. We hypothesized that TGFβ levels in cerebrospinal fluid (CSF) of schizophrenic patients would be altered because TGFβ can influence neural cell adhesion moelecule (N-CAM) expression in vitro. The levels of TGFβ1 and β2 in CSF of patients with schizophrenia and normal controls measured by ELISA showed no differences. There was evidence that the stability of TGFβ in CSF may be altered in schizophrenia. For a limited sample, TGFβ1 and N-CAM concentrations were significantly correlated in normal patients (r = 0.98) but not in schizophrenics. The results do not support an active neurodegeneration or anti-inflammatory response in the central nervous system, which is reflected in the CSF of chronic schizophrenics. © 1997 American College of Neuropsychopharmacology [Neuropsychopharmacology 16:83–87,1997]
... Neurotransmission [200] Nerve growth factor Cell proliferation and survival of neuroepithelium [201] Reelin Brain development [202] Retinoic acid Differentiation of neuroepithelium [203] Shh Differentiation, proliferation, and survival of neuroepithelium [204] SCO-spondin Differentiation, proliferation, and survival of neuroepithelium [24,25,205] Transforming growth factor β1-β2 Regeneration and pathological processes [206,207] Wnts (Wnt4, 5A) Differentiation and proliferation of neuroepithelium, brain morphogenesis [109,191,208,209] ...
Cerebrospinal fluid is a clear fluid that occupies the ventricular and subarachnoid spaces within and around the brain and spinal cord. Cerebrospinal fluid is a dynamic signaling milieu that transports nutrients, waste materials and neuroactive substances that are crucial for the development, homeostasis and functionality of the central nervous system. The mechanisms that enable cerebrospinal fluid to simultaneously exert these homeostatic/dynamic functions are not fully understood. SCO-spondin is a large glycoprotein secreted since the early stages of development into the cerebrospinal fluid. Its domain architecture resembles a combination of a matricellular protein and the ligand-binding region of LDL receptor family. The matricellular proteins are a group of extracellular proteins with the capacity to interact with different molecules, such as growth factors, cytokines and cellular receptors; enabling the integration of information to modulate various physiological and pathological processes. In the same way, the LDL receptor family interacts with many ligands, including β-amyloid peptide and different growth factors. The domains similarity suggests that SCO-spondin is a matricellular protein enabled to bind, modulate, and transport different cerebrospinal fluid molecules. SCO-spondin can be found soluble or polymerized into a dynamic threadlike structure called the Reissner fiber, which extends from the diencephalon to the caudal tip of the spinal cord. Reissner fiber continuously moves caudally as new SCO-spondin molecules are added at the cephalic end and are disaggregated at the caudal end. This movement, like a conveyor belt, allows the transport of the bound molecules, thereby increasing their lifespan and action radius. The binding of SCO-spondin to some relevant molecules has already been reported; however, in this review we suggest more than 30 possible binding partners, including peptide β-amyloid and several growth factors. This new perspective characterizes SCO-spondin as a regulator of cerebrospinal fluid activity, explaining its high evolutionary conservation, its apparent multifunctionality, and the lethality or severe malformations, such as hydrocephalus and curved body axis, of knockout embryos. Understanding the regulation and identifying binding partners of SCO-spondin are crucial for better comprehension of cerebrospinal fluid physiology.
Psychotic disorders are severe mental disorders with poorly understood etiology. Biomarkers in the cerebrospinal fluid (CSF) could provide etiological clues and diagnostic tools for psychosis; however, an unbiased overview of CSF alterations in individuals with psychotic disorders is lacking. The objective of this study was to summarize all quantifiable findings in CSF from individuals with psychotic disorders compared to healthy controls (HC). Studies published before January 25th, 2023 were identified searching PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO. Screening, full-text review, data extraction, and risk of bias assessments were performed by two independent reviewers following PRISMA guidelines. Findings in patients and healthy controls were compared and summarized using random-effects analyses and assessment of publication bias, subgroup and sensitivity analyses were performed. 145 studies, covering 197 biomarkers, were included, of which 163 biomarkers have not previously been investigated in meta-analyses. All studies showed some degree of bias. 55 biomarkers measured in CSF were associated with psychosis and of these were 15 biomarkers measured in ≥2 studies. Patients showed increased levels of noradrenaline (standardized mean difference/SMD, 0.53; 95% confidence interval/CI, 0.16 to 0.90) and its metabolite 3-methoxy-4-hydroxyphenylglycol (SMD, 0.30; 95% CI: 0.05 to 0.55), the serotonin metabolite 5-hydroxyindoleacetic acid (SMD, 0.11; 95% CI: 0.01 to 0.21), the pro-inflammatory neurotransmitter kynurenic acid (SMD, 1.58; 95% CI: 0.34 to 2.81), its precursor kynurenine (SMD,0.99; 95% CI: 0.60 to 1.38), the cytokines interleukin-6 (SMD, 0.58; 95% CI: 0.39 to 0.77) and interleukin-8 (SMD, 0.43; 95% CI: 0.24 to 0.62), the endocannabinoid anandamide (SMD, 0.78; 95% CI: 0.53 to 1.02), albumin ratio (SMD, 0.40; 95% CI: 0.08 to 0.72), total protein (SMD, 0.29; 95% CI: 0.16 to 0.43), immunoglobulin ratio (SMD, 0.45; 95% CI: 0.06 to 0.85) and glucose (SMD, 0.48; 95% CI: 0.01 to 0.94). Neurotensin (SMD, -0.67; 95% CI: -0.89 to -0.46) and γ-aminobutyric acid (SMD, -0.29; 95% CI: -0.50 to -0.09) were decreased. Most biomarkers showed no significant differences, including the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. These findings suggest that dysregulation of the immune and adrenergic system as well as blood-brain barrier dysfunction are implicated in the pathophysiology of psychotic disorders.
Clinical and pre-clinical studies have demonstrated an important role of neuroinflammation in the etiology of schizophrenia. While the underlying mechanisms remain poorly understood, there are some studies demonstrating an association between maternal immune activation and behavioral changes in adult offspring and identifying early life infection as a trigger for schizophrenia; in addition, inflammatory markers were found to be increased in the schizophrenic post-mortem brain. During maternal immune activation, pro-inflammatory mediators such as cytokines, chemokines, antibodies, and acute-phase proteins are released in the maternal bloodstream, thus increasing the permeability of the placental barrier and the fetal blood-brain barrier, allowing the inflammatory mediators to enter the fetal brain. In the central nervous system (CNS), these pro-inflammatory mediators are able to activate microglial cells that can release pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6. As a consequence, circulating immune cells may infiltrate the brain, increasing cytokine levels and releasing antibodies that aggravate the neuroinflammation. Neuroinflammation may affect processes that are pivotal for normal brain maturation such as myelination, synaptic pruning, and neuronal remodeling. Microglial cell activation and pro-inflammatory mediators have been extensively studied in schizophrenic post-mortem brain samples. Some results of these investigations demonstrated an increase in microglial activation markers, cytokines, and chemokines in post-mortem brain samples from individuals with schizophrenia. In contrast, there are studies that have demonstrated low levels of microglial activation makers in the schizophrenic post-mortem brain. Thus, based on the important role of neuroinflammation as a trigger in the development of schizophrenia, this chapter aims (1) to enumerate evidence of neuroinflammation and microglial activation from pre-clinical schizophrenia models, (2) to show links between schizophrenia and neuroinflammation in clinical studies, and (3) to identify mechanisms by which microglial activation may influence in the development of schizophrenia.
Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942–2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.62; 95% CI 0.24–1.00) and affective disorders (4 studies [302 patients]; SMD = 0.43; 95% CI 0.25–0.61, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.38; 95% CI 0.12–0.65, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.77; 95% CI 0.36–1.18, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.60; 95% CI 0.23–0.98), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = −0.62; 95%CI −1.13 to −0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.38; 95% CI 0.02–0.74; I2 = 64%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17–0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2–6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.
Few studies have been conducted examining cytokines in cerebrospinal fluid of patients compared to healthy volunteers. The goals of this study were: 1) to report original data detailing cytokine levels in the cerebrospinal fluid (CSF) of 10 patients with a schizophrenia spectrum disorder (SSD) diagnosis and 10 healthy controls and 2) to conduct a meta-analysis of the available data on cytokine levels in the CSF of patients with SSD compared to healthy controls, including our new data. Cytokine concentrations were measured using the Q-plex Human Cytokine Screen array in CSF of 10 patients with SSD and 10 healthy volunteers. For the meta-analysis, an electronic PubMed and Google Scholar search without restrictions was conducted for articles that reported on cytokine levels in CSF in patients with an SSD compared to healthy controls. Our original data revealed statistically significant increases in levels of interleukin-8 (IL-8) and interleukin-1 beta (IL-1β) in the CSF of patients with an SSD compared to healthy volunteers. Our meta-analysis showed statistically significant increases in interleukin-6 (IL-6) and IL-8 in patients compared to healthy volunteers. Effect sizes between treated and untreated patients for IL-6 were of similar magnitude. However, IL-6 levels were higher in early stage schizophrenia patients compared to chronic schizophrenia patients. Studies with larger sample sizes, comprehensive assessments and ideally in the context of a randomized controlled intervention to minimize the impact of confounding factors are needed to fully understand the role of cytokines and inflammatory markers in the pathophysiology and treatment of schizophrenia.
Introduction:
Schizophrenia, bipolar disorder, and major depressive disorder (MDD) have all been associated with immune system dysfunction, including aberrant cerebrospinal fluid (CSF) levels of cytokines and tryptophan catabolites; however, the pattern of alterations has not been compared across disorders. We performed a meta-analysis of CSF cytokine and tryptophan catabolites in patients with these major psychiatric disorders.
Methods:
Articles were identified by searching Pub Med, PsycInfo, and Web of Science, and the reference lists of these studies.
Results:
Twenty-eight studies met the inclusion criteria (16 schizophrenia, 4 bipolar disorder, and 9 MDD). CSF levels of IL-1β and kynurenic acid were significantly increased in patients with schizophrenia and bipolar disorder compared to healthy controls (P < .001). CSF levels of IL-6 and IL-8 were significantly increased in patients with schizophrenia and MDD compared to healthy controls (P ≤ .013).
Discussion:
There is preliminary evidence for similarities in the pattern of CSF cytokine and tryptophan catabolite alterations across major psychiatric disorders, although findings must be interpreted with caution in light of small numbers of studies/subjects. Many CSF alterations are also concordant with those in the peripheral blood, particularly for schizophrenia. Findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.
The purpose of this study was to elucidate the pathophysiology of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine, transforming growth factor-ß 1 (TGFß 1 ), in the central nervous system (CNS).
Galbreath and colleagues generated transgenic mice that overexpressed TGFß 1 in the CNS in an effort to examine the role of this cytokine in the astrocytic response to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that were heterozygous for the transgene with wild-type females.
One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, which was characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and ultimately death. The presence of the TGFß 1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample cuts of tail. The animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develope hydrocephalus.
Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemistry. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls, and it demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFß 1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the TGFß 1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed the occurrence of overexpression of the TGFß 1 cytokine in brain, cerebrospinal fluid, and plasma.
The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFß 1 in the CNS causes hyrdocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and additionally, should help in the search for novel treatment strategies.
Objectives:
Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. An etiopathological role for immunologic abnormalities in schizophrenia was hypothesized. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, antiinflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Transforming Growth Factor Beta 1 (TGFB1) signaling is critical for many biological processes, including proliferation, development, differentiation and regeneration. Multiple members of the TGFB1 superfamily play a role in the developing nervous system and are regulated by neuronal activity. We conducted family-based study to assess whether TGFB1 gene is associated with susceptibility to schizophrenia in Polish population.
Methods:
Two functional polymorphisms: rs1800469 (C-509T) and rs1800470 (T869C) of TGFB1 gene were analyzed within a group of 147 trios (patients diagnosed with schizophrenia and their healthy parents) using Transmission Disequilibrium Test (TDT).
Results:
No association of these polymorphisms with schizophrenia was found in Polish population.
Conclusions:
Further studies on larger groups along with correlation with circulating protein levels are needed.
The phenomenological uniqueness of each patient with schizophrenia is determined by complex symptomatology, particularly the overlapping of symptoms and their prominence in certain phases of this mental disorder. Establishing biological markers is an important step in the further objectivisation and quantification of schizophrenia. Identifying the cytokine profiles that precede a psychotic episode could direct the strategies for relapse prevention and be useful in predicting disease progression and treatment response. In the context of infl ammation, TGF-β exerts potent anti-inflammatory and immunosuppressive functions by inhibiting pro-inflammatory cytokine synthesis, but it can also have pro-inflammatory functions through its stimulatory effects on inflammatory Th17 cells. It has been shown that the T helper cell type-1 and type-17 responses are reduced and type-2 response is increased in patients with schizophrenia. Both data from the literature and our results also indicate the presence of an anti-inflammatory response through production of the TGF-β regulatory cytokine. A meta-analysis of plasma cytokine alterations suggested that TGF-β is the state marker for acute exacerbation of schizophrenia, and we showed that TGF-β can also be a valuable marker for psychosis. Hyperactivity of TGF-β signalling pathways in schizophrenia may be both a neuroprotective mechanism and a possible therapeutic target.
Objective:
Schizophrenia is a chronic psychotic disorder in which genetics and environmental factors such as infection and the corresponding immune response play a role in the etiopathogenesis. The aim of this study was to compare some immune factors such as nuclear factor-B (NF-B) activation, myeloperoxidase (MPO), the anti-inflammatory cytokine interleukin-4 (IL-4), and regulatory cytokine transforming growth factor- (TGF-) in schizophrenia patients and an age- and gender-matched control group.
Method:
Plasma levels of IL-4, TGF-, MPO, and NF-B activation in 20 subjects with treatment-resistant schizophrenia and 20 age- and gender-matched healthy controls were analyzed. Disease severity was evaluated using the Brief Psychiatric Rating Scale (BPRS).
Results:
Plasma TGF- levels were found to be significantly lower and NF-B to be significantly higher in antipsychotic treatment-resistant schizophrenia patients than in controls in this study. No significant differences were found between the patient and control groups for serum IL-4 and MPO levels.
Conclusion:
The low TGF- level in treatment-resistant schizophrenia patients in the symptom exacerbation period indicates that there is inadequate Th1/Th2 balance. Large-scale studies are required to investigate whether this is responsible for resistance in schizophrenia. The fact that the increase in NF-B that we found in treatment-resistant schizophrenia patients in this study has also been reported in the first attack in untreated schizophrenia patients in previous studies indicates that NF-B plays a role in the disorder's physiopathology from the beginning.
Interleukin (IL)-1 beta and IL-6 levels in plasma and cerebrospinal fluid (CSF) of 14 medicated schizophrenic patients and 9 controls were measured by enzyme-linked immunosorbent assay. Almost no detectable levels of IL-6 in plasma or CSF from patients or controls were found. With regard to mean plasma or CSF levels of IL-1 beta there were no statistically significant differences between the two groups investigated. The dose of neuroleptic medication the patients used did not correlate with the IL-1 beta plasma levels. For the whole series of subjects (n = 23) or for the schizophrenic patients (n = 14) no correlation between the plasma and CSF levels of IL-1 beta was found.
Abstract The beta transforming growth factors (TGF-) are suggested to regulate developmental processes since they are distinctly expressed during embryogenesis and exert pleiotropic effects on cell growth and differentiation. In the present study the expression of TGF- isoforms was investigated in the postnatal and adult mouse brain. As shown by in situ hybridization, TGF-2 was expressed in the choroid plexus, hippocampus, dentate gyrus and cerebellar Purkinje neurons, both postnatally and in adults. Furthermore, TGF-2 expression was observed postnatally in immature cerebellar neurons of both the external and internal granule cell layers. In the external granule cell layer, the frequency of TGF-2 transcripts increased until postnatal day 10 and declined thereafter. In contrast to TGF-2, no TGF-1 mRNA was detected in cerebellar granule cells. TGF-3 expression was widely distributed in postnatal brains although at very low levels. The significance of TGF-2 production by cerebellar granule cells was further investigated using cultures of small cerebellar neurons. In these cultures reverse polymerase chain reaction analysis revealed expression of TGF-2 but low or almost undetectable levels of TGF-1 or -3 mRNAs. Likewise, only TGF-2 protein in its latent form was identified in the culture supernatant; the release of TGF-2 was maximal during the second day in vitro. Furthermore, TGF- was found to inhibit the proliferation of cultured small cerebellar neurons. Taken together, these data suggest that TGF-2 is involved in the regulation of postnatal development of the cerebellum.
The development of Candida meningitis in a patient following partial resection of a glioblastoma raised suspicion that transforming growth factor (TGF-beta), an immunosuppressive cytokine known to be produced by this tumor, would be elevated in his cerebrospinal fluid (CSF). By using a highly specific bioassay, the concentration of TGF-beta was found to be 609 pg/mL, which was 10-fold greater than the mean CSF TGF-beta value in control subjects with no neurologic disease. Increased CSF TGF-beta levels were also detected in patients with other central nervous system (CNS) diseases: malignancies and AIDS dementia complex. These findings suggest that TGF-beta may play an immunopathogenetic role in the CNS.
Transforming growth factor (TGF)-beta 1 content was measured for the first time in the brain (caudate nucleus, putamen, and cerebral cortex) and in ventricular cerebrospinal fluid (VCSF) from control and parkinsonian patients by a sandwich enzyme immunoassay. The concentrations of TGF-beta 1 were significantly higher in the dopaminergic striatal regions in parkinsonian patients than those in controls, but were not significantly different in the cerebral cortex between parkinsonian and control patients. Furthermore, the concentrations of TGF-beta 1 in VCSF were significantly higher in parkinsonian patients than those in non-parkinsonian control patients. Since TGF-beta 1 has potent regulatory activity on cell growth, these results suggest that TGF-beta 1 may have some significant modulatory role in the process of neurodegeneration in Parkinson's disease.
The expression of neural cell adhesion molecule (NCAM) by olfactory keratin+ basal cells was investigated in vitro. In primary cultures from embryonic day 14.5 or newborn mouse olfactory epithelium (OE), flat keratin+ basal cells were negative for NCAM-immunostaining. Transforming-growth factor-beta 1, beta 2 (TGF-beta 1, beta 2) or a high concentration of Ca2+ induced these cells to express NCAM. We obtained a cell line, designated DBC1.2, from embryonic day 14.5 mouse OE. All DBC1.2 cells were positive for keratin-immunostaining, whereas nearly all cells were negative for NCAM-immunostaining. Therefore, DBC1.2 cells seemed to derive from dark basal cells. DBC1.2 cells were also induced to express NCAM by the treatment with TGF-beta s or a high Ca2+ concentration. Western blotting revealed that the components of the NCAM expressed by DBC1.2 were 120 and 140 kDa, but not 180 kDa, isoforms. Since NCAM is the cell adhesion molecule mainly expressed in nervous tissues, these results suggest a cell lineage relationship or interactions between olfactory keratin+ basal cells and olfactory sensory neurons.
The olfactory epithelium (OE) is unique in the mammalian nervous system as a site of continual neurogenesis. Though many studies have described this process in vivo and olfactory neurogenesis can be demonstrated in vitro, the specific factors that modulate this process have not been defined. Noting the common ectodermal origin and structural similarity between the OE and epidermis, peptide factors known to modulate epidermal differentiation were tested in OE cultures. Our results demonstrate that EGF acts as a mitogen for the basal cells that give rise to olfactory neurons and that transforming growth factor-beta s (TGF-beta s) promote neurogenesis. Using a neutralizing antibody, we show that it is likely that the endogenous neurogenic factor is TGF-beta 2, or a very closely related factor.
Transforming growth factors beta are multifunctional proteins and regulators of cell proliferation and differentiation. Transforming growth factor-beta s have the capacity to rescue adult neurons from ischemia- and glutamate-induced cell death and are prominent in the embryonic and adult brain including striatum and substantia nigra. In the present study we show that transforming growth factors-beta 1, -2, and -3 promote, in a dose-dependent fashion, in vitro survival of tyrosine hydroxylase-immunoreactive dopaminergic neurons isolated from the embryonic rat mesencephalon floor. The magnitude of the effect, which was half-maximal at a concentration of 20 pM, was identical for all three transforming growth factor-isoforms and matched that of fibroblast growth factor-2. Unlike fibroblast growth factor-2, however, transforming growth factor-beta s did not increase numbers of astroglial cells visualized by using antibodies to glial fibrillary acidic protein, and had no effect on cell proliferation monitored by incorporation of BrdUrd. Transforming growth factor-beta s were significantly more potent than fibroblast growth factor-2 in protecting dopaminergic neurons against N-methyl-4-phenylpyridinium ion toxicity. RT-PCR analysis indicated that the effect of transforming growth factor-beta s is not mediated by glial cell-derived neurotrophic factor, which was not detectable in cultures at various time points. On the other hand transforming growth factor-beta 2 mRNA could be detected in freshly isolated and cultured mesencephalic cells, and its immunoreactivity has also been demonstrated in the embryonic day 14 mesencephalon floor. We conclude that transforming growth factor-beta has trophic and protective effects on developing dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Although the pathogenesis of schizophrenia is unknown, there are data which indicate that the disease may be due to neurodevelopmental disturbances. Cell recognition molecules such as N-CAM and L1 antigen are involved in cell-cell interactions during development and in plasticity of the nervous system and could therefore be altered in relation to ongoing or established pathological processes. Using the Western blot technique, we found significant increases in N-CAM immunoreactive proteins and decreases in L1 antigen in the CSF of schizophrenic patients as compared to normal controls. The decrease in L1 antigen was observed in the 140-kDa band, and N-CAM was increased only in the 120-kDa band. The 120-kDa band of N-CAM and the 140-kDa band of L1 antigen were prominent components of CSF, but in serum these bands were minor or not detectable. Neuroleptic treatment did not significantly change either N-CAM or L1 antigen concentrations in CSF. It is possible that these CSF proteins are derived from CNS cells as secreted soluble N-CAM isoforms and L1 peptides. Our results suggest the possibility of a specific pattern of abnormal cellular function in the CNS in schizophrenia.
As part of a multidimensional study of cerebrospinal fluid biogenic amine metabolites in schizophrenia, the relationship between neurochemical measures and psychopathology assessed using the Psychiatric Symptom Assessment Scale (PSAS) was analyzed. In a group of 20 unmedicated patients, 3,4-dihydroxyphenylacetic acid (DOPAC) was a predictor of symptom severity in a stepwise multiple regression model. Values of 3-hydroxykynurenine and metanephrine in the unmedicated state predicted clinical response in a stepwise multiple regression model, as measured by improvement in PSAS mean item score following 6 weeks on a standard dose of neuroleptic. In a subgroup of 14 patients in whom both off- and on-medication concentrations of cerebrospinal fluid biogenic amines and metabolites were measured, change in 3-hydroxykynurenine predicted clinical outcome in a multiple regression model. These findings point toward the need to examine the role of the kynurenine pathway of tryptophan metabolism in the pathophysiology of schizophrenia.