Nerve growth factor serum levels in treatment-resistant schizophrenic patients following electroconvulsive therapy.

BACKGROUND: Electroconvulsive Therapy (ECT) has been widely applied to treat schizophrenia (SCZ) in the presence of resistance to pharmacotherapy. The mechanism of action of ECT in schizophrenia has not been fully clarified, though its intrinsic mechanism presents analogies with some neurobiological processes mediated by nerve growth factor (NGF). OBJECTIVES: The aim of this study was to investigate in patients with treatment-resistant schizophrenia (TRS) the effect of ECT on acute and long-term NGF serum levels and the association with the clinical outcomes. METHODS: Twelve male inpatients with TRS underwent eight sessions of ECT. Blood samples were collected during the first and the eighth ECT at the following time points: 5 minutes before the induction of seizure and then at 0, 5, 15 and 30 minutes after seizure. RESULTS: Following ECT treatment, a substantial clinical improvement in symptom severity was indicated by a significant reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscales scores. Even though the baseline NGF levels showed an increase over time, there were no statistical differences in NGF at time 0 at the first and the eighth ECT session. Furthermore, no correlation was observed between the severity of schizophrenic symptoms and NGF levels. CONCLUSIONS: This is the first study addressing peripheral NGF during ECT treatment in TRS, as well as the first study in which NGF has been evaluated in different ECT sessions at various time points. These findings may potentiate the knowledge about the neurotrophic effects of ECT and the role of NGF in synaptic plasticity related to possible mechanisms of schizophrenia treatment.

Neurological Soft Signs and Corpus Callosum morphology in schizophrenia.

OBJECTIVE: Neurological Soft Signs (NSS) have been found to be more prevalent in schizophrenic patients. A breakdown in intracortical functional connectivity, including interhemispheric communication, has been suggested in the pathogenesis of schizophrenia. Indeed, problems with interhemispheric information transfer via the Corpus Callosum (CC) have been documented in schizophrenics. Our study goal was to relate NSS to CC morphology. METHODS: CC Magnetic Resonance Imaging (MRI) measurements were collected from 29 right-handed male schizophrenia inpatients. NSS were evaluated employing the Neurological Evaluation Scale (NES). We examined the scores obtained from the NES total and the three NES subscales: Integrative Sensory Function, Motor Coordination, and Sequencing Of Complex Motor Acts. We compared CC morphology of patients with "high" NSS with that of patients with "low" NSS. Correlation analyses were performed to further clarify the relationship between CC size, NSS, and total lifetime antipsychotic consumption. RESULTS: Patients with "high" scores at the Sequencing Of Complex Motor Acts subscale showed a smaller CC rostral body, whereas patients with "high" scores at the Integrative Sensory Function subscale showed a smaller CC splenium. For both the NES total and the Sequencing Of Complex Motor Acts subscale, "high" scores were accompanied by an increase of the CC genu. Correlation analyses revealed a significant inverse correlation between the CC rostral body size and the Sequencing Of Complex Motor Acts subscale score. In addition, a significant positive correlation was shown between the CC genu size and both the NES total and the Sequencing Of Complex Motor Acts subscale scores. The presence of NSS and the accompanying CC structural abnormalities were independent on antipsychotic treatment. CONCLUSIONS: Our data provide evidence for an association between NSS and CC morphology and further support the hypothesis of a disturbed interhemispheric functional connectivity in schizophrenia.

Ibuprofen and lipoic acid diamide as co-drug with neuroprotective activity: pharmacological properties and effects in beta-amyloid (1-40) infused Alzheimer's disease rat model.

Both oxidative stress and inflammation are elevated in brains of Alzheimer's disease patients, but their pathogenic significance still remains unclear. Current evidence support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease, and ibuprofen has the strongest epidemiological support. In the present work our attention was focused on (R)-alpha-lipoic acid considered as a potential neuroprotective agent in Alzheimer's disease therapy. In particular, we investigated a new co-drug (1) obtained by joining (R)-alpha-lipoic acid and ibuprofen via a diamide bond, for evaluating its potential to antagonize the deleterious structural and cognitive effects of beta-amyloid (1-40) in an infused Alzheimer's disease rat model. Our results indicated that infusion of beta-amyloid (1-40) impairs memory performance through a progressive cognitive deterioration; however, ibuprofen and co-drug 1 seemed to protect against behavioural detriment induced by simultaneous administration of beta-amyloid (1-40) protein. The obtained data were supported by the histochemical findings of the present study: beta-amyloid protein was less expressed in 1-treated than in ibuprofen and (R)-alpha-lipoic acid alone-treated cerebral cortex. Taken together, the present findings suggest that co-drug 1 treatment may protect against the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid (1-40) in rats. Thus, co-drug 1 could prove useful as a tool for controlling Alzheimer's disease-induced cerebral amyloid deposits and behavioural deterioration.

Toll-like receptor-2 agonist functionalized biopolymer for mucosal vaccination.

The objective of this study was to provide a new water-soluble chitosan derivative being functionalized with a Toll-like receptor-2 (TLR-2) agonist. At first, we synthesized the water-soluble TLR-2 agonist omega-amido-[N(alpha)-palmitoyl-oxy-S-[2,3-bis(palmitoyl-oxy)-(2R)-propyl]-[R]-cysteinyl]-alpha-amino poly(ethylene glycol) (Pam(3)Cys-PEG-NH(2)), which was characterized by (1)H and (13)C NMR as well as mass spectroscopy. Secondly, Pam(3)Cys-PEG-NH(2) was then successfully grafted to 6-O-carboxymethyl-N,N,N-trimethyl chitosan polymers (CM-TMC) using EDC/NHS as condensing agents. The copolymer was analysed by means of (1)H and (13)C NMR and FTIR spectroscopy. (13)C NMR spectroscopy did not deliver evidence that an amide bond was formed between CM-TMC and Pam(3)Cys-PEG-NH(2). However, (1)H NMR and FTIR spectroscopy demonstrated clearly that successful grafting took place. Based upon these results, this new TLR-2 functionalized biopolymer merits further investigations as material for vaccine delivery systems.

Influence of obstetric complication severity on brain morphology in schizophrenia: an MR study.

INTRODUCTION: The purpose of this study was to determine if a causal relationship exists between obstetric complications (OCs) severity and linear magnetic resonance (MR) measurements of brain atrophy in patients with schizophrenia. MATERIALS AND METHODS: Linear measurements of ventricular enlargement (bifrontal span, Evans ratio, and bicaudate ratio) and hippocampal atrophy (interuncal distance) were completed on MR images obtained in 47 patients with schizophrenia. Regression analysis was used to look at association with OCs severity, assessed by the "Midwife protocol" of Parnas and colleagues. The relationship between MR measurements and phenomenologic variables such as age at onset, illness duration, and exposure to antipsychotic medications was explored. The relationship between MR measurements, OCs severity, and symptom presentation was also investigated. RESULTS: OCs severity was significantly associated with MR measurements of ventricular enlargement (bifrontal span, Evans ratio). As the severity of OCs increased, bifrontal span and Evans ratio increased. This effect was independent of age at onset, illness duration, or even antipsychotic treatment. Interestingly, bifrontal span, Evans ratio, and OCs severity score all showed a significant positive correlation with hallucinatory symptomatology. CONCLUSION: Although confirmatory studies are needed, our findings would support the idea that environmental factors, in this case severe OCs, might partly contribute to ventricular abnormalities in schizophrenia.

Brain abnormalities in schizophrenia. A qualitative comparative study of schizophrenic patients and control individuals assessed by magnetic resonance imaging.

The present study examined, by means of Magnetic Resonance Imaging (MRI), the qualitative brain abnormalities in a group of 58 schizophrenic patients compared to a group of 58 matched control individuals. The possible relationships between these abnormalities and the demographic and clinical features of the participants in the study were also investigated. Schizophrenic patients presented a higher percentage of bland-moderate enlargement of the periencephalic-subarachnoid spaces (p=0.01) and a widespread cerebral atrophy, the latter below the threshold of significance (p=0.06). In the subset of patients with ventricular asymmetry (right larger than left) the age was significantly lower compared to the age of patients without this abnormality (p=0.04). In the subset of patients with cerebellar cisterns enlargement the age as well as the age of onset was higher in comparison to the one of patients without this abnormality (p=0.02; p=0.006). Taking together with previous studies, these findings underline the importance of qualitative assessment of brain morphology in research and clinical evaluation of patients with schizophrenia.

Ultradian variation of nerve growth factor plasma levels in healthy and schizophrenic subjects.

Some studies in animal models showed that several neurotrophins may be implicated in the regulation of light-dependent suprachiasmatic pacemaker and in other functions implicated in long-term memory acquisition during sleep. However, no data are known about the role played by NGF in ultradian regulation in humans. The aim of this study was to investigate whether or not there is a natural diurnal fluctuation during daytime in healthy and schizophrenic subjects with a normal light/dark cycle. In a sample of 33 subjects (10 male schizophrenics and 23 healthy subjects) an ELISA assay was used to study the ultradian NGF cycle in blood samples at 9.00, 13.00 and 20.00 hours. The study showed an ultradian rhythm of NGF in healthy subjects with a "V" trend: higher at 9:00 and 20:00 and lower at 13:00. We also show significant differences between male and female controls. No NGF ultradian rhythm among schizophrenic patients compared to healthy subjects was found. The results of this study lead to a rhythmic NGF regulation that appears altered in schizophrenics, where higher levels in the morning and lower levels in the evening were observed, compared to the controls, and support the hypothesis of a role played by NGF in schizophrenia.

[Neurotrophic factors and brain damage in hypoxic-ischemic encephalopathy: a role of nerve growth factor?]. / Fattori neurotrofici e danno cerebrale nell'encefalopatia ipossico-ischemica: un ruolo del nerve growth factor?

Hypoxic-ischaemic damage in perinatal brain is a major risk factor of a variety of serious human neurological disorders. The mechanisms leading to neuronal damage and death remain largely unknown, but animal models indicated that cell death via apoptotic mechanism(s) might be one important aspect of these events. Neurotrophic factors are protein molecules produced and released by several tissues which seem to play a crucial role not only in growth, differentiation and function of brain neurons, but also in the mechanisms of neuronal death. Indeed, experiments carried out on animal models support the hypothesis that the neurotrophins NGF and BDNF are able to prevent and/or reduce neuronal death induced by hypoxic-ischaemic events. In this brief review, the established and emerging evidences supporting this hypothesis are presented and discussed.

Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders.

Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients.

Data and hypotheses on the role of nerve growth factor and other neurotrophins in psychiatric disorders.

Nerve growth factor (NGF) was discovered and characterized for its role on the growth, differentiation and maintenance of specific neurons of the peripheral nervous system. Subsequent studies revealed that NGF is synthesized and released within the central nervous system and exerts a trophic and functional role on basal forebrain cholinergic neurons; it is involved in a protective role following brain insults induced by an epileptic status, seizure, as well as surgical and chemical lesions.More recently our collaborative studies provided evidence that NGF is implicated in neurobehavioral response including cerebral alterations associated with psychiatric disorders. In this brief review, ongoing and emerging data are presented and discussed.

Haloperidol administration in humans lowers plasma nerve growth factor level: evidence that sedation induces opposite effects to arousal.

Studies reported in recent years have indicated that the level of nerve growth factor (NGF), in both the brain and in the bloodstream, increases following stressful events and anxiety-associated behaviour. These observations prompted us to investigate whether an anti-arousal drug would induce an opposite effect. We have reported that the administration of haloperidol (HA), a neuroleptic drug clinically used for psychiatric disorders, decreases NGF levels in the hypothalamus of adult male mice. In the present study, we showed that HA reduced the basal NGF plasma levels in 8 neuroleptic-free schizophrenic patients. These observations strengthen the hypothesis that NGF may play a functional role in stress-coping responses.