M. Frigo

Increased cytokine release from peripheral blood cells after acute stroke

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-α release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-α release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-α release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorragic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-α production in peripheral blood cells, which are a major source of serum cytokines after stroke.

Thalidomide sensory neurotoxicity: A clinical and neurophysiologic study

The clinical and neurophysiologic data from 65 patients taking thalidomide were reviewed. Thalidomide sensory neurotoxicity was found to be cumulative dose dependent but occurs only when the total dose is relatively high (>20 g). The risk of developing sensory neuropathy is around 10% below this threshold but increases with higher doses.

Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment

Peripheral‐type benzodiazepine receptors were measured in human circulating lymphocytes using 3H‐PK 11195 as specific ligand. In a group of outpatients with anxiety disorders a significant decrease of receptor density (– 37%) was found compared with age‐matched controls. In these patients long‐term diazepam treatment restored binding density to normal levels: the effect persisted after drug withdrawal. Acute i.v. diazepam administration did not change receptor density. The observed receptor changes could reflect a down‐regulation phenomenon and indicate that lymphocyte function reflect central nervous events.

Benzodiazepine receptors and diazepam binding inhibitor: A possible link between stress, anxiety and the immune system

This review summarizes the evidence available on the involvement in stress of different classes of benzodiazepine receptors and their putative endogenous ligand, diazepam binding inhibitor (DBI), with particular reference to their role in modifications of the immune response. The presented data from in vitro, experimental, and clinical studies suggest that benzodiazepine receptors and DBI play a major role in regulating steroid production in both the adrenals and central nervous system, and may be involved in the activation of the hypothalamic-pituitary-adrenal axis in stress response.

Diazepam binding inhibitor (DBI) increases after acute stress in rat

Diazepam binding inhibitor (DBI) acts in brain by binding to GABAA/benzodiazepine receptors (GBR) and to mitochondrial benzodiazepine receptors (MBR). Because DBI acting at MBR, has been shown to be an effector of ACTH-induced steroidogenesis and stress is known to change the level of GBR and MBR, the model of acute noise stress in rats was used to study modifications of DBI and GRB or the content of MBR in various areas of the brain and adrenal gland. It was found that, in the brain of stressed rats, DBI and its processing products (ODN-like immunoreactivity), increased selectively in the hippocampus. This increase in the content of DBI was preceded and followed by a net decrease of GBR and an increase of MBR. Similarly, in adrenal cortex, the content of DBI and MBR increased during the first hour, following acute stress and this increase paralleled the increase in plasma corticosterone. These data suggest that DBI, acting on MBR may regulate steroidogenic function in stress.

Creutzfeldt–Jakob disease with a novel four extra-repeat insertional mutation in the PrP gene

The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.

Characterization of peripheral benzodiazepine receptors in human blood mononuclear cells

In the present study, peripheral-type benzodiazepine receptors in human circulating mononuclear cells were characterized, using [3H]PK 11195 as specific ligand. The specific binding was saturable, with a Bmax of 14 pmol/mg protein and a Kd of 7 nM. The pharmacological characterization, using different displacing drugs, indicated a mitochondrial type of peripheral benzodiazepine receptor since it was not coupled to the GABA receptor and was displaced by protoporphyrin IX. These data indicate that human circulating mononuclear cells possess benzodiazepine recognition sites, similar to non-neuronal receptors. The role of these receptors and possible modifications in different diseases need to be investigated.

Cerebrospinal fluid levels of diazepam‐binding inhibitor in neurodegenerative disorders with dementia

We investigated CSF levels of diazepam-binding inhibitor (DBI), a recently discovered neuropeptide that allosterically modulates GABAergic transmission, in various neurodegenerative disorders with dementia (28 patients with Parkinsons disease, 10 with Alzheimers disease, 7 with Huntingtons chorea). We applied a battery of neuropsychological tests to determine the degree of dementia and to exclude the presence of mood alterations. CSF DBI levels were elevated in parkinsonian subjects with dementia and in patients with Alzheimers disease, but decreased in Huntingtons chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic System.

Acute noise stress in rats increases the levels of diazepam binding inhibitor (DBI) in hippocampus and adrenal gland

We investigated the effect of acute noise-induced stress on the concentrations of diazepam binding inhibitor (DBI) and its processing products in brain regions and adrenal glands of rats. DBI levels in hippocampus began to increase at 15 and 30 min and became significantly higher (+100%) at 90 and 120 min after stress; they returned to normal values at 360 min. While basal DBI levels were similar in the left and right hippocampus, the stress-induced increase of DBI levels was significantly higher in the left compared to the right side. A significant increase was also detected in the adrenals; here, the time course of DBI increase paralleled that of previously reported plasma corticosterone in stressed rats, being significantly higher 30 min after stress, and recovering to normal values at 60 and 90 min. After acute noise-induced stress, no significant change of DBI levels was detectable in cerebral cortex, striatum, hypothalamus and cerebellum. The present study reports for the first time the occurrence of a modification of DBI and its processing products (ODN-like immunoreactivity) in an experimental model of stress, and suggests a role for these neuropeptides in emotional responses.

Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis

Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).