Samir Ahboucha

Papillary tumor of the pineal region.

Primary papillary tumors of the central nervous system are rare. We have encountered a series of six papillary tumors of the pineal region with distinctive features that appear to represent a clinicopathologic entity. The tumors occurred in four women and two men, ranging in age from 19 to 53 years. Imaging studies showed a large well-circumscribed mass in the pineal region. The tumors were characterized by an epithelial-like growth pattern, in which the vessels were covered by a layer of tumoral cells. In papillary areas, the neoplastic cells were large, columnar or cuboidal, with a clear cytoplasm. Nuclei, round or infolded, were found generally at the basal pole of tumoral cells. Immunohistochemically, the tumor cells showed strong staining for cytokeratin, S-100 protein, neuron-specific enolase, and vimentin but only weak or no staining for epithelial membrane antigen and glial fibrillary acid protein. Ultrastructural examination of two cases revealed abundant rough endoplasmic reticulum with distended cisternae filled with secretory product, microvilli, and perinuclear intermediate filaments. The morphofunctional features of these papillary tumors of the pineal region, remarkably uniform within this series, are similar to those described for ependymal cells of the subcommissural organ, and the papillary tumors of the pineal region may be derived from these specialized ependymocytes.

Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with either acute or chronic liver failure. More than two decades ago, the role of altered GABAergic neurotransmission was proposed following evidence of “increased GABAergic tone” in HE. Increased GABAergic tone was based on several observations: (i) Similarity of visual evoked response potential patterns between rabbits with galactosamine-induced fulminant hepatic failure and animals treated with various allosteric agonists of the GABA receptor complex (GRC). (ii) Spontaneous activities of isolated Purkinje neurons from rabbits with galactosamine-induced fulminant hepatic failure are more depressed by GRC modulator compounds compared to normal animals. (iii) Flumazenil, a high selective benzodiazepine antagonist at the GRC, ameliorates behavioral symptoms and EEG activity in some HE patients. Pathophysiological mechanisms put forward to explain increased GABAergic tone in HE include (1) increase in brain GABA content due to increased brain GABA uptake through altered permeability of the blood brain barrier, (2) alteration of the integrity of constituents of the GRC, and (3) increase of endogenous GRC modulators such as benzodiazepines (and more recently neurosteroids) with potent agonist properties at the GRC. Studies performed subsequently excluded alterations of either GABA content or GRC integrity in favor of increased brain concentrations of endogenous agonists. While the role of endogenous benzodiazepines remains controversial, the presence of neurosteroids with GABA agonist properties affords a plausible explanation for increased GABAergic tone in HE.

Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy

Although equation 2 conforms more closely to the classic definition of energy, it should be realized that equation 2 is itself an approximation of the actual total energy. More importantly, TEED is correlated only with battery drain and effective stimulation over a limited range of stimulus parameters. There are published empirical relationships between amplitude and pulse width (PW) described by the strengthduration curve. At narrow PWs, there is an inverse relationship between stimulus intensity and PW at threshold. That is, the threshold stimulus charge is practically constant. In addition, at frequencies below 100Hz, there is an inverse relationship between stimulus intensity and frequency. Namely, frequency times amplitude is practically constant in this frequency range. Considering these two observations together, it appears that TEED using either definition will be approximately constant at threshold levels with narrow PWs in the frequency range below 100Hz. This can be viewed as the “optimal” or minimum value of TEED for this region of stimulus parameters. However, for other stimulus parameters the concept breaks down and any connection between TEED and efficient stimuli is tenuous and difficult to interpret. Concerning the observation on the importance of voltage in our first article, we do not see any artificial conclusion. Indeed, in the first part of the study the voltage was shown to be important but only with high frequency of stimulation, and there was a significant worsening of the tapping with high voltage but low frequency. In our second article, we could not publish all the settings we used for space limitation. When we first started noticing clinically different findings at low and high frequencies, the voltage was kept constant and only the PW was mildly increased. Afterward, we studied several different settings and we confirmed that, with very closely spaced voltages but various frequencies, the effect on chorea and bradykinesia was quite different. In the published assessment, we confirmed the observations made since the beginning, although there was an opposite relationship with the TEED. In conclusion, we apologize for any confusion our nonstandard formula for TEED may have caused. It was used chiefly as a tool for varying stimulus parameters. However, TEED itself seems to be irrelevant in the clinical setting.

Chronic lead intoxication affects glial and neural systems and induces hypoactivity in adult rat

Lead is an environmental toxin and its effects are principally manifested in the brain. Glial and neuronal changes have been described during development following chronic or acute lead intoxication, however, little is known about the effects of chronic lead intoxication in adults. In this study we evaluated immunohistochemically the glial and dopaminergic systems in adult male Wistar rats. 0.5% (v/v) lead acetate in drinking water was administrated chronically over a 3-month period. Hypertrophic immunoreactive astrocytes were observed in the frontal cortex and other brain structures of the treated animals. Analysis of the astroglial features showed increased number of astrocyte cell bodies and processes in treated rats, an increase confirmed by Western blot. Particular distribution of glial fibrillary acidic protein immunoreactivity was observed within the blood vessel walls in which dense immunoreactive glial processes emanate from astrocytes. Glial changes in the frontal cortex were concomitant with reduced tyrosine hydroxylase immunoreactive neuronal processes, which seem to occur as a consequence of significantly reduced dopaminergic neurons within the nucleus of origin in the substantia nigra. These glial and neuronal changes following lead intoxication may affect animal behavior as evidenced by reduced locomotor activity in an open field test. These findings demonstrate that chronic lead exposure induces astroglial changes, which may compromise neuronal function and consequently animal behavior.

Role of Endogenous Benzodiazepine Ligands and Their GABA-A-Associated Receptors in Hepatic Encephalopathy

Benzodiazepine receptor ligands are suggested to play a role in the pathogenesis of hepatic encephalopathy (HE). Accumulation of these ligands in brain was suggested to explain in part the notion of“increased GABAergic tone,” the rational for which aroseinitially from reports of a beneficial effect of the selective benzodiazepine antagonist flumazenil in HE patients. It was suggested on the basis of the effect of flumazenil in human HE that liver failuremay result in alterations of the density and/or affinity of the benzodiazepine-associated GABA-A receptor site. Subsequent controlled-clinical trials showed that fumazenil had a transient beneficial effect in only a subpopulation of HE patients. In contrast to the antagonists, partial inverse agonists of the benzodiazepine receptor have unequivocal beneficial effects on behavioral and electrophysiologicalperformance in all experimental models of HE studied so far. Benzodiazepine-associated GABA-A receptors have consistently been demonstrated to be unaltered in both human and experimental HE. Contrary to initial reports, the so-called “endogenous benzodiazepines” do not appear to be significantly related to the pathogenesis of HE. On the other hand, nonbenzodiazepine GABA-A receptor complex modulators, such as neurosteroids, recently identified in brain in human and experimental HE, may provide a new mechanistic basis for this disorder and lead to novel treatments for human HE.

The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy

Both acute and chronic liver failure induce cerebral complications known as hepatic encephalopathy (HE) and thought to selectively involve brain astrocytes. Alterations of astrocytic-neuronal cross talk occurs affecting brain function. In acute liver failure, astrocyte undergo swelling, which results in increased intracranial pressure and may lead to brain herniation. In chronic liver failure, Alzheimer-type II astrocytosis is a characteristic change. Neurosteroids (NS) synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) are suggested to play a role in HE. NS bind and modulate different types of membrane receptors. Effects on the gamma amino butyric acid (GABA)-A receptor complex are the most extensively studied. For example, the NS tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of GABA-A receptors. As a consequence of modulation of these receptors, NS are well-known to modulate inhibitory neurotransmission in the central nervous system. Some NS bind to intracellular receptors, and in this way may also regulate gene expression. In HE, it has been well documented that neurotransmission and gene expression alterations occur during the progression of the disease. This review summarizes findings of relevance for the involvement of NS in human and experimental HE.

An interaction between benzodiazepines and neuroactive steroids at GABAA receptors in cultured hippocampal neurons

Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE. In the present study, we determined the effect of the benzodiazepine partial inverse agonist, Ro15-4513, and the benzodiazepine antagonist, flumazenil on modulation of the GABA(A) mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 microM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 microM). In contrast, flumazenil (10 microM) had no effect on the ability of allopregnanolone to potentiate GABA(A) currents but it blocked the effects of Ro15-4513. The frequency of spontaneous synaptic activity was significantly reduced in the presence of allopregnanolone (0.1 microM) from 1.5+/-0.7 to 0.1+/-0.04Hz. This action was partially reversed by Ro15-4513 (10 microM) but was not significantly influenced by flumazenil (10 microM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA(A) receptors. Our results may provide a rational basis for the use of benzodiazepine inverse agonists in the management and treatment of hepatic encephalopathy in patients with liver failure.

Increased Brain Concentrations of Endogenous (Non-benzodiazepine) GABA-A Receptor Ligands in Human Hepatic Encephalopathy

It has been suggested that alterations of GABAergic neurotransmission are implicated in the pathophysiology of hepatic encephalopathy (HE). Increased concentrations of endogenous benzodiazepines with positive allosteric modulatory properties at the GABA-A receptor complex were proposed as a pathophysiological mechanism to explain increased GABAergic tone in HE. However, results of controlled trials with benzodiazepine receptor antagonists have yielded equivocal results and increases in benzodiazepine levels in body fluids of cirrhotic patients were suggested to be largely accounted for by previous pharmaceutical benzodiazepine intake. In the present study the issue of benzodiazepine receptor ligands in brains of cirrhotic patients, and their contribution to alterations of GABA-A receptor complex in HE are addressed. “Benzodiazepine-like” ligands were present in trace amounts in autopsied brain tissue from control subjects (0.2 ± 0.2 ng/g tissue), and from cirrhotic patients not previously exposed to benzodiazepine medication (0.8± 0.4 ng/g tissue). In contrast, these ligands accumulate in brain extracts from cirrhotic patients previously exposed to benzodiazepines by up to 200-fold (161.5± 93.2 DE ng/g tissue). Brain extracts from cirrhotic patients increased the binding of the GABA-A receptor agonist [3H]muscimol. This increase was minimal with brain extracts from controls (6.8± 2.8%), but was significant with brain extracts from cirrhotic patients without (29.4± 2.7%), or with (55.1± 7.6%) previous exposure to benzodiazepines. Addition of flumazenil, a selective benzodiazepine receptor antagonist did not significantly modify the increase of [3H]muscimol binding by brain extracts from patients without prior exposure to benzodiazepines and only partially inhibited the increase of [3H]muscimol binding in presence of brain extracts from cirrhotic patients previously exposed to benzodiazepines. These findings suggest the presence of nonbenzodiazepine substances (possibly neurosteroids) with positive allosteric modulatory properties at the GABA-A receptor complex in brain in hepatic encephalopathy.

Aluminum affects glial system and behavior of rats

Aluminum (Al) has been associated with neuronal dysfunction. These neuronal changes may involve glial alterations. We intend to evaluate the consequence of Al on the glial system and the behavior of rats exposed chronically to 0.3% of aluminum chloride in drinking water during 4 months in adulthood (A) or since intra-uterine age (IU); animals from this latter group were sacrificed at four months of age. Our data show an intense glial fibrillary acidic protein (GFAP)-immunoreactivity with a high density of astrocytes in both treated groups compared with controls. However, in IU rats, astrocytes display prominent glial cell bodies and processes. A and IU rat groups perform a significantly reduced locomotor activity. However, using the dark/light box test, the IU rats prefer to spend more time in the enlightened compartment compared to other groups. Behavioral and glial changes caused by Al exposure bring support for the role of Al in brain dysfunction involving glial alterations.

Effects of chronic lead intoxication on rat serotoninergic system and anxiety behavior.

Chronic lead exposure has been shown to produce behavioral disturbances in human and animal models. These disturbances are associated with alterations in monoaminergic neurotransmission in the central nervous system (CNS), some of which have been attributed to serotonin (5-HT). This study was undertaken to investigate the chronic effects of lead exposure on the serotoninergic system in the dorsal raphe nucleus (DRN) and the consequences of its toxicity on rat behavior. Adult male Wistar rats were chronically exposed for 3 months to 0.5% lead acetate in drinking water. The serotoninergic system was evaluated using immunohistochemistry and the anxiety behavior was assessed by the light/dark box test. The results show that chronic lead exposure induces a significant increase of blood and brain lead levels in treated rats compared with controls. The density of the immunoreactive serotoninergic cell bodies was significantly higher in treated rats in all parts of the DRN. Assessment of animal behavior using the light/dark box test showed that lead-treated rats spent significantly more time in the light chamber compared with controls (P=0.001). These findings suggest that lead exposure may possibly induce increased anxiety as a consequence of changes in neuronal 5-HT content in the DRN.