Neurosteroid-mediated regulation of brain innate immunity in HIV/AIDS: DHEA-S suppresses neurovirulence.

Neurosteroids are cholesterol-derived molecules synthesized within the brain, which exert trophic and protective actions. Infection by human and feline immunodeficiency viruses (HIV and FIV, respectively) causes neuroinflammation and neurodegeneration, leading to neurological deficits. Secretion of neuroinflammatory host and viral factors by glia and infiltrating leukocytes mediates the principal neuropathogenic mechanisms during lentivirus infections, although the effect of neurosteroids on these processes is unknown. We investigated the interactions between neurosteroid-mediated effects and lentivirus infection outcomes. Analyses of HIV-infected (HIV(+)) and uninfected human brains disclosed a reduction in neurosteroid synthesis enzyme expression. Human neurons exposed to supernatants from HIV(+) macrophages exhibited suppressed enzyme expression without reduced cellular viability. HIV(+) human macrophages treated with sulfated dehydroepiandrosterone (DHEA-S) showed suppression of inflammatory gene (IL-1ß, IL-6, TNF-α) expression. FIV-infected (FIV(+)) animals treated daily with 15 mg/kg body weight. DHEA-S treatment reduced inflammatory gene transcripts (IL-1ß, TNF-α, CD3ε, GFAP) in brain compared to vehicle-(ß-cyclodextrin)-treated FIV(+) animals similar to levels found in vehicle-treated FIV(-) animals. DHEA-S treatment also increased CD4(+) T-cell levels and prevented neurobehavioral deficits and neuronal loss among FIV(+) animals, compared to vehicle-treated FIV(+) animals. Reduced neuronal neurosteroid synthesis was evident in lentivirus infections, but treatment with DHEA-S limited neuroinflammation and prevented neurobehavioral deficits. Neurosteroid-derived therapies could be effective in the treatment of virus- or inflammation-mediated neurodegeneration.

Lambda-cyhalothrin alters locomotion, mood and memory abilities in Swiss mice.

Lambda-cyhalothrin (LCT) is a type II pyrethroid widely used in agriculture for plant protection against pests. However, pyrethroids represents a risk for rural female farmworkers, and few studies addressed LCT-behavioural alterations in mice. The present study evaluates the effect of LCT on behaviour of eight weeks aged female mice. Mice were divided into three groups including treated mice that received through gavage (i) 0.5 mg/kg bw and (ii) 2 mg/kg of LCT dissolved in corn oil, and (iii) the vehicle controls. Behavioural tests assess the locomotor activity using open field test, the anxiety by the dark-light box test, the learning memory with novel object recognition test, the memory retention by the elevated plus maze test, and the spatial working memory using the Y-maze test. Subacute treatment with low doses of LCT decreases total distance travelled, induces anxiogenic effect by reducing the time spent in the enlightened compartment, alters memory retention by increasing the latency time, and also affects learning memory by reducing the recognition index parameter. However, LCT does not significantly alter spatial working memory. In conclusion, LCT-treated female mice show an alteration in locomotor activity, mood state and memory abilities probably related to oxidative stress and altered neurotransmission.

The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a serious cerebral complication of both acute and chronic liver failure. In acute liver failure, astrocytes undergo swelling which results in increased intracranial pressure and may lead to brain herniation and death. In chronic liver failure, Alzheimer-type II astrocytosis is the characteristic neuropathologic finding. Patients with liver failure manifest severe alterations of their quality of life including sleep disorders as well as memory, learning, and locomotor abnormalities. Neurosteroids (NS) are synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) and are suggested to play a role in the pathogenesis of HE. NS bind and modulate different types of neural 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 the GABA-A receptor. As a consequence of modulation of these receptors, NS stimulate inhibitory neurotransmission in the CNS, and neuroinhibitory changes including "increased GABA-ergic tone" have been suggested as pathophysiological mechanisms in HE. Moreover, some NS bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins are altered in HE. This review summarizes findings consistent with the involvement of NS in human and experimental HE.

Reduced plasma dehydroepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis.

Fatigue is a common debilitating complication of primary biliary cirrhosis (PBC), the pathophysiologic mechanism of which is poorly understood. Recently, the neuroactive steroid dehydroepinadrosterone sulfate (DHEAS) was reported to be implicated in Chronic Fatigue Syndrome in the absence of liver disease. The present study was undertaken to analyse fatigue scores and their relationship with disease severity and circulating levels of DHEAS as well as its precursors DHEA and pregnenolone in PBC patients with (n=15) or without fatigue (n=10) compared to control subjects (n=11). Fatigue was assessed using the fatigue impact scale (FIS) including cognitive, physical and psychosocial subclasses. Steroids were measured by radioimmunoassay or gas chromatography/mass spectrometry. Plasma concentrations of DHEAS were significantly reduced in PBC patients with fatigue as compared to controls, while those of its precursors DHEA and pregnenolone remained within the control range. Plasma levels of DHEAS in PBC patients were significantly correlated with fatigue severity as reflected by total FIS scores including total (rp=-0.42; p=0.018), as well as the cognitive (rp=-0.37; p=0.03), physical (rp=-0.48; p=0.006) and psychosocial (rp=-0.35; p=0.04) subclasses of fatigue scores. No correlation of fatigue scores was observed with indices of liver function. These findings suggest that reduced levels of the neurosteroid DHEAS may contribute to fatigue in patients with PBC; substitutive therapy using DHEAS or its precursor DHEA could be beneficial in the management of fatigue in patients with low levels of DHEAS.

An interaction between benzodiazepines and neuroactive steroids at GABA A 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 levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma.

It has been suggested that neurosteroids with agonist properties at the central GABA-A receptor are implicated in the pathogenesis of hepatic encephalopathy (HE) in chronic liver disease. In order to address this issue, gas chromatography/mass spectrometry was used to measure the neurosteroids pregnenolone, allopregnanolone, and tetrahydrodeoxycorticosterone (THDOC) in postmortem brain tissue from controls, cirrhotic patients who died without HE, a patient who died in uremic coma, and cirrhotic patients who died in hepatic coma. Exposure of rat cerebral cortical membranes to brain extracts from hepatic coma patients resulted in a 53% (p < 0.001) increase in binding of [3H]muscimol, a GABA-A receptor ligand. Subsequent GC/MS analysis showed that concentrations of the GABA-A receptor agonist neurosteroid allopregnanolone were significantly increased in brain tissue from hepatic coma patients compared to patients without HE or controls (p < 0.001). Brain allopregnanolone concentrations were significantly correlated with the magnitude of induction of [3H]muscimol binding (r2 = 0.82, p < 0.0001). Concentrations of allopregnanolone comparable to those observed in hepatic coma brains are pathophysiologically relevant. Concentrations of the neurosteroid precursor pregnenolone were also increased in brain tissue from hepatic coma patients, while those of a second neurosteroid THDOC were below the levels of detection in all groups. Brain concentrations of benzodiazepine receptor ligands estimated by radioreceptor assay were not significantly increased in cirrhotic patients with or without hepatic coma. These findings suggest that increased levels of allopregnanolone rather than "endogenous benzodiazepines" offer a cogent explanation for the phenomenon of "increased GABAergic tone" previously proposed in HE.

Differential regional responsiveness of astroglia in mild hepatic encephalopathy: An Immunohistochemical approach in bile duct ligated rat.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. However, the pathomechanisms of the disease remains obscure. Neuropathological studies have demonstrated a primary gliopathy in humans as well as in animal models of chronic and acute liver failure. Here, we have investigated in an animal model of mild HE: the bile duct ligated rat (BDL) at the cirrhotic stage (4 weeks after surgery), the expression of the key marker of mature astrocytes; the glial fibrillary acidic protein (GFAP) in different brain areas such as: Substantia nigra pars compacta (SNc), Ventral tegmental area (VTA), hippocampus, dorsal striatum and brain cortex by means of immunohistochemistry. The immunohistochemical study showed, in BDL compared to the operated controls (shams), a diminished astrocyte reactivity corresponding to a loss of GFAP expression within SNc, VTA, hippocampus and dorsal striatum (p<0.05),whereas in the brain cortex astrocytes appeared strongly immunoreactive with increased GFAP expression (p<0.05) as compared to shams. Our finding demonstrated differential astroglial responses which depend to the specificity of the area investigated and its particular neuronal neighboring environment, and could have possible outcomes on the diverse neuronal functions especially those observed during the different episodes of hepatic encephalopathy.

Differential effects of ammonia on the benzodiazepine modulatory site on the GABA-A receptor complex of human brain.

Ammonia is a key factor in the pathogenesis of encephalopathies associated with liver failure. A direct effect of ammonia on GABAergic neurotransmission was proposed as a mechanism that may explain its neurotoxic effect on the basis of electrophysiological and biochemical studies performed in animal models of liver failure. In the present study, we investigated using a radiometric assay the effect of ammonia on the binding of GABA-A receptor ligands to membranes from normal human brains. Ammonium tartrate significantly decreased the maximal binding of [3H]flunitrazepam to well-washed frontal cortical membranes (366+/-63 fmol/mg protein in absence of ammonia versus 294.1+/-51 fmol/mg protein in presence of 2 mM ammonia; p<0.05). The efficacy of the effects of ammonia was within the millimolar range (IC50=4.8 mM). This effect was not seen in cerebellum or hippocampus. Ammonia exposure decreased the maximal binding of [3H]flumazenil (284.9+/-24.2 fmol/mg protein in absence of ammonia versus 146.4+/-15.6 fmol/mg protein in presence of 2 mM ammonia; p<0.01). This effect was seen with a greater potency (Imax=32.4%) and a lower IC50 (0.1 mM). Inhibition of [3H]flumazenil binding was significant in all brain regions. The apparent ammonia-induced decrease of [3H]flunitrazepam and [3H]flumazenil binding was due to a decrease in the binding affinities of these ligands for the benzodiazepine site. In contrast, ammonium tartrate exposure did not cause significant changes to the binding of [3H]muscimol in any brain region. These findings demonstrate that ammonia interacts negatively with components of the benzodiazepine-associated site at the GABA-A receptor complex in human brain in contrast to previous reports in the rat, and thus, does not support the notion that ammonia directly activates the GABA-A receptor complex resulting in increased GABAergic neurotransmission in human hepatic encephalopathy. These findings also suggest that positron emission tomography studies in cirrhotic patients using [11C]flumazenil may be underestimating GABA-A receptor sites depending upon the degree of hyperammonemia of the patient.

Differential patterns of glial fibrillary acidic protein-immunolabeling in the brain of adult lizards.

The present study describes by means of immunohistochemistry the comparative distribution of glial fibrillary acidic protein (GFAP)-positive cells in the forebrain and midbrain of three species of lizards: Eumeces algeriensis, Scincoidae; Agama impalearis, Agamidae; Tarentola mauritanica, Gekkonidae. In the species studied, the different types and proportions of glial cells expressing GFAP showed considerable variation. These cells include radial glia, oval cells, tanycytes, ependymocytes, glia limitans, and astrocytes. In Eumeces, astrocytes are particularly abundant and their processes form numerous perivascular end-feet; in addition well-differentiated ependymal cells and glia limitans express GFAP. These mature glial features are concordant with the relatively advanced phylogenetic level of Eumeces. In Tarentola, relatively few GFAP-expressing glial cells are observed, consisting mainly of radial glia and tanycytes. These features indicate a relatively immature state of the glial cell populations in this species. In Agama, GFAP-immunostained cells are confined to the periventricular and subpial brain areas; the ventricular lining contains numerous GFAP-immunopositive tanycytes and well-differentiated glia limitans. This pattern indicates that the glial cell profile in Agama exhibits characteristics intermediate between Eumeces and Tarentola, a feature which is discordant with the relatively primitive phylogenetic level of Agamidae compared to Gekkonidae. Together, the results of the present study provide novel data on the characterization of GFAP-expressing cell populations in different species of lizards. We suggest that the different glial patterns observed in the lizard brain correlates with developmental and functional aspects.

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.

Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy.

To assess the possible implication of the allosteric coupling of different modulatory sites at the GABA-A receptor complex in hepatic encephalopathy (HE), we investigated in autopsied frontal cortex of six cirrhotic patients and six appropriately-matched controls, the modulatory effects of the benzodiazepine site agonist flunitrazepam on the binding of [3H]muscimol and the effect of the neurosteroid site agonist allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) on the binding of [3H]muscimol and [3H]flunitrazepam. There were no significant differences in either the magnitude E(max): 11.5+/-1.1% (controls) versus 10.2+/-2.2% (HE patients) or the efficacy EC(50): 20.2+/-5.5 nM (controls) versus 17.7+/-6.2 nM (HE patients) of flunitrazepam modulation of [3H]muscimol binding. Allopregnanolone also showed modulation of both sites to a comparable extent in brain tissue from cirrhotic patients and controls E(max): [3H]muscimol, 15.1+/-2.8% (controls) versus 13.8+/-1.9% (HE patients); [3H]flunitrazepam, 17.9+/-2.3% (controls) versus 19.1+/-2.3% (HE patients), EC(50): [3H]muscimol, 386.5+/-25.8 nM (controls) versus 373.8+/-13.1 nM (HE patients); [3H]flunitrazepam, 49.8+/-22.9 nM (controls) versus 55.5+/-14.0 nM (HE patients). These findings demonstrate unequivocally that the GABA-A sites and their benzodiazepine and neurosteroid modulatory sites manifest normal allosteric coupling in brain in human HE. Therefore, if increased "GABAergic tone" is implicated in the pathophysiology of HE, this must be the consequence of increased brain concentrations of endogenous benzodiazepine and/or neurosteroid ligands for components of the GABA-A receptor complex rather than alterations of the receptor proteins themselves.

Loss of tyrosine hydroxylase expression within the nigro-striato-cortical pathways in the cirrhotic rat: the possible restorative effect of the neurosteroid dehydroepiandrosterone sulfate.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder occurring as a consequence of both acute and chronic liver failure. Advanced HE is generally accompanied with extrapyramidal symptoms including rigidity and tremor, which may reflect alterations of the dopaminergic system. Recently we reported a beneficial effect of the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) in cirrhotic rats, however the mechanisms of such an effect by DHEAS were not addressed. In the present study, we describe the changes of the dopaminergic system occurring in the cirrhotic rats and concomitantly we investigated the effect of DHEAS on this system in Sprague-Dawley rats using the expression of tyrosine hydroxylase (TH) as a neuronal marker. Rats were submitted to bile duct ligation (BDL) surgery and TH immunohistochemistry was assessed in the Substantia nigra pars compacta (SNc), striatum, ventral tegmental area (VTA) and the cortex. TH immunoreactivity showed a significant diminution in both SNc and VTA concomitantly with the cortical and the striatal outputs in the BDL rats vs. controls. Three daily injections of 5mg/kg of DHEAS to BDL rats significantly normalized TH expression decrease in both SNc and VTA as well as dopaminergic projections to the striatum and the cortex of BDL rats. The present data support an involvement of the dopaminergic system in mild HE and a possible beneficial effect of the neurosteroid DHEAS as a potential pharmacological treatment of mild HE.

Increased Reissner's fiber material in the subcommissural organ and ventricular area in bile duct ligated rats.

Hepatic encephalopathy is a common neuropsychiatric complication of acute and chronic liver failure. Whether brain structures with strategic positions in the interface of blood-brain barriers such as the circumventricular organs are involved in hepatic encephalopathy is not yet established. Among the circumventricular organs, the subcommissural organ secretes a glycoprotein known as Reissner's fiber, which condenses and forms an ever-growing thread-like structure into the cerebrospinal fluid. In the present work we describe the Reissner's fiber material within the subcommissural organ and its serotoninergic innervation in an animal model of chronic hepatic encephalopathy following bile duct ligation in experimental rats. The study involved immunohistochemical techniques with antibodies against Reissner's fiber and 5-hydroxytryptamine (5-HT). Four weeks after surgical bile duct ligation, a significant rise of Reissner's fiber immunoreactivity was observed in all subcommissural organ areas compared with controls. Moreover, significant Reissner's fiber immunoreactive materials within the ependyma and inside the parenchyma close to the ventricular borders were also seen in bile duct ligated rats, but not in control rats. Increased Reissner's fiber material in bile duct ligated rats seems to be related to a reduction of 5-HT innervation of the subcommissural organ, the ventricular borders and the nucleus of origin, the dorsal raphe nucleus. Our data describe alterations of the subcommissural organ/Reissner's fiber material and the subcommissural organ 5-HT innervation probably due to a general 5-HT deficit in bile duct ligated rats.

GABAergic neurosteroids: the "endogenous benzodiazepines" of acute liver failure.

Acute liver failure (ALF) or fulminant hepatic failure represents a serious life-threatening condition. ALF is characterized by a significant liver injury that leads to a rapid onset of hepatic encephalopathy (HE). In ALF, patients manifest rapid deterioration in consciousness leading to hepatic coma together with an onset of brain edema which induces high intracranial pressure that frequently leads to herniation and death. It is well accepted that hyperammonemia is a cardinal, but not the sole, mediator in the pathophysiology of ALF. There is increasing evidence that neurosteroids, including the parent neurosteroid pregnenolone, and the progesterone metabolites tetrahydroprogesterone (allopregnanolone) and tetrahydrodeoxycorticosterone (THDOC) accumulate in brain in experimental models of ALF. Neurosteroids in ALF represent good candidates to explain the phenomenon of "increased GABAergic tone" in chronic and ALF, and the beneficial effects of benzodiazepine drugs. The mechanisms that trigger brain neurosteroid changes in ALF are not yet well known, but could involve partially de novo neurosteroidogenesis following activation of the translocator protein (TSPO). The factors that contribute to TSPO changes in ALF may include ammonia and cytokines. It is possible that increases in brain levels of neurosteroids in ALF may result in auto-regulatory mechanisms where hypothermia may play a significant role. Possible mechanisms that may involve neurosteroids in the pathophysiology of HE, and more speculatively in brain edema, and inflammatory processes in ALF are suggested.

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.

Reduced brain levels of DHEAS in hepatic coma patients: significance for increased GABAergic tone in hepatic encephalopathy.

Increased neurosteroids with allosteric modulatory activity on GABA(A) receptors such as 3α-5α tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of "increased GABAergic tone" in hepatic encephalopathy (HE). However, it is not known how changes of other GABA(A) receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81±0.88 ng/g tissue) compared to control values (9.70±0.79 ng/g, p<0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43±1.74 ng/g tissue), and in a patient who died in uremic coma (12.56 ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50 µM) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1 µM) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE.

Neurosteroids and hepatic encephalopathy: an update on possible pathophysiologic mechanisms.

Cerebral complications of liver failure either due to chronic or acute manifestations lead to a neurological disorder known as Hepatic encephalopathy (HE). Neurosteroids, synthesized in the brain mainly by astrocytes but also in other brain cells independently from peripheral steroidal sources such as adrenal and gonads, are suggested to play a role in the pathogenesis of HE. The mechanisms by which neurosteroids affects brain function are not totally elucidated but may involve both genomic and non genomic effects. On one hand, neurosteroids bind and modulate different types of neuronal membrane receptors. While neurosteroid may affect directly postsynaptic receptors including GABA(A), 5-HT3, NMDA, glycine, and opioid receptors which have been involved in HE, neurosteroids effects through GABA(A) receptors may also compromise indirectly the function of neurons networking with GABAergic interneurons. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins are altered in HE. The mechanisms that trigger brain neurosteroid changes in HE are not yet well-known, but could involve (i) ammonia and manganese (in chronic HE)-induced translocator protein (TSPO) activation, (ii) neuroinflammation or (iii) blood-brain transfer of lipophylic neuroactive steroids. The present review summarizes evidence for the involvement of neurosteroids in HE and possible mechanisms for their altered brain production and central effects in human and experimental HE.

Chronic exposure to aluminum reduces tyrosine hydroxylase expression in the substantia nigra and locomotor performance in rats.

Aluminum (Al) is a neurotoxic agent that accumulates in the substantia nigra of patients affected by Parkinson's disease and in other cerebral areas of different neurodegenerative pathologies. Al has been associated with neuronal and glial dysfunctions, and neuronal changes have been suggested to affect several neurotransmitter systems including the dopaminergic system. The present study was designed to evaluate by means of immunohistochemistry using antibodies against tyrosine hydroxylase (TH; the rate-limiting enzyme of dopamine synthesis) the effects of chronic Al exposure (0, 3%) in drinking water during 4 months in adulthood or since intra-uterine age in the substantia nigra. Our results show a significant decrease in the number of cells labeled by the antibody against TH in rats treated with Al compared to controls. The TH-immunoreactive decrease following Al treatment is accentuated in the rat group treated since intrauterine age. In both treated groups, Al exposure induced a significant decrease of locomotor performance. Interestingly, as for TH-immunoreactivity, the decreased locomotor activity was also accentuated in the group treated since intrauterine age. The Al-induced TH alterations may be one of the causes of aluminum-induced neurotoxicity.

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.

Proopiomelanocortin in the arcuate nucleus of the rodent Meriones shawi: effects of dehydration.

Proopiomelanocortin (POMC) is a 36kDa glycoprotein implicated in homeostatic balance. We used in situ hybridization histochemistry coupled with quantitative autoradiography to determine the anatomical distribution of POMC mRNA-expressing neurons in the arcuate nucleus (AN) and to examine the effects of prolonged dehydration on POMC gene expression in a semi-desert rodent, Meriones shawi (Shaw's Jird). In the hypothalamus of control animals, POMC mRNA-expressing neurons were exclusively localized in the AN and they showed a differential distribution and density along its rostro-caudal subdivisions. In dehydrated animals, water deprivation caused a decrease in POMC mRNA labeling in the AN. These results suggest that dehydration stress can induce negative regulation of POMC gene expression in this species. A comparative study of weight variation between control and dehydrated animals showed a weight loss followed by stabilization of weight during prolonged dehydration.