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Biomedical subjects

S Govoni

Publications and source records attributed to S Govoni.

At least 217 records · Page 12Linked to original sources
PubMedDate not supplied

Chronic lead treatment differentially affects dopamine synthesis in various rat brain areas.

The effect of chronic dietary lead exposure on brain nigrostriatal, mesolimbic and mesocortial systems was studied. The results show no modification of the dopamine receptors measured either as dopamine sensitive adenylate cyclase or as [3H]spiroperidol binding. On the other hand, dopamine synthesis seems to be reduced in striatum, unaffected in substantia nigra and increased in nucleus accumbens and in the frontal cortex. The increase of DA synthesis observed in some brain areas might be involved in determining the hyperactive behaviour that follows lead intoxication.

Adenylyl Cyclases↗
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Age related differences in dopamine-stimulated adenylate cyclase sensitivity to "in vivo" chronic ethanol treatment.

The effect of chronic ethanol consumption on adenylate cyclase activity was measured in striatal membranes derived from aged male rats. The results indicate that the cyclic AMP generating system of old rats has a different sensitivity to ethanol effect compared to the adult animals. In young animals the basal adenylate cyclase activity was enhanced by alcohol consumption while the DA stimulated cyclic AMP production was reduced. In contrast, in 24 months old rats ethanol reduced the basal adenylyl cyclase and enhanced the response to DA indicating a supersensitivity of adenylate cyclase linked DA receptors. This observation was further supported by 3H-Spiperone binding studies. In fact, a higher Bmax was measured in striatal membranes of aged ethanol-dependent rats in comparison to control.

Adenylyl Cyclases↗
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Chronic ethanol induces changes in opiate receptor function and in met-enkephalin release.

Ethanol induces supersensitivity of striatal delta-opiate receptor sites labelled by 3H-Etorphine. This effect may be ascribed to the diminished enkephalin release detected in striatal slices after chronic ethanol consumption. On the other hand, Kd values for 3H-Met-enkephalin and 3H-DHM (mu-opiate receptors) specific binding are enhanced. The different sensitivity of the two classes of opiate receptors to ethanol may be due to specific effects on enkephalinergic transmission. It has been hypothesized that the decrease of 3H-Met-enkephalin and 3H-DHM affinity for their receptors takes place because endogenous substances from ethanol metabolism (for example salsolinol) behave as mu opioid agonists. This hypothesis is confirmed by "in vitro" studies demonstrating that salsolinol displaces 3H-Met-enkephalin and 3H-DHM but not 3H-DADLE binding. On the contrary, it seems that delta-receptors become supersensitive because of the decreased endogenous peptide release.

Animals↗
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Chronic ethanol exposure alters dopaminergic signal transduction processes.

A number of data suggest that the chronic ethanol treatment induces derangements of cell membrane structure leading to modifications of membrane related processes. In particular, alterations have been observed in the mechanisms of neurotransmitter recognition and in the coupling of the receptor with the effector system. Phosphorylation of specific proteins by cyclic AMP stimulated protein kinases represent the final step in the biological response in several distinct functional processes. Ethanol neurotoxic action therefore may affect neurotransmitter availability and release as well as receptors effector systems and protein phosphorylation. In this line, chronic ethanol treatment in rats decreases cyclic AMP dependent protein kinase activity in rat striatal membrane fractions. When lysine rich histone type III was used as exogenous substrate, cyclic AMP stimulated 32P incorporation was still decreased in the ethanol group. These data favor the hypothesis of a decreased capability of the enzyme to phosphorylate in response to cAMP.

Alcoholism↗
PubMedDate not supplied

Altered calcium signal transduction after chronic ethanol consumption.

Calcium and calcium-calmodulin dependent phosphorylation of several protein bands was found altered in synaptosomal membranes prepared from ethanol treated rats. The ethanol induced effect on Ca++ and Ca++-calmodulin phosphorylation presented regional differences. In particular 32P incorporation was lower in the striatum and cerebellum, higher in the hippocampus and unmodified in the cortex. Part of the phosphorylated bands had an apparent molecular weight similar to that of the phosphoproteins involved in neurotransmission. These results extend previous observations indicating that calcium movement control is modified during chronic ethanol consumption and suggest that ethanol may interfere at various steps in the calcium-promoted events.

Alcoholism↗
PubMedDate not supplied

Acute ethanol and acetaldehyde administration produce similar effects on L-type calcium channels in rat brain.

The present study investigates the effect of acute ethanol and acetaldehyde administration on neuronal L-type calcium channels by measuring the binding of 3H-nitrendipine (3H-NTP). Acute ethanol (3 g/kg orally) transiently increases (+40% at 40 min) 3H-NTP binding. Acetaldehyde has a similar effect, but the onset of action is shorter; in fact the binding increase peaks 15 min following administration and is completely reversible within 2 hours. Disulfiram pretreatment does not modify the effect produced by acute ethanol on 3H-NTP binding. The results indicate that acetaldehyde may participate in mediating the action of ethanol on voltage sensitive L-type calcium channels with consequent alterations of neuronal excitability.

Acetaldehyde↗
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Chronic alcohol intake modifies phorbol ester binding in selected rat brain areas.

3H-Phorbol 12,13 dibutyrate binding to rat brain was modified by chronic ethanol treatment. Among the areas examined hippocampus and cortex showed a decrease in Bmax values of 32 and 24% respectively. No significant effect was observed in hypothalamus and cerebellum. In vitro ethanol did not modify the binding in all the areas except at molar concentrations. In hippocampus and cortex the direct measurement of protein kinase C activity indicated that the decrease in phorbol ester binding was accompanied with a concomitant decrease in kinase activity. The results indicate that chronic ethanol treatment leads to an inhibition of brain protein kinase C function.

Animals↗
PubMedDate not supplied

Effects of chronic ethanol intake at a low dose on the rat brain dopaminergic system.

The effects of 8-week ethanol treatment (3% v/v in drinking water) on the rat brain dopaminergic system were investigated. Chronic ethanol consumption induced a significant increase in the number of dopamine D1 receptor sites in the caudate putamen. Conversely, no significant changes were observed in D2 receptor density or affinity. Biochemical results were in agreement with behavioral data, as amphetamine-induced locomotor hyperactivity was significantly higher in ethanol-treated rats in comparison to controls. Moreover, grooming behavior in response to SKF 38393, a selective agonist of D1 receptors was potentiated in ethanol-treated rats, whereas locomotor hyperactivity induced by LY 171555 (a selective agonist of D2 receptors) was not affected by ethanol treatment. The results indicate that changes in dopamine receptors may occur in the central nervous system at levels of ethanol intake that do not induce tolerance or dependence.

Alcohol Drinking↗
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Alcohol and the brain: setting the benefit/risk balance.

This article reviews the literature and presents some unpublished data on the CNS effects of alcohol at doses not producing tolerance and dependence. The available evidence indicates that the effect of low doses of ethanol may qualitatively differ from those produced in animal models mimicking alcoholism. For example, rats exposed for two months to alcohol in drinking water at a concentration (3%) not inducing tolerance or dependence, as assessed by lack of withdrawal signs upon treatment suspension, appear to be less stressed in the two-way avoidance-learning tests. Accordingly, the treated rats perform better and learn faster than sucrose-fed controls, while this behavior is disrupted by high levels of ethanol intake. These initial observations suggest that discontinuity may exist between the effects of low and high doses of this substance and underscore the need to expand research on the effects of alcohol on the CNS to include the bottom end of the dose-response curve.

Alcoholism↗
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Neuronal differentiation modifies the effect of ethanol exposure on voltage-dependent calcium channels in NG 108-15 cells.

The effect of prolonged (72 h) ethanol (200 mM) exposure on the labeling of L-type (using tritiated PN 200-110) and N-type (using iodinated omega-conotoxin) voltage-dependent calcium channels was investigated in cultured NG 108-15 cells. In undifferentiated cells ethanol produced an 80% increase in PN 200-110 Bmax and no changes in omega-conotoxin binding. Differentiation had a profound effect on the response of cells to ethanol, which in differentiated neuron-like cells decreased omega-conotoxin binding (-53.5%) leaving PN 200-110 labeling of L-type channels unaffected. The effect was time dependent and reversible upon ethanol withdrawal. The decreased omega-conotoxin binding was accompanied by a reduced ability of omega-conotoxin to inhibit K+ -stimulated calcium uptake. The results demonstrate that in cultured NG 108-15 cells ethanol differentially affects DHP and omega-conotoxin-sensitive, voltage-dependent calcium channels and that the effect is also modulated by differentiation of the cell to a neuronal phenotype.

Animals↗
PubMedDate not supplied

Increased natural killer cell cytotoxicity in Alzheimer's disease may involve protein kinase C dysregulation.

Increased cytokine-mediated cytotoxic natural killer (NK) cell activity has recently been demonstrated in patients with senile dementia of the Alzheimer's type (SDAT). In the present study, we evaluated whether protein-kinase C (PKC), a main regulatory enzyme involved in the mechanism of exocytosis by NK cells, has a role in the cytotoxic response of NK cells (during IL-2 and IFN-beta exposure) from SDAT patients. Our data demonstrate the presence of an increased cytotoxic response by NK cells to IL-2 (mean increase +102%) and IFN-beta (mean increase +132%) in SDAT patients in comparison with healthy elderly subjects (+75% and +88% for IL-2 and IFN-beta, respectively). A smaller suppression of NK cytotoxicity after cortisol was also observed in SDAT (mean decrease -24%) than in the control group (-44%). The NK cell activity of SDAT patients was inversely correlated with the cognitive status as evaluated by the analysis of MMSE (Mini Mental State Examination) score. A comparison of young and elderly healthy subjects revealed no variations in NK cell activity. A physiological decrease in cytosolic PKC activity was demonstrated in healthy old subjects after IL-2 and IFN-beta incubation, but not in SDAT patients, while no variations in kinase activity were observed after cortisol incubation. The decreased activity with cytokines was associated with reduced levels of PKC alpha and betaII isoforms. An alteration in cytokine-mediated NK cell activity associated with PKC dysregulation is therefore suggested to occur in patients with SDAT. These changes may indicate the existence of an immunological component to the pathogenesis and progression of the disease.

Adult↗
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STAT signalling in the mature and aging brain.

Activation of the Janus kinases (JAK) and signal transducers and activator of transcription (STAT) proteins in response to specific cytokines and growth factors has been investigated primarily in cells of non-neuronal origin. More recently, the JAKs and the STATs have also been found to be active in the developing and mature brain, providing evidence for important roles played by these molecules in the control of neuronal proliferation, survival and differentiation. Nothing, however, is known about their occurrence and role(s) in the aged brain. We, therefore, investigated the presence of Stat3 and Stat1 in aged-rat brain, and have found that the Stat3 protein was markedly down regulated with respect to adult tissue, while Stat1 remained invariant. We also investigated the potential role of some growth factors in the activation of the JAK/STAT in mature neurons, exposing primary neuronal cells to ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Besides CNTF, which is known to recruit Stat3, we found that Stat3 was also tyrosine phosphorylated by bFGF. These data are indicative of an important role of Stat3 and Stat1 in regulating the physiological status of mature neurons.

Aging↗
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Chronic low doses of ethanol affect brain protein kinase C and ultrasonic calls in rats.

Few studies have investigated neurobehavioral and neurochemical consequences of chronic consumption of low doses of ethanol. The present study shows that in rats exposure to 3% ethanol (v/v in drinking water) for 2 months decreased both calcium-dependent and -independent protein kinase C (PKC) activities in the cortex and in the hippocampus. This treatment also reduced ultrasonic calls (UCs), an index of emotional and motivational states of the animal. In addition, at cortical level of ethanol-treated rats, we observed a correlation between calcium-dependent activities and UCs. These results suggest that nonaddicting doses of ethanol affect brain PKC activities and that this enzyme may be involved in the ethanol modulation of emotional and motivational behaviors.

Animals↗
PubMedDate not supplied

Bladder instability: a re-appraisal of classical experimental approaches and development of new therapeutic strategies.

1 Despite the growing social interest in human urinary tract disorders, the aetiology of detrusor instability remains poorly understood. Myogenic and neural impairment of detrusor activity caused by CNS or autonomic injuries can results in dysfunctions of normal voiding of the bladder such as urinary incontinence. 2 The contractility of human detrusor smooth muscle is critically dependent on acetylcholine-induced muscarinic receptor activation. Biochemical and functional in vivo and in vitro studies suggest the presence of an heterogeneous population of muscarinic receptor subtypes (M1-M4) localized at muscular and neutral sites. There is increasing evidence on the prejunctional auto- and hetero-regulation of acetylcholine release from parasympathetic nerve endings in modulating detrusor muscle contraction during micturition. 3 Activation of P2X purinoreceptors closely associated with the parasympathetic varicosities seems to be implicated to varying extent in the contractility in normal or instable human detrusor. Interestingly, P2X(1) subtype expression on smooth muscle increases considerably in the symptomatically obstructed bladder. A striking absence of P2X(3) and P2X(5) subtypes was observed in the cholinergic innervation of detrusor from patients with urgent incontinence. Thus, it is likely that alteration of the neural acetylcholine control can play a critical role in pathological states. 4 If the failures in storage and voiding can be recognized urodynamically, considerable difficulties remain in investigating the underlying functional changes especially because the study of the pathophysiology requires techniques that can be justified in animals but not in humans. 5 Recently, to solve this problem an alternative technique using human smooth muscle cells in culture has been developed. Human cell lines may be relevant in investigating the molecular pathways in physiological and pathological conditions. 6 The potential development of novel molecular therapeutic strategies such as gene therapy and tissue engineering is also discussed.

Acetylcholine↗
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Dehydroepiandrosterone sulfate decreases the interleukin-2-mediated overactivity of the natural killer cell compartment in senile dementia of the Alzheimer type.

Since dehydroepiandrosterone sulfate (DHEAS) has been involved in the regulation of cellular immunity, the aim of the presence study was to evaluate whether the age-dependent reduction of DHEAS was associated with changes of natural killer (NK) immune function in healthy elderly subjects and in patients with senile dementia of the Alzheimer type (SDAT). Circulating DHEAS was determined throughout 24 h (circadian profile). NK cytotoxic activity was measured as spontaneous and induced cytotoxicity during exposure with DHEAS (10(-7) M), interleukin-2 (IL-2; 100 IU) and IL-2 (100 IU) coincubated with DHEAS (10(-7) M). DHEAS was significantly reduced in healthy elderly subjects (mesor M +/- SD = 2.3 +/- 0.5 micromol/l) and SDAT (1.6 +/- 0.4 micromol/l) patients compared to healthy young subjects (6.7 +/- 0.9 micromol/l; p < 0.001); significant differences were also found when healthy elderly subjects and SDAT patients were compared (p < 0.01). A significant inverse correlation between age and DHEAS levels was demonstrated in SDAT and healthy elderly subjects (p < 0.05). The decrease in 24-hour DHEAS secretion was associated with a higher NK cytotoxic response to DHEAS in the healthy elderly subject group than in healthy subjects of young age (p < 0.01). Increased NK cell activity during IL-2 incubation was found in patients with SDAT in comparison with the healthy elderly subject (p < 0.001). On the contrary, NK cell cytotoxic response of SDAT patients was less pronounced during DHEAS exposure and when DHEAS was coincubated with IL-2 (p < 0.001). These data suggest an immunomodulatory role of DHEAS on NK functional activity in physiological aging and SDAT. The antagonizing effect of DHEAS on NK overactivity during exposure with cytokines might counteract some neuroimmune components related to the pathogenesis and progression of the disease.

Adult↗
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Apolipoprotein E epsilon 4 allele in Alzheimer's disease and vascular dementia.

The frequency of the epsilon 4 allele of the apolipoprotein E (apoE) is increased in familial and sporadic late-onset Alzheimer's disease, but its prevalence in non-Alzheimer dementias in Caucasian populations is unknown. We found that the frequency of the apoE epsilon 4 allele was 0.45 in 93 Alzheimer's disease patients, 0.46 in 23 vascular dementia patients, 0.31 in 13 dementia of the frontal type patients, and 0.18 in 51 elderly controls. The association of apoE epsilon 4 allele is not unique to Alzheimer's disease, and its importance as a risk factor for the disease should be reconsidered.

Adult↗