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A Guidotti

Publications and source records attributed to A Guidotti.

At least 37 records · Page 2Linked to original sources
PubMed2001

The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders.

Allopregnanolone (3alpha,5alpha-TH PROG) and 5alpha-dihydroprogesterone (5alpha-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABA(A) receptors or by changing specific GABA(A) receptor subunit gene expression, respectively. We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3alpha,5alpha-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology. The mechanism by which fluoxetine and other selective serotonin reuptake inhibitors normalize 3alpha,5alpha-TH PROG CSF levels appears to involve a direct stimulation of 3alpha-hydroxysteroidoxidoreductase (3alpha-HSD), an enzyme that catalyses the reduction of 5alpha-DH PROG into 3alpha,5alpha-TH PROG. Here, we propose the use of socially-isolated mice that have a downregulation of 3alpha,5alpha-TH PROG and of 5alpha-DH PROG expression to establish a model to study the behavioral consequences of this deficiency. After 4-6 weeks of isolation, these mice exhibit increased anxiety and aggressive behavior and also a decreased response to the administration of GABA-mimetic drugs. In these mice, the decrease in 3alpha,5alpha-TH PROG is selectively normalized by the use of fluoxetine in doses that reduce behavioral abnormalities. In addition, the expression of 5alpha-reductase Type I mRNA and protein was lower in socially-isolated mice than that in group-housed mice whereas 3alpha-HSD mRNA expression remained unchanged. The results of these studies may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.

20-alpha-Dihydroprogesterone↗
PubMed2000

Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex.

The expression of telencephalic reelin (Reln) and glutamic acid decarboxylase mRNAs and their respective cognate proteins is down-regulated in postmortem brains of schizophrenia and bipolar disorder patients. To interpret the pathophysiological significance of this finding, immunoelectron microscopic experiments are required, but these cannot be carried out in postmortem human brains. As an alternative, we carried out such experiments in the cortex of rats and nonhuman primates. We found that Reln is expressed predominantly in layer I of both cortices and is localized to bitufted (double-bouquet), horizontal, and multipolar gamma-aminobutyric acid-ergic interneurons, which secrete Reln into extracellular matrix. Reln secretion is mediated by a constitutive mechanism that depends on the expression of a specific signal peptide present in the Reln carboxy-terminal domain. Extracellular matrix Reln is found to aggregate in proximity of postsynaptic densities expressed in apical dendrite spines, which include also the alpha(3) subunit of integrin receptors. Most pyramidal neurons of various cortical layers express the mouse-disabled 1 (Dab1) protein, which, after phosphorylation by a soluble tyrosine kinase, functions as an adapter protein, probably mediating a modulation of cytoskeleton protein expression. We hypothesize that the decrease of neuropil and dendritic spine density reported to exist in the neocortex of psychiatric patients may be related to a down-regulation of Reln-integrin interactions and the consequent decrease of cytoskeleton protein turnover.

Animals↗
PubMed2000

Reelin secretion from glutamatergic neurons in culture is independent from neurotransmitter regulation.

Reelin (Reln) is a glycoprotein that in postnatal and adult mammalian brain is believed to be secreted from telencephalic GABAergic interneurons and cerebellar glutamatergic granule neurons into the extracellular matrix. To address the question of whether Reln neurosecretion occurs via a regulated or a constitutive process, we exposed postnatal rat cerebellar granule neurons (CGNs) maintained in culture for 7-9 days to: (i) 100 microM N-methyl-D-aspartate (NMDA) in a Mg(+2)-free medium to stimulate NMDA-selective glutamate receptors and Ca(2+)-dependent neurotransmitter release, (ii) 50 mM KCl to depolarize the cells and elicit Ca(2+)-dependent exocytosis, (iii) 10-100 microM nicotine to activate excocytosis by nicotinic receptors present in these cells, (iv) 10 microM 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulfonamide in combination with 10 microM dizocilpine to block alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and NMDA-preferring glutamate receptors activated by endogenously released glutamate, or (v) EGTA (5 mM) to virtually eliminate extracellular Ca(2+) and block Ca(2+)-dependent exocytosis. Although, CGNs express and secrete Reln (measured by quantitative immunoblotting), none of the above-mentioned conditions that control regulated exocytosis alters the stores or the rate of Reln release. In contrast, application of either: (i) a Reln antisense oligonucleotide (5'-GCAATGTGCAGGGAAATG-3') (10 microM) that reduces Reln biosynthesis or (ii) brefeldin A (5 x 10(-5) M), an inhibitor of the traffic of proteins between the endoplasmic reticulum and the Golgi network, sharply curtail the rate of Reln secretion. Because, in subcellular fractionation studies, we have shown that Reln is not contained in synaptic vesicles, these data suggest that Reln secretion from CGNs does not require Ca(2+)-dependent exocytosis, but probably is related to a Reln pool stored in Golgi secretory vesicles mediating a constitutive secretory pathway.

Animals↗
PubMed2000

Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance.

The partial allosteric modulators (PAMs) of gamma-aminobutyric acid-gated Cl(-) current intensities at gamma-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition.

Alprazolam↗
PubMed2000

Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells.

Reelin regulates telencephalic and cerebellar lamination during mammalian development and is expressed in several structures of the adult brain; however, only traces of reelin were believed to be in peripheral tissues. Because reelin structurally resembles extracellular matrix proteins, and because many of these proteins are expressed in blood, we hypothesized that reelin also might be detectable in the circulation. Reelin (420 kDa) and two reelin-like immunoreactive bands (310 and 160 kDa) are expressed in serum and platelet-poor plasma of rats, mice, and humans, but these three bands were not detectable in serum of homozygous reeler (rl/rl) mice. Reelin plasma levels in heterozygous (rl/+) mice were half of those in wild-type littermates. Western blotting and immunocytochemistry using antireelin mAbs indicated that reelin-like immunoreactivity was expressed in a subset of chromaffin cells within the rat adrenal medulla and in a subset of cells coexpressing alpha-melanocyte-stimulating hormone within the pituitary pars intermedia. However, surgical removal of adrenal or pituitary failed to decrease the amount of reelin (420-kDa band) expressed in serum. Adult liver expressed one-third of the reelin mRNA concentration expressed in adult mouse cerebral cortex. Full-length reelin protein was detectable in liver extracts in situ; acutely isolated liver cells also secreted full-length reelin in vitro. Liver appears to be a prime candidate to produce and maintain the circulating reelin pool. It now becomes relevant to ask whether circulating reelin has a physiologic role on one or more peripheral target tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol.

Allopregnanolone (ALLO), a potent positive-allosteric modulator of the action of GABA at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: 5alpha-reductase and 3alpha-hydroxysteroidoxidoreductase. The concentration of ALLO in various parts of the mouse brain varies substantially, from 15 pmol/g in the olfactory bulb, to approximately 6 pmol/g in the frontoparietal cortex, and 2.7 pmol/g in the cerebellum. The systemic administration of 48 micromol/kg of the Type I and Type II 5alpha-reductase inhibitor, (17beta)-17-[bis (1-methylethyl) amino carbonyl)] androsta-3, 5-diene-3-carboxylic acid (SKF 105,111), reduced brain ALLO content by 80-90% in 30 min; the rate constant (k) of ALLO decrease in each brain area can be utilized to establish the rate of ALLO biosynthesis, which is higher in the olfactory bulb (62 pmol/g/h) than in the frontoparietal cortex (24 pmol/g/h) or cerebellum (11 pmol/g/h). The duration of the righting reflex loss elicited by the potent GABA(A) receptor agonist muscimol was reduced in SKF 105,111-treated ALLO-depleted mice. SKF 105,111 treatment had no effect on muscimol metabolism or on brain levels of pregnenolone and progesterone; however, the brain levels of 5alpha-DHP, the precursor of ALLO, were also decreased. Administration of ALLO at a dose of 15 micromol/kg i.p. by itself did not alter the muscimol-induced loss of the righting reflex; but it completely blocked the effect of SKF 105,111. To elucidate the possible molecular mechanism by which a decrease of brain ALLO content can shorten the duration of the righting reflex loss elicited by muscimol, we patch-clamped neocortical pyramidal neurons of mice pretreated with SKF 105,111 or vehicle, and studied the efficiency of muscimol in eliciting Cl- currents. The current amplitude was significantly smaller in neurons from SKF 105,111-treated mice, especially at lower doses (0.1-1 microM) of muscimol, and the muscimol dose-response (0.1-10 microM) relationship displayed cooperativity (nH=1.4). These data suggest that ALLO synthesized in brain plays an important physiological permissive role in the modulation of GABA-gated Cl- channel function.

5-alpha-Dihydroprogesterone↗
PubMed2000

Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study.

BACKGROUND: Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. METHODS: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. RESULTS: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. CONCLUSIONS: The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.

Activating Transcription Factor 1↗
PubMed2000

Expression and function of striatal nAChRs differ in the flinders sensitive (FSL) and resistant (FRL) rat lines.

Rats of Flinders Sensitive (FSL) and Flinders Resistant lines (FRL) differ in their susceptibility to physiological and associated behavioral responses elicited by nicotine. In the present study, we measured dopamine (DA) content in striatal dialysates to investigate the sensitivity of FSL and FRL rats to nicotine delivered locally through a microdialysis probe placed in the striatum. We also measured the expression density of striatal high-affinity nicotinic acetylcholine receptors (nAChRs), and that of mRNAs encoding for alpha3, alpha4, alpha7 and beta2 nAChR subunits in both lines. The DA content of dialysates was measured before and after a 1-min perfusion of nicotine (6, 10 or 20 nmoles/min) and the resulting DA increase was taken as a measure of the alkaloid's intrinsic activity for nAChRs involved in the release of DA. The nicotine-induced increase of striatal DA release was greater in FSL than in FRL rats for all concentrations of nicotine, suggesting that the intrinsic activity of nicotine was greater in the FSL than in the FRL rats. This was further supported by our finding that the density of high-affinity nAChRs in the striatum of FSL rats was 44% greater than in the FRL rats, whereas affinity (K(D)) was virtually the same in the two lines of rats. Also the expression of mRNAs encoding for alpha(4), alpha(7), and beta(2) subunits in the striatum was greater in FSL than in FRL rats (attomol/microg total RNA, alpha(4):98+/-10 vs. 77+/-7; alpha(7):279+/-16 vs. 184+/-16; beta(2):310+/-19 vs. 201+/-12). We hypothesize that the difference in nicotine-induced DA release in the striatum of FSL and FRL rats depends on the difference in nAChR subunit expression in the striatum between the two lines. The Flinders rats could be used as a model for nicotine self-administration studies to evaluate the susceptibilities of FSL and FRL rats to nicotine dependence.

Animals↗
PubMed2000

New neurochemical markers for psychosis: a working hypothesis of their operation.

Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrounds dendrites, spines and neurite arborizations, and binds to integrin receptors located on post-synaptic densities of apical dendritic spines. Experiments in rodents (including wild type or reeler heterozygous mice) and non-human primates suggest the Reln secreted in the extracellular matrix of neocortex, via integrin receptors, modulates the function of the adaptor protein DAB1(drosophila disable-gene) homologous product) thereby participating in dynamic processes associated with plasticity changes in dendrites, dendritic spines and their synapses. A local protein synthesis at dendritic spines (ie the activity regulated cytoskeleton associated protein, Arc) probably acts as a signal for plastic modulatory activities in synapses operative in neural group interactions. A research strategy directed toward identifying specific neurochemical markers operative in the etiopathology of psychotic disorders lead to the identification of a downregulation (30-50%) of Reln and glutamic acid decarboxylase 67(GAD67) expression in prefrontal cortex and other brain areas of schizoprenia and bipolar disorder patients with psychosis. These downregulations were not due to neuronal damage, postmortem interval, or antipsychotic medication. The dysfunction of GABAergic interneurons observed in psychotic brains in combination with reduced Reln expression and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients. This downregulation of neuropile plasticity may be a factor to be considered in the etiology of the disintegration of consciousness, which is one of the primary signs of psychosis.

Animals↗
PubMed1999

Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice.

gamma-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the delta subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the delta subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.

Animals↗
PubMed1999

The phenotypic characteristics of heterozygous reeler mouse.

Histological and behavioral traits are associated with reelin (Reln) haplo-insufficiency in heterozygous reeler mouse (rl+/-). These phenotypic traits are an approximately 50% decrease of brain Reln mRNA and Reln protein, an accumulation of nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d)-positive neurons in subcortical white matter, an age-dependent decrease in prepulse inhibition of startle (PPI), and neophobic behavior on the elevated plus-maze. Possible analogies between these rl+/- phenotypic traits and signs of psychosis vulnerability are discussed.

Aging↗
PubMed1999

Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression.

Reelin (Reln) is a protein with some structural analogies with other extracellular matrix proteins that functions in the regulation of neuronal migration during the development of cortical laminated structures. In the cortex of adult animals, Reln is expressed primarily in gamma-aminobutyric acid (GABA)ergic neurons and is secreted into perineuronal nets. However, only 50-60% of GABAergic interneurons express Reln. We have characterized this subpopulation of cortical GABAergic neurons that expresses Reln by using two strategies: (i) a double immunolabeling procedure to determine the colocalization of Reln with neuropeptides and Ca2+-binding proteins and (ii) a combination of Golgi staining and Reln immunolabeling to determine the morphology of the rat cortical cells that store Reln. Many interneurons that express Neuropeptide Y (NPY) or somatostatin (but none of those that express parvalbumin) are Reln-immunopositive. A small population of calbindin-positive interneurons and very few calretinin-positive cells express Reln immunopositivity. Golgi staining revealed that layer I horizontal cells, layer II-V bitufted neurons, and some deep cortical layer Martinotti cells express Reln. Basket and chandelier cells are often immunopositive to parvalbumin, but never to Reln. Although Reln is secreted by GABAergic neurons, its target are not the GABA receptors, but rather may be extrasynaptically located in perineuronal nets and concerned with the modulation of neuronal plasticity. Dab1, the target adapter protein that presumably mediates transcription regulation via the extrasynaptic actions of Reln, is expressed predominantly in pyramidal neurons, but it can also be detected in a small population of GABAergic neurons that are neither horizontal nor bitufted neurons.

Animals↗
PubMed1999

Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss.

Allopregnanolone [3alpha-hydroxy-5alpha-pregnan-20-one] (ALLO), a potent neurosteroid that positively modulates gamma-aminobutyric acid (GABA) action at various GABA(A) receptor subtypes is synthesized in nanomolar concentrations and stored non uniformly in various brain structures of mammals. We have measured brain ALLO content and its precursors by negative ion chemical ionization-mass-spectrometry after purification and separation of the different steroids with HPLC and gas chromatography. Our procedure measures steroids in the femtomolar range with structural information and unsurpassed selectivity. We were able to establish an association between the decrease in content of ALLO in mouse brain cortex elicited by either long-lasting social isolation or by the administration of 17beta-17 [bis (1-methylethyl) amino carbonyl] androstane-3,5-dilene-3-carboxylic acid (SKF 105111). an inhibitor of Types I and II 5alpha reductases, and the shortening of the righting reflex loss elicited by pentobarbital (PBT). SKF 105111 added to cortical brain slices in concentrations up to 10(-5) M failed per se to alter GABAergic currents or their potentiation by PTB recorded from pyramidal neurons. Fluoxetine (1.45 or 2.9 micromol/kg i.p.) doses that fail to change the PTB-induced loss of righting reflex and the level of brain ALLO in group-housed mice normalized both parameters in socially-isolated mice. In addition, we could detect both fluoxetine actions in socially isolated mice pretreated with doses of p-chlorophenylalanine (1.2 mmol/kg i.p. at 72, 48, and 24 h) that substantially inhibit brain serotonin 5HT synthesis as shown by an 80% drop of brain 5HT content. These studies for the first time have provided evidence suggesting that the endogenous cortical stores of ALLO physiologically upregulate GABAergic tone and by such a mechanism play a permissive or facilitatory role on the PTB-induced loss of the righting reflex. In the absence of such a permissive physiological influence by endogenous ALLO, the righting reflex inhibition by PTB is down regulated.

5-alpha Reductase Inhibitors↗
PubMed1999

Gangliosides attenuate ethanol-induced apoptosis in rat cerebellar granule neurons.

Ethanol significantly enhances cell death of differentiated rat cerebellar granule neurons on culture in a serum-free medium containing a depolarizing concentration of KCl (25 mM), 5 microM MK-801 (an NMDA receptor antagonist), and 20-200 mM ethanol for 1-4 days. Cell death augmented by ethanol was concentration- and time-dependent with neurons displaying hallmark apoptotic morphology and DNA fragmentation that correlated with the activation of cytosolic caspase-3. Inclusion of 5 microM MK-801 or 100 microM glycine in culture media did not alter rates of cell death indicating ethanol toxicity is mediated via an NMDA receptor-independent pathway. Preincubation with 50 microM gangliosides GM1, GD1a, GD1b or GT1b for 2 h, or preincubation with 10 microM LIGA20 (a semisynthetic GM1 with N-dichloroacetylsphingosine) for 10 min, attenuated caspase-3 activity and ethanol-induced cell death. Data show native gangliosides and a synthetic derivative are potently neuroprotective in this model of ethanol toxicity, and potentially serve as useful probes to further unravel the mechanisms relevant to neuronal apoptosis.

Animals↗
PubMed1999

[Possibility of false negative results in the diagnosis of lung neoplasms with computerized tomography].

PURPOSE: To describe the radiological appearance of overlooked malignant pulmonary lesions at CT and to analyze the reasons of misdiagnosis. MATERIAL AND METHODS: Ten patients with pulmonary malignant lesions (PML) overlooked at first CT examination were selected among patients with lung cancer who were referred to our institution between 1994 and 1997. CT scans were evaluated by consensus of two chest radiologists with different experience in chest radiology, who were blinded to the final diagnosis. RESULTS: The overlooked pulmonary lesions were 5 endobronchial cancers and 5 central solitary nodules. The mean diameter of the lesions ranged 1 to 2 cm. Furthermore, 7 patients had associated pleural and/or parenchymal abnormalities. The technical quality of CT examinations was considered good in 2 cases, acceptable in 6 cases, poor in 2 cases. PML were correctly identified in 6/10 cases by the first (more experienced) radiologist and in 4/10 by the second radiologist. Four cases were considered suspect for the presence of PML by the first radiologist, 2 by the second. CONCLUSIONS: Endobronchial location of the tumors and their small size were the most frequent causes of misdiagnosis of PML at chest CT in our series. However, a systematic evaluation of CT scans can reduce the percentage of missed lesions.

Aged↗
PubMed1998

Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3 alpha, 5 alpha-tetrahydroprogesterone (allopregnanolone) availability?

Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity. Allopregnanolone (ALLO) is of great significance for neuropsychiatric research because it binds with high affinity at nanomolar concentration to various gamma-aminobutyric acid (GABA)A receptor subtypes and potently facilitates GABA action at these receptors. Fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats increase brain ALLO content without altering the brain content of other steroids, including ALLO's precursor 5 alpha dihydroprogesterone. Moreover the improvement in depression symptomatology following administration of fluoxetine or fluvoxamine to unipolar depressed patients for 8-10 weeks is related to the increase of ALLO content in cerebrospinal fluid. Because ALLO via its action at GABAA receptors may relieve anxiety and dysphoria, the increase in ALLO brain content elicited by fluoxetine or other SSRIs may participate in the beneficial anxiolytic and antidysphoric clinical action of this class of drugs. Preliminary experiments suggest that the effect of SSRIs on ALLO biosynthesis is independent from serotonin reuptake inhibition and may be due to a specific SSRI action on the enzymes that synthesize ALLO from its precursor.

Animals↗
PubMed1998

The semisynthetic glycosphingolipid LIGA20 potently protects neurons against apoptosis.

LIGA20 (a semisynthetic GM1 with n-dichloroacetyl sphingosine) having antinecrotic properties was evaluated as an antiapoptotic agent using cerebellar granule cells as a neuronal model. Neurons exposed to medium containing 5 mM K+ in absence of serum (apoptotic medium) for up to 22 h resulted in 65% cell death, accompanied by oligonucleosomal laddering, and a 15-fold-increase in caspase-3 activity. The relationships between times required for enzyme activation and cell death suggests a linkage between these two events. Pretreatment with 10 microM LIGA20 for 10 min significantly attenuated the aforementioned apoptotic changes. LIGA20 also attenuated apoptosis induced by Pb2+, ethanol, and C6-ceramide. Data show that LIGA20 is a versatile neuroprotective agent protecting cells from multiple pathways of cell death.

Animals↗