Biomedical subjects

Flavio Moroni

Publications and source records attributed to Flavio Moroni.

At least 19 recordsLinked to original sources

PubMed2007

Carboxymethyl beta-glucan binds to corneal epithelial cells and increases cell adhesion to laminin and resistance to oxidative stress.

PURPOSE: Polysaccharides are frequently used as viscoelastic agents to improve pharmacokinetics of ophthalmic preparations. Recently, polysaccharides from yeast cell walls such as beta-glucans have emerged as bioactive molecules endowed with immunomodulatory and cytoprotective properties. In this study, we investigated the effects of carboxymethyl beta-glucan (CMG), a water-soluble derivative of yeast beta-glucan, on cultured rabbit corneal epithelial cells. METHODS: We developed a fluorescein-labeled CMG to visualize its binding to corneal cells by means of digital microscopy and image deconvolution. The effects of CMG on adhesion and survival of corneal epithelial cells exposed to noxious stimuli were also studied. RESULTS: CMG binds defined regions scattered throughout the body of corneal cells, suggesting binding specificity. Tridimensional reconstruction of fluorescence shows that binding is localized mainly at the plasma and nuclear membranes. Interestingly, CMG binding is highly represented at the level of focal adhesion of cells spreading onto laminin. Accordingly, CMG promotes adhesion of corneal epithelial cells to laminin without affecting their proliferation rate. CMG also protects cells from oxidative stress-dependent cell death, being ineffective in preventing ultraviolet B cytotoxicity. CONCLUSIONS: Data show that CMG dynamically binds to corneal epithelial cells, promoting cell adhesion and resistance to oxidative stress.

Animals↗

PubMed2006

Neither energy collapse nor transcription underlie in vitro neurotoxicity of poly(ADP-ribose) polymerase hyper-activation.

Poly(ADP-ribose)polymerase-1 (PARP-1) overactivation is a key event in neurodegeneration but the underlying molecular mechanisms wait to be unequivocally identified. Energy failure, transcriptional derangement and deadly nucleus-mitochondria cross-talk have been proposed as mechanisms responsible for PARP-1 neurotoxicity. In this study, we sought to determine how these mechanisms contributes to PARP-1-dependent neuronal death. We report that the PARP-1 activating agent methyl-nitrosoguanidine (MNNG) caused poly(ADP-ribosyl)ation-dependent death of pure mouse cortical neurons in culture. Upon PARP-1 hyperactivation, NAD and ATP storages only partially decreased, neurons rapidly acquired apoptotic morphology, apoptosis inducing factor and cytochrome c were released from mitochondria and caspase activation occurred. No evidence for p53 activation was found, lactate dehydrogenase release occurred only 18h later, and JNK kinase was constitutively activated and not affected by PARP-1 activation. The PARP-1 inhibitors 6-(5)H-phenanthridinone and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ-34) prevented nucleotide depletion and cell death, whereas the transcription inhibitor actinomycin D did not affect PARP-1-dependent neurotoxicity. Together, our findings provide the first evidence that neither energy collapse nor transcriptional changes are involved in PARP-1-dependent apoptotic neuronal death, and support the existence of a poly(ADP-ribose)-mediated death signaling targeting mitochondria.

Adenosine Triphosphate↗

PubMed2006

Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain.

Pharmacological manipulation of gene expression is considered a promising avenue to reduce postischemic brain damage. Histone deacetylases (HDACs) play a central role in epigenetic regulation of transcription, and inhibitors of HDACs are emerging as neuroprotective agents. In this study, we investigated the effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on histone acetylation in control and ischemic mouse brain. We report that brain histone H3 acetylation was constitutively present at specific lysine residues in neurons and astrocytes. It is noteworthy that in the ischemic brain tissue subjected to 6 h of middle cerebral artery occlusion, histone H3 acetylation levels drastically decreased, without evidence for a concomitant change of histone acetyl-transferase or deacetylase activities. Treatment with SAHA (50 mg/kg i.p.) increased histone H3 acetylation within the normal brain (of approximately 8-fold after 6 h) and prevented histone deacetylation in the ischemic brain. These effects were accompanied by increased expression of the neuroprotective proteins Hsp70 and Bcl-2 in both control and ischemic brain tissue 24 h after the insult. It is noteworthy that at the same time point, mice injected with SAHA at 25 and 50 mg/kg had smaller infarct volumes compared with vehicle-receiving animals (28.5% and 29.8% reduction, p < 0.05 versus vehicle, Student's t test). At higher doses, SAHA was less efficient in increasing Bcl-2 and Hsp70 expression and did not afford significant ischemic neuroprotection (13.9% infarct reduction). Data demonstrate that pharmacological inhibition of HDACs promotes expression of neuroprotective proteins within the ischemic brain and underscores the therapeutic potential of molecules inhibiting HDACs for stroke therapy.

Animals↗

PubMed2006

Poly(ADP-ribose) accumulation and enhancement of postischemic brain damage in 110-kDa poly(ADP-ribose) glycohydrolase null mice.

Poly(ADP-ribose) (PAR) is a polymer synthesized by poly(ADP-ribose) polymerases (PARPs) and metabolized into free adenosine diphosphate (ADP)-ribose units by poly(ADP-ribose) glycohydrolase (PARG). Perturbations in PAR synthesis have been shown to play a key role in brain disorders including postischemic brain damage. A single parg gene but two PARG isoforms (110 and 60 kDa) have been detected in mouse cells. Complete suppression of parg gene causes early embryonic lethality, whereas mice selectively lacking the 110 kDa PARG isoform (PARG(110)(-/-)) develop normally. We used PARG(110)(-/-) mice to evaluate the importance of PAR catabolism to postischemic brain damage. Poly(ADP-ribose) contents were higher in the brain tissue of PARG(110)(-/-) than PARG(110)(+/+) mice, both under basal conditions and after PARP activation. Distal middle cerebral artery occlusion caused higher increase of brain PAR levels and larger infarct volumes in PARG(110)(-/-) mice than in wild-type counterparts. Of note, the brain of PARG(110)(-/-) mice showed reduced heat-shock protein (HSP)-70 and increased cyclooxygenase-2 expression under both control and ischemic conditions. No differences were detected in brain expression/activation of procaspase-3, PARP-1, Akt, HSP-25 and interleukin-1beta. Our findings show that PAR accumulation worsens ischemic brain injury, and highlight the therapeutic potential of strategies capable of maintaining PAR homeostasis.

Adenosine Triphosphate↗

PubMed2006

Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts.

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1(-/-) than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP-27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1(-/-) than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-kappaB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

Animals↗

PubMed2005

Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction.

To obtain further information on time course and mechanisms of cell death after poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, we used HeLa cells exposed for 1 h to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. This treatment activated PARP-1 and caused a rapid drop of cellular NAD(H) and ATP contents, culminating 8-12 h later in cell death. PARP-1 antagonists fully prevented nucleotide depletion and death. Interestingly, in the early 60 min after challenge with N-methyl-N'-nitro-N-nitrosoguanidine, mitochondrial membrane potential and superoxide production significantly increased, whereas cellular ADP contents decreased. Again, these events were prevented by PARP-1 inhibitors, suggesting that PARP-1 hyperactivity leads to mitochondrial state 4 respiration. Mitochondrial membrane potential collapsed at later time points (3 h), when mitochondria released apoptosis-inducing factor and cytochrome c. Using immunocytochemistry and targeted luciferase transfection, we found that, despite an exclusive localization of PARP-1 and poly(ADP-ribose) in the nucleus, ATP levels first decreased in mitochondria and then in the cytoplasm of cells undergoing PARP-1 activation. PARP-1 inhibitors rescued ATP (but not NAD(H) levels) in cells undergoing hyper-poly(ADP-ribosyl)ation. Glycolysis played a central role in the energy recovery, whereas mitochondria consumed ATP in the early recovery phase and produced ATP in the late phase after PARP-1 inhibition, further indicating that nuclear poly(ADP-ribosyl)ation rapidly modulates mitochondrial functioning. Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death.

Adenosine Diphosphate↗

PubMed2005

Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-1 and enhances proliferation of glia cells, in vitro.

1. Kynurenic (KYNA) and quinolinic (QUIN) acids are neuroactive tryptophan metabolites formed along the kynurenine pathway: the first is considered a non-competitive antagonist and the second an agonist of glutamate receptors of NMDA type. The affinity of these compounds for glutamate receptors is, however, relatively low and does not explain KYNA neuroprotective actions in models of post-ischemic brain damage. 2. We evaluated KYNA effects on the release of fibroblast growth factor (FGF)-1, a potent neurotrophic cytokine. Because KYNA exhibits a neuroprotective profile in vitro and in vivo, we anticipated that it could function as an autocrine/paracrine inducer of FGF-1 release. Studies were performed in several models of FGF-1 secretion (FGF-1 transfected NIH 3T3 cells exposed to heat shock, A375 melanoma cells exposed to serum starvation, growth factor deprived human endothelial cells). To our surprise, KYNA, at low concentration, inhibited FGF-1 release in all cellular models. QUIN, a compound having opposite effects on glutamate receptors, also reduced this release, but its potency was significantly lower than that of KYNA. 3. KYNA and QUIN also displayed a major stimulatory effect on the proliferation rate of mouse microglia and human glioblastoma cells, in vitro. 4. Our data suggest that minor changes of local KYNA concentration may modulate FGF-1 release, cell proliferation, and ultimately tissue damage in different pathological conditions.

Animals↗

PubMed2005

Group I metabotropic glutamate receptors stimulate the activity of poly(ADP-ribose) polymerase in mammalian mGlu1-transfected cells and in cortical cell cultures.

Group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) coupled to phospholipase C have been widely investigated for their possible role in excitotoxic and post-ischemic neuronal death. Recently, phospholipase C has been shown to directly stimulate the activity of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair that has been proposed to play a key role in necrotic cell death. In this study, we investigated whether the stimulation of group I mGlu receptors leads to an increase in PARP activity, as detected by flow cytometry, immunodot blot and immunocytochemistry, both in baby hamster kidney cells transfected with mGlu1a or mGlu5a receptors and in cultured cortical cells. Our results show that the group I mGlu receptor agonist DHPG elicited a significant increase in PARP activity that was completely abolished by the administration of the mGlu1 antagonist 3-MATIDA and partially prevented, in cortical neurons, by the mGlu5 antagonist MPEP. To evaluate whether this pathway is involved in post-ischemic neuronal death, we used a sublethal model of oxygen-glucose deprivation in mixed cortical cell cultures. DHPG exacerbated neuronal death, and this effect was significantly prevented by the application of the PARP inhibitor DPQ. This novel pathway may contribute to the effects of mGlu1 receptors in the mechanisms leading to post-ischemic neuronal death.

Animals↗

PubMed2004

Inhibition of poly(ADP-ribose) glycohydrolase by gallotannin selectively up-regulates expression of proinflammatory genes.

Poly(ADP-ribose)-polymerase-1 (PARP-1) and poly(ADP-ribose) (PAR) are emerging key regulators of chromatin superstructure and transcriptional activation. Accordingly, both genetic inactivation of PARP-1 and pharmacological inhibition of PAR formation impair the expression of several genes, including those of the inflammatory response. In this study, we asked whether poly(ADP-ribose) glycohydrolase (PARG), the sole depoly(ADP-ribosyl)ating enzyme identified so far, also regulates gene expression. We report the novel finding that inhibition of PARG by gallotannin triggered nuclear accumulation of PAR and concomitant PAR-dependent expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), but not of interleukin-1beta and tumor necrosis factor-alpha, in cultured RAW 264.7 macrophages. Remarkably, silencing of PARG by means of small interfering RNA selectively impaired gallotannin-induced expression of iNOS and COX-2. Consistent with a PAR-dependent transcriptional activation, increases of iNOS and COX-2 transcripts were not caused by activation of transcription factors such as nuclear factor-kappaB, activator protein-1, signal transducer and activator of transcription-1 or interferon regulatory factor-1, nor by mRNA stabilization. Overall, our data provide the first evidence that pharmacological inhibition of PARG leads to PAR-dependent alteration of gene expression profiles in macrophages.

Animals↗

PubMed2004

Stereoselective synthesis and preliminary evaluation of (+)- and (-)-3-methyl-5-carboxy-thien-2-yl-glycine (3-MATIDA): identification of (+)-3-MATIDA as a novel mGluR1 competitive antagonist.

The synthesis of the (+)- and (-)-isomers of 3-methyl-5-carboxy-thyen-2-yl-glycine (3-MATIDA), heterocyle isosters of carboxyphenylglycines (CPGs), a known class of competitive metabotropic glutamate receptors, was accomplished by a stereoselective Ugi condensation. The two isomers were tested as potential rat mGluR1 ligand and the (+) isomer was found to be a moderately potent antagonist, while the (-) one was inactive.

Animals↗

PubMed2004

Differential role of poly(ADP-ribose) polymerase-1in apoptotic and necrotic neuronal death induced by mild or intense NMDA exposure in vitro.

Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) plays a key role in the mechanisms responsible for neuronal death. In the present study, we examined the effects of the PARP-1 inhibitor 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinone (DPQ) in two models of N-methyl-d-aspartate (NMDA)-induced neurotoxicity. The exposure of mixed cultured cortical cells to 300 microM NMDA for 10 min induced a caspase-dependent type of apoptotic neuronal death. Conversely, exposure to 2 mM NMDA for 10 min led to the appearance of morphological features of necrosis, with no increase in caspase-3 activity and depletion in adenosine triphosphate (ATP) levels. DPQ (10 microM) reduced the NMDA-induced PARP activation, restored ATP to near control levels and significantly attenuated neuronal injury only in the severe NMDA exposure model. Similar results were obtained when pure neuronal cortical cultures were used. PARP-1 activation thus appears to play a preferential role in necrotic than in caspase-dependent apoptotic neuronal death.

Adenosine Triphosphate↗

PubMed2004

Erythropoietin attenuates post-traumatic injury in organotypic hippocampal slices.

Recent experimental evidence indicates that erythropoietin (Epo), in addition to its hormonal role in regulating red cell production, operates as a neuroprotective agent. So far, the neuroprotective effect of human recombinant Epo (rhEpo) has been mainly demonstrated in models of cerebral ischemia/hypoxia and in selected in vivo studies of traumatic neuronal injury. To further investigate the potential role of this multifunctional trophic factor in post-traumatic cell death, we examined the protective effects of rhEpo in a newly developed model of mechanical trauma in organotypic hippocampal slices. Organotypic rat hippocampal slices were subjected to traumatic injury by allowing a stylus to impact on the CA1 area with an energy of 6 microJ. Hippocampal damage was identified and measured 24 and 48 h later with the fluorescent dye propidium iodide (PI). In untreated slices, the impact induced a significant increase in the mean hippocampal PI fluorescence, co-localized with the area of impact at 24 h (primary post-traumatic injury) and progressively spread to the whole slice between 24 and 48 h (secondary post-traumatic injury). Addition of rhEpo (1-100 UI/mL) or of the NMDA antagonist MK-801 (30 microM) immediately after the traumatic injury reduced hippocampal damage by approximately 30% when observed 24 h later. At 48 h after trauma, the protective effect of rhEpo was greater (by about 47%) and significantly more pronounced than that of MK-801 (28%). Our results suggest that the neuroprotective activity of rhEpo is particularly effective against delayed, secondary post-traumatic damage. This well tolerated agent could provide a therapeutic benefit in pathologies involving post-traumatic neurodegeneration.

Animals↗

PubMed2003

Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage.

Poly(ADP-ribose) polymerases (PARPs) are a group of protein-modifying and nucleotide-polymerizing enzymes able to catalyze the transfer of multiple ADP-ribose units from NAD to substrate proteins. In the human genome, 16 different genes encoding for members of this emerging family of enzymes have been identified. Known family members are PARP-1, PARP-2, PARP-3, vPARP, tankyrase 1 and tankyrase 2, each of them with a possible specific role in cell biology. The most studied member of the family is PARP-1, which is abundantly present in the nucleus and is involved in the maintenance of genomic stability. In pathological conditions, highly reactive radical species may cause DNA damage and PARP-1 hyperactivation. This may lead to necrotic cell death through massive NAD consumption. We show that following middle cerebral artery occlusion, rats treated with PARP inhibitors displayed reduced brain infarct volumes. Similarly, PARP inhibitors reduced neuronal death induced by oxygen-glucose deprivation (OGD) or excitotoxins in primary cultures of murine cortical cells. On the contrary, PARP inhibitors did not attenuate the OGD-induced selective loss of CA1 pyramidal cells in rat organotypic hippocampal slices. In addition, they were not neuroprotective against transient bilateral carotid occlusion in gerbils. We observed that post-ischemic brain damage was predominally necrotic in cultured cortical cells, whereas a caspase-dependent apoptotic process was responsible for the CA1 pyramidal cell loss in hippocampal slices. Hence, it appears reasonable to propose PARP inhibitors as useful therapeutic agents in pathological brain conditions were necrosis predominates.

Animals↗

PubMed2003

Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia.

Excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme catalyzing the transfer of ADP-ribose units from NAD to acceptor proteins, induces cellular energy failure by NAD and ATP depletion and has been proposed to play a causative role in a number of pathological conditions, including ischemia/reperfusion injury. In this study, we used an in vitro enzyme activity assay to characterize a series of newly synthesized isoquinolinone derivatives as potential PARP-1 inhibitors. Several compounds displayed powerful inhibitory activity: thieno[2,3-c]isoquinolin-5-one (TIQ-A) displayed a submicromolar IC50 of 0.45 +/- 0.1 microM, whereas the 5-hydroxy and 5-methoxy TIQ-A derivatives had IC50 values of 0.39 +/- 0.19 and 0.21 +/- 0.12 microM, respectively. We then examined the neuroprotective effects of the newly characterized compounds in cultured mouse cortical cells exposed to 60 min of oxygen and glucose deprivation (OGD). When PARP-1 inhibitors were present in the incubation medium during OGD and the subsequent 24-h recovery period, they significantly attenuated neuronal injury. TIQ-A provided neuroprotection even when added to the culture 30 min after OGD and was able to reduce the early activation of PARP induced by OGD as detected by flow cytometry. When the IC50 values observed in the PARP-1 activity assay for selected compounds were compared with their IC50 values for the neuroprotective activity, a significant correlation (r = 0.93, P < 0.01) was observed. Our results suggest that TIQ-A and its derivatives are a new class of neuroprotectants that may be helpful in studies aimed at understanding the involvement of PARP-1 in physiology and pathology.

Animals↗

PubMed2003

Topically applied minoxidil may cause fetal malformation: a case report.

BACKGROUND: Minoxidil is a K(+) channel opener able to cause relaxation of vascular smooth muscles and modify cell growth and cell fate or migration. It is now widely used for its hair growth promoting effects. When locally applied, it is absorbed through the skin and may have systemic pharmacological effects. CASE: A 28-year-old white pregnant woman daily applied minoxidil 2% to her scalp because of hair loss. At the 22nd gestational week, after a routine ultrasound test showing significant brain, heart, and vascular malformations of the fetus, pregnancy was interrupted. The placenta had numerous ischemic areas and a discrepancy between gestational age and villi maturation. In the villi, capillaries were increased in number, significantly enlarged, and excessively marginalized. The fetus' heart was increased in volume and had a globose shape, the aorta had a distal stenosis. The sigmoid colon was significantly increased in length and a mesentery commune was present. The brain had enlarged ventricles and abundant hemorrhages. Histological examination showed areas of demyelinization with gliosis, signs of excessive and inappropriate angiogenesis, and capillary rearrangement. CONCLUSIONS: Further knowledge on minoxidil-induced fetal toxicity would be beneficial before allowing its use in pregnant women.

Abnormalities, Drug-Induced↗

PubMed2003

Studies on the neuroprotective action of kynurenine mono-oxygenase inhibitors in post-ischemic brain damage.

Kynurenine 3-mono-oxygenase (KMO) inhibitors facilitate kynurenic acid (KYNA) neosynthesis and reduce the formation of 3OH-kynurenine (3-HK) and quinolinic acid (QUIN). They also attenuate post-ischemic brain damage and decrease glutamate (Glu) content in brain extracellular spaces. To investigate KMO mechanism(s) of neuroprotection, we performed experiments in gerbils subjected to bilateral carotid occlusion and in organotypic rat hippocampal slice cultures exposed to oxygen and glucose deprivation (OGD). In gerbils, direct application of KYNA (100 nM, through reverse microdialysis in the hippocampus) completely prevented the increase in Glu output induced by transient (5 min) occlusion of the carotids. In rat hippocampal slices exposed for 30 min to OGD, KMO inhibitors (m-nitrobenzoyl)-alanine (mNBA, 30-100 microM) or 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048, 1-10 microM) reduced post-ischemic neuronal death and increased KYNA concentrations in the incubation medium. KYNA may antagonize glycineb or alpha7 nicotinic acetylcholine receptors but the concentrations in the incubation medium never reached values that could efficiently antagonize receptor function. On the contrary, 3-HK (1-10 microM) added to slices exposed to OGD in the presence of KMO inhibitors completely prevented the neuroprotective effects of the inhibitors. Our findings suggest that KMO inhibitors reduce OGD-induced pyramidal cell death by decreasing 3-HK (and possibly QUIN) synthesis.

Animals↗

PubMed2003

Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors.

An excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme able to catalyze the transfer of ADP-ribose from NAD to acceptor proteins, is involved in the progression of neuronal damage after brain insult. Potent and selective PARP-1 inhibitors have neuroprotective properties in experimental models of brain ischemia. As a follow up of our previous structure-activity relationship study and in search for novel potent PARP-1 inhibitors, a series of 4H-thieno[2,3-c]-isoquinolin-5-one derivatives was designed and synthesized. Tested for their ability to inhibit PARP-1, these novel derivatives showed high inhibitory potency. The unsubstituted derivative TIQ was selected for further characterization and found to be endowed with strong neuroprotective properties in models of cerebral ischemia.

Animals↗

PubMed2003

5-hydroxyindole causes convulsions and increases transmitter release in the CA1 region of the rat hippocampus.

1 5-hydroxyindole (5-OHi) is a proposed tryptophan metabolite able to cause convulsions when systemically injected into rodents. We studied its effects using microdialysis in vivo and electrophysiological approaches in vitro. 2 Local administration of 5-OHi into the CA1 region of the rat hippocampus, via a microdialysis probe, significantly increased glutamate concentrations in the dialysates. 3 In rat hippocampal slices, using extracellular recordings in the CA1 region, 5-OHi (30-300 microM) increased the amplitude of population spikes and fEPSPs. 4 In the same preparation, using intracellular recordings in CA1 pyramidal neurons, 5-OHi reduced the latency of firing induced by direct depolarization and increased both evoked excitatory and slow inhibitory postsynaptic potential amplitudes, without affecting the resting membrane potential, the after-hyperpolarization or the neuronal input resistance. It also altered GABA(A)-mediated neurotransmission by increasing the frequency and the amplitude of pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSC). 5 In separate experiments, performed by measuring AMPA or NMDA-induced depolarization in cortical wedges, 5-OHi did not modify glutamate receptor agonist responses. 6 Our results show that 5-OHi causes convulsions, modifies the properties and the function of the hippocampal circuitry, and facilitates the output of both excitatory and inhibitory transmitters.

Action Potentials↗