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F Laliberte

Publications and source records attributed to F Laliberte.

12 recordsLinked to original sources
PubMed2006

Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline.

A major obstacle in the therapeutic development of phosphodiesterase-4 (PDE4) inhibitors is the production of adverse side effects such as nausea and vomiting. Immunohistochemical detection of Fos-like immunoreactivity (FLI) was used to address the neuroanatomical basis for the pharmacological actions of PDE4 inhibitors. The potent and selective PDE4 inhibitors 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline (PMNPQ) and rolipram elevated FLI in brain regions potentially relevant to the anti-depressant and emetic effects of PDE4 inhibition. PMNPQ and rolipram elevated FLI in the locus coeruleus, habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. Consistent with the emetic effects of PDE4 inhibitors such as PMNPQ and rolipram, these compounds elevated FLI in caudal brainstem nuclei such as the area postrema and nucleus of the solitary tract. Administration of the NK(1) antagonist RP 67580 prior to PMNPQ reversed increases in FLI produced by PMNPQ in these regions. RP 67580 did not, however, reduce PMNPQ-induced FLI in limbic structures. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, habenula and nucleus accumbens in the anti-depressant activity of such compounds.

Analgesics↗
PubMed1998

CDP840: a novel inhibitor of PDE-4.

We present the in vitro characterization of a novel phosphodiesterase type 4 inhibitor, CDP840 (R-[+]-4-[2-¿3-cyclopentyloxy-4-methoxyphenyl¿-2-phenylethyl]pyridine), which has shown efficacy in a phase II allergen challenge study in asthmatics without adverse effects. CDP840 potently inhibits PDE-4 isoenzymes (IC50 2-30 nM) without any effect on PDE-1, 2, 3, 5, and 7 (IC50 > 100 microM). It exhibited no significant selectivity in inhibiting human recombinant isoenzymes PDE-4A, B, C or D and was equally active against the isoenzymes lacking UCR1 (PDE-4B2 and PDE-4D2). In contrast to rolipram, CDP840 acted as a simple competitive inhibitor of all PDE-4 isoenzymes. Studies with rolipram indicated a heterogeneity within all the preparations of PDE-4 isoenzymes, indicative of rolipram inhibiting the catalytic activity of PDE-4 with both a low or high affinity. These observations were confirmed by the use of a PDE-4A variant, PDE-4A330-886, which rolipram inhibited with low affinity (IC50 = 1022 nM). CDP840 in contrast inhibited this PDE-4A variant with similar potency (IC50 = 3.9 nM), which was in good agreement with the Kd of 4.8 nM obtained from [3H]-CDP840 binding studies. Both CDP840 and rolipram inhibited the high-affinity binding of [3H]-rolipram binding to PDE-4A, B, C, and D with similar Kd app (7-19 nM and 3-5 nM, respectively). Thus, the activity of CDP840 at the [3H]-rolipram binding site was in agreement with the inhibitor's activity at the catalytic site. However, rolipram was approximately 100-fold more potent than CDP840 at inhibiting the binding of [3H]-rolipram to mouse brain in vivo. These data clearly demonstrate that CDP840 is a potent selective inhibitor of all PDE-4 isoenzymes. In contrast to rolipram, CDP840 was well-tolerated in humans. This difference, however, cannot at present be attributed to either isoenzyme selectivity or lack of activity in vitro at the high-affinity rolipram binding site (Sr).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline.

Extracellular phospholipases A2 play an important role in articular and extra-articular inflammatory processes. Secretory non-pancreatic phospholipase A2 (PLA2) has been implicated in the pathogenesis of articular inflammation in rheumatoid arthritis, whereas pancreatic PLA2 contributes to the tissue damage associated with acute pancreatitis. Since in experimental models lipophilic tetracyclines such as minocycline and doxycycline are antiinflammatory, we examined their effects on PLA2 activity using two assay systems in vitro. We found that minocycline and to a lesser degree doxycycline were markedly inhibitory to both pancreatic and non-pancreatic PLA2. Using [14C]oleic acid labeled Escherichia coli membrane phospholipids as substrate, the IC50 values for minocycline and doxycycline were 3.6 x 10(-5) M (18 micrograms/mL) and 0.98 x 10(-4) M (47 micrograms/mL), respectively. In a scooting mode assay using the synthetic phospholipid 1-palmitoyl-2-(10-pyrenedecanoyl)-3-L-phosphatidylmethanol as substrate, IC50 values for minocycline were 5 microM (2.47 micrograms/mL) for non-pancreatic PLA2 and 8 microM (3.95 micrograms/mL) for pancreatic PLA2. Addition of excess calcium up to 50 mM did not reverse the inhibitory activity of tetracyclines. We conclude that lipophilic tetracyclines inhibit PLA2, probably by interaction with the substrate, and may be a useful adjunct in the therapy of inflammatory conditions in which PLA2 is implicated pathogenetically.

Animals↗
PubMed1988

Immunohistochemistry of angiotensin I-converting enzyme in rat eye structures involved in aqueous humor regulation.

Angiotensin-converting enzyme (ACE) was localized by immunohistochemical methods in rat eye structures involved in aqueous humor secretion and reabsorption, i.e., the ciliary processes, the trabeculum, and Schlemm's canal. The three-layer peroxidase-antiperoxidase method was used with light and electron microscopy. In the ciliary processes, ACE was found on the basal plasma membrane of the internal epithelium facing the aqueous humor and on vesicles in its vicinity, whereas neither the external epithelium nor the blood vessels running through the ciliary processes were immunoreactive. A faint ACE immunoreactivity was found on some endothelial cell plasma membranes of both the internal collector channels and Schlemm's canal. These results suggest that the ciliary process internal epithelium could be an important site for the production of angiotensin II and/or the metabolism of bradykinin. In addition, the present investigation provides evidence for ACE involvement in aqueous humor secretion, whereas its involvement in aqueous humor reabsorption may be minor.

Animals↗
PubMed1987

Cellular and subcellular immunohistochemical localization of angiotensin-converting enzyme in the rat adrenal gland.

Angiotensin-converting enzyme (ACE) was localized by immunocytochemical methods in the rat adrenal gland. The three-layer peroxidase-antiperoxidase method was used with light and electron microscopy. At the cortical level, ACE immunoreactivity occurred only on the luminal side of vascular endothelial cell membranes in the adrenal capsule, whereas no ACE activity was found in the zona glomerulosa, fasciculata, or reticularis. ACE immunoreactivity was found mainly but not exclusively on the luminal side of all the types of vessels in the adrenal medulla such as capillaries, venous sinuses, and arteriae medullae. In addition, ACE was localized on the plasma membrane of chromaffin cells but never in Schwann cells nor in nerve fibers. These results provide evidence for a local production of angiotensin II at the vascular level in the adrenal gland. In addition, the presence of ACE on the plasma membrane of chromaffin cells suggests that angiotensin II or other peptides, such as bradykinin, could be metabolized here.

Adrenal Cortex↗
PubMed1981

Immunoenzymatic study of the protein pathway through the glomerular barrier in rat glomerulonephritides.

Circulating anti-horseradish peroxidase (HRP) IgG antibodies were used in the rat to study the glomerular leakage of proteins in glomerulonephritis (GN) induced by aminonucleoside (AN) and in glomerulonephritis induced by mercuric chloride to produce anti-glomerular basement membrane (GBM) antibodies. In ANGN, autologous albumin and fibrinogen were also detected by immunoperoxidase techniques. In both types of GN, the proteins studied were observed in the glomerular urinary space and proximal tubular cells. No channels were visible in the lamina densa. No accumulation of proteins was seen under the epithelial slits that were not closed. In ANGN, accumulation of proteins was observed in the subepithelial space where the podocytes act as a barrier (closed slits, subepithelial blind pockets, areas covered by broad sheets of cytoplasm), but no accumulation was seen in the lamina rara externa under normal or enlarged slits and areas of large epithelial cytoplasm detachment. Statistical analysis showed that in ANGN, at the time of maximal proteinuria, the number of "micropinocytotic" vesicles in the GBM-embedded part of podocytes was not increased as compared with controls. Such vesicles were not labeled. We conclude that in both types of GN, the permeability of the GBM is diffusely increased and that the plasma proteins pass into the urinary space via an extracellular pathway.

Animals↗
PubMed1977

[Ultrastructural study of the glomerular filtration barrier and of tubular reabsorption with anti-peroxidase antibodies and their fragments].

Using anti-peroxidase Sheep IgG or their pepsic or papainic fragments intravenously injected to Wistar Munich normal Rats, the glomerular filtration barrier was localized at the lamina densa in ultrastructural studies. No evidence was found favoring the existence of a second barrier. The filtration barrier is absolute for the IgG but not for the pepsic and especially the papainic fragments which are reabsorbed by the proximal tubule.

Animals↗
PubMed1971

Glomerulonephritis with - and 1C-globulin deposits induced in rats by mercuric chloride.

Repeated subcutaneous injections of 0.15 or 0.25 mg/100 g of body weight of HgCl(2) may induce a membranous glomerulonephritis in rats. This glomerulonephritis with subepithelial deposits is similar, by electron microscopy and immunohistochemistry, to experimental chronic glomerulonephritis caused by immune complexes and to the human membranous glomerulonephritis.

Animals↗