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Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes labeled with [ 3H]PK 11195
No full textEvidence suggests that peripheral-type benzodiazepine receptors (PBRs) may play a role in hepatic encephalopathy (HE), a condition associated with increased levels of ammonia in brain. In the present study, the regulation of [
3H]PK 11195-binding to PBRs in cultured rat astrocytes that had been previously exposed to NH
4Cl was investigated. 24 h treatment of 21–28-day-old cultures with 2, 5 or 10 mM NH
4Cl resulted in 25 ± 3, 48 ± 3 and 42 ± 4% increase in the number of [
3H]PK 11195-binding sites, respectively. No further change in [
3H]PK 11195-binding was observed after exposure of astrocytes to 5 mM NH
4Cl for 48 or 72 h. Ammonia treatment did not cause any significant alteration in the affinity of [
3H]PK 11195 for PBRs. The present study demonstrates the susceptibility of the PK 11195-binding site of PBRs in cultured astrocytes to ammonia and suggests that increase in brain ammonia concentration causes a supersensitivity of PBRs
PK 11195 reduces the brain availability of lindane in rats and the convulsions induced by this neurotoxic agent
No full textThe effect of pretreatment with PK 11195, a ligand of the ‘peripheral-type’ benzodiazepine receptor (PBR), on convulsions induced by lindane (γ-hexachlorocyclohexane, γ-HCH) in rats was examined, to determine whether the mechanism of this convulsant activity may be mediated through the PBR. PK 11195 elicited a protective effect against the convulsant activity of orally administered lindane. It reduced the frequency of animals exhibiting convulsions and delayed the time to onset of these seizures. The concentration of lindane in the brain was found to be significantly lower in PK 11195 pretreated rats and a high correlation between blood and brain lindane concentrations was obtained. When similar experiments were repeated with α-HCH, a non-convulsant isomer of HCH, brain and blood concentrations were again found to be significantly reduced in PK 11195 pretreated animals. We conclude that the ‘nticonvulsant’ action of PK 11195 was not due to an interaction of PK 11195 and lindane on common CNS target sites, but by an action of PK 11195 on the gastrointestinal tract of the animal, delaying the absorption of lindane into the bloodstream.This work has been supported by grants from the CEC programmes BRIDGE (BIOT-CT90-0183) and BIOTECH (CT93-0224), the Spanish CICYT (SAL91-0707), FIS (95/1955) and SAF (94-0076) projects and the European Science Foundation
Inhibition of glucose-induced insulin secretion by a peripheral-type benzodiazepine receptor ligand (PK 11195)
No full textInternational audienceWe have recently shown that benzodiazepines with high affinity for peripheral-type receptors such as 4'-chlordiazepam inhibit insulin secretion in vitro. PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxami de], a potent and selective ligand for peripheral benzodiazepine binding sites, was also shown to inhibit insulin release from rat pancreatic islets. Both substances have been reported to interact with mitochondrial binding sites. Hence, the present study was performed to investigate the effects of PK 11195 on insulin secretion induced by either a metabolic or a non-metabolic stimulus. In the rat isolated pancreas perfused at a constant pressure with a Krebs-bicarbonate buffer containing a slightly stimulating glucose concentration (8.3 mM), PK 11195 (10(-7)-10(-5) M) induced a progressive and concentration-dependent decrease in insulin secretion. Simultaneously, we recorded the effects on the pancreatic flow rate; in contrast to 4'-chlordiazepam, previously shown to induce vasodilation in the same preparation, PK 11195 was ineffective. The differential effects of these two substances on vascular resistance and insulin secretion may suggest the existence of different subtypes of peripheral benzodiazepine receptors on pancreatic beta-cells and vessels. A metabolic stimulation of insulin secretion was induced by a glucose increment from 4.2 mM to 8.4 mM or by 2 mM alpha-ketoisocaproic acid (KIC), which is directly metabolized in the mitochondria; these stimulations could be reduced by 10(-5) M PK 11195 (P<0.05). In contrast, the drug was ineffective on the insulin secretion induced by 5 mM or 10 mM KCl in the presence of a nonstimulating glucose concentration (4.2 mM). These results suggest that PK 11195 inhibits insulin secretion by interfering with mitochondrial oxidative metabolism
Biodistribution and dosimetry of [I-123]iodo-PK 11195:a potential agent for SPET imaging of the peripheral benzodiazepine receptor
No full textThe highest concentrations of the peripheral benzodiazepine receptor (PBR) are found in the kidneys and heart. In addition, the PER has been reported to reflect neuro-inflammatory damage by co-localisation with activated microglia. PK 11195 is a high-affinity ligand for the PER. The aim of this study was to investigate in humans the biodistribution and dosimetry of [I-123]iodo-PK 11195, a potential single-photon emission tomography tracer for the PER. Five healthy volunteers were injected with 112 MBq of [I-123]iodo-PK 11195. Sequential whole-body scans were performed up to 72 h post injection. Multiple blood samples were taken, and urine was collected to measure the fraction voided by the renal system. Decay-corrected regions of interest of the whole-body images were analysed, and geometric mean count rates were used to determine organ activity. Organ absorbed doses and effective dose were calculated using the MIRD method. [I-123]iodo-PK 11195 was rapidly cleared from the blood, mainly by the hepatobiliary system. Approximately 22% was voided in urine after 48 h. Average organ residence times were 0.74, 0.44 and 0.29 h for the liver, upper large intestine and lower large intestine, respectively. The testes received the highest dose. 109.4 mu Gy/MBq. All other organs investigated received doses of less than 50 mu Gy/MBq. The effective dose was 40.3 mu Sv/MBq. In conclusion, [I-123]iodo-PK 11195 is a suitable agent for the visualisation of the PER and indirectly for the imaging of neuro-inflammatory lesions. Taking into account the radiation burden of 7.46 mSv following an administration of 185 MBq, a [I-123]iodo-PK 11195 investigation has to be considered an ICRP risk category IIb investigation.</p
Binding of PK 11195 to bacterial TSPO of <i>Pseudomonas fluorescens</i> MF37.
No full text<p>(a) Demonstration of the binding of [<sup>3</sup>H] PK 11195 at the position of the TSPO-immunoreactive band visualized by western blots in <i>P. fluorescens</i> MF37 extracts. (b) Scatchard plot showing the binding characteristics of PK 11195 to TSPO of <i>P. fluorescens</i> MF37. The maximal binding potential (Bmax) is 0.087 pmole.µ g<sup>−1</sup> bacterial protein and the Kd is 0.92 nM.</p
Optimized palladium-based approaches to analogues of PK 11195
No full textInternational audienceThe peripheral-type benzodiazepine receptor ligands such as PK 11195 and Ro 5-4864 were found more than twenty years ago in the course of research on neurobiology. These ligands were instrumental in pointing out an involvement of the peripheral-type benzodiazepine receptor (PBR) in apoptosis processes. With in mind an improvement of the solubility of PK 11195 in biological media, we report here improved reaction conditions for the palladium-based arylation reaction of alkyl 1-bromoisoquinoline-3-carboxylates and its ethyl 4-bromoquinoline-2-carboxylate isomer. The use of [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium as a precatalyst enabled a much improved preparation of an array of the 1-arylisoquinoline-3-carboxylates as well as 4-arylquinoline-3-carboxylates. This work should pave the way for the design of chemical probes aiming at the elucidation of the PBR biological role(s)
Benzodiazepine receptors along the nephron: [3H]PK 11195 binding in rat tubules
No full textAbstractBinding of [3H]PK 11195, an isoquinoline carboxamide derivative, was measured in microdissected tubule segments of rat nephron. High specific binding capacities (1.1–1.8 fmol·mm−1) were found in the thick ascending limb of the Henle's loop and in the collecting tubule, whereas specific binding could not be detected in the proximal tubule. In the medullary collecting tubule, the association and dissociation rate constants at 4°C were k1 = 3.0 × 106 M−1·min−1 and k−1 = 0.021 min−1; the ratio k−1/k1 = 7.0 nM was in agreement with the estimated equilibrium dissociation constant (Kd = 2.4 nM). [3H]PK 11195 binding sites from medullary ascending limb and medullary collecting tubule revealed the following sequence of specificity: PK 11195 = Ro 5-4864 ⪢ clonazepan, indicating that tubule binding sites might be the peripheral benzodiazepine receptors of the rat kidney
Chronic MA treatment increases [<sup>3</sup>H]PK 11195 binding in the brain.
No full textRepresentative in vitro autoradiographic images of [3H]PK 11195 binding in coronal brain sections of rats chronically treated with vehicle or with LD MA (4mg/kg) or with HD MA (8mg/kg). Significant effects of methamphetamine treatment on [3H]PK 11195 specific binding were observed in the highlighted areas, i.e. PrL: prelimbic cortex, Ins: insular cortex, Cing: cingulate cortex, CPu: caudate-putamen (striatum), nAc: nucleus accumbens, Rhi: rhinal cortex, dcn: deep cerebellar nuclei.</p
Effects of PK 11195 on endogenous ALA-PpIX accumulation.
No full textTHP-1 macrophages were incubated for 3 hours with 5-aminolevulinic acid (ALA) with or without PK 11195. (A) Red fluorescence of intracellular PpIX was identified by fluorescence microscope. Scar bar: 0.1 mm. (B) Fluorescence intensity of PpIX was measured by fluorescence microplate reader. ***P ##P < 0.01 compared to ALA treated group.</p
Biodistribution and dosimetry of [I-123]iodo-PK 11195: a potential agent for SPET imaging of the peripheral benzodiazepine receptor
No full textThe highest concentrations of the peripheral benzodiazepine receptor (PBR) are found in the kidneys and heart. In addition, the PER has been reported to reflect neuro-inflammatory damage by co-localisation with activated microglia. PK 11195 is a high-affinity ligand for the PER. The aim of this study was to investigate in humans the biodistribution and dosimetry of [I-123]iodo-PK 11195, a potential single-photon emission tomography tracer for the PER. Five healthy volunteers were injected with 112 MBq of [I-123]iodo-PK 11195. Sequential whole-body scans were performed up to 72 h post injection. Multiple blood samples were taken, and urine was collected to measure the fraction voided by the renal system. Decay-corrected regions of interest of the whole-body images were analysed, and geometric mean count rates were used to determine organ activity. Organ absorbed doses and effective dose were calculated using the MIRD method. [I-123]iodo-PK 11195 was rapidly cleared from the blood, mainly by the hepatobiliary system. Approximately 22% was voided in urine after 48 h. Average organ residence times were 0.74, 0.44 and 0.29 h for the liver, upper large intestine and lower large intestine, respectively. The testes received the highest dose. 109.4 mu Gy/MBq. All other organs investigated received doses of less than 50 mu Gy/MBq. The effective dose was 40.3 mu Sv/MBq. In conclusion, [I-123]iodo-PK 11195 is a suitable agent for the visualisation of the PER and indirectly for the imaging of neuro-inflammatory lesions. Taking into account the radiation burden of 7.46 mSv following an administration of 185 MBq, a [I-123]iodo-PK 11195 investigation has to be considered an ICRP risk category IIb investigation
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