Interaction of fluorescein derivatives with glibenclamide binding sites in rat brain.

In rat brain, [3H]glibenclamide binds with high affinity to sulfonylurea receptors associated with ATP-sensitive potassium (KATP) channels. KATP channels may play a modulatory role in neurotransmitter release and are involved in acute pathological events occurring in the brain. Fluorescein derivatives, which are suitable tools for the labelling of nucleotide binding sites, influence KATP channels and sulfonylurea receptors properties in insulinoma and cardiac cells. In this study, a negative allosteric action of fluorescein derivatives on glibenclamide binding sites has been shown in rat cortical neurons. This supports the hypothesis of interactions between nucleotide- and sulfonylurea-binding sites within the sulfonylurea receptor.

Quantitative assessment of quinolinic acid-induced striatal toxicity in rats using radioligand binding assays.

To validate specific, sensitive and quantitative markers of the rat model of Huntington's disease produced by the intrastriatal injection of quinolinic acid, we used striatal homogenate binding assays for [3H]MK-801-labelled N-methyl-D-aspartate receptors, [3H]SCH 23390-labelled D1 and [3H]sulpiride-labelled D2 dopamine receptors, [3H]CGS 21680-labelled adenosine A2 receptors, [3H]GBR 12935-labelled dopamine uptake sites, [3H]hemicholinium-3-labelled high affinity choline uptake sites and [3H]PK 11195-labelled glial cells, in 3 groups of rats: 1) lesioned only, 2) pretreated with MK-801, an antagonist of the N-methyl-D-aspartate receptor, to assess the non-N-methyl-D-aspartate-mediated toxicity of quinolinic acid, and 3) pretreated with MK-801 plus scopolamine, an anticholinergic drug that prevents MK-801 neuronal toxicity. [3H]MK-801 and [3H]PK 11195 are sensitive markers of quinolinic acid toxicity. In addition, [3H]SCH 23390, [3H]CGS 21680 and [3H]hemicholinium-3, are found to be specific markers of quinolinic acid-induced toxicity on striatonigral and striatopallidal projecting neurons, and on large interneurons, respectively. MK-801 pretreatment prevented the quinolinic acid-induced reduction in binding of [3H]MK-801, [3H]SCH 23390 and [3H]CGS 21680 but failed to do so for [3H]sulpride and [3H]hemicholinium-3, suggesting that quinolinic acid may act by mechanisms other than direct activation of N-methyl-D-aspartate receptors. Combined pretreatment with MK-801 and scopolamine increased the protection against quinolinic acid, suggesting an involvement of the cholinergic system.

Sulfonylurea binding sites in normal human brain and in Parkinson's disease, progressive supranuclear palsy and Huntington's disease.

In human brain, [3H]glibenclamide binds with high affinity (KD about 3.5 nM) to sulfonylurea binding sites which are associated with ATP-sensitive potassium (KATP) channels. Regarding to the important neuromodulatory action of KATP channels in some neuronal populations, sulfonylurea binding sites were measured in several cortical areas (frontal and temporal cortex, hippocampus) and striatum (caudate nucleus and putamen) in controls and patients with Parkinson's disease or progressive supranuclear palsy. There was no modification of [3H]glibenclamide specific binding in the cerebral regions studied in both pathologies. These results indicate that KATP channels do not seem to be involved in the pathophysiology of these degenerative processes. Brain samples from five patients with Huntington's disease were studied. A small decrease in sulfonylurea binding sites was measured in the frontal cortex, caudate nucleus and putamen which could be due to the loss of either neurons or nerve endings. This low decrease contrasts with the dramatic diminution of many other markers associated with the profound striatal degeneration occurring in Huntington's disease.

NMDA glutamatergic receptors, labelled with [3H]MK-801, in brain samples from drug-free depressed suicides.

Glutamate receptors of the NMDA-subtype were quantitated by binding of [3H]dizocilpine maleate (MK-801) in nine brain regions from 22 suicide victims (20-60 yr), with a firm retrospective diagnosis of depression, who had not recently received antidepressant drugs, and 20 age- and sex-matched controls. [3H]MK-801-binding did not differ between suicides and controls in any region studied. Suicides who died violently did not differ from non-violent suicides and controls. A significative negative correlation was found between age and NMDA receptor-binding in the frontal cortex of suicide victims, but not in controls. This preliminary study provides little evidence for an important role of NMDA-binding sites in the pathophysiology of depression.

[3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

The interactions existing between glutamatergic and dopaminergic systems, notably in the basal ganglia, suggest that glutamatergic antagonists may have therapeutic interest in extrapyramidal disorders characterized by impaired dopaminergic transmission. The binding of [3H]dizocilpine maleate (MK-801) to glutamate receptors of the N-methyl-D-aspartate (NMDA)-subtype was characterized in temporal and frontal cortex, in hippocampus and in subcortical areas (caudate nucleus and putamen) from controls and patients with Parkinson's disease or progressive supranuclear palsy. The binding affinity (KD) and the maximal specific binding capacity (Bmax) of [3H]MK-801 were unchanged in all the cerebral regions studied in both diseases. This indicates the existence of preserved NMDA glutamate receptors, which is required for potential therapeutic efficacy of specific antagonists.