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1.
Neurochem Res ; 39(8): 1502-10, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24858241

ABSTRACT

It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer's disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer's disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer's disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer's disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer's disease < old controls). Differences among groups were observed also in thioflavin-T-based fluorescence (young controls = multiple sclerosis < Alzheimer's disease < old controls) and the most marked change from native to thioflavin-T-based fluorescence was found in young controls (28-40 years old people). Both ferrofluid and spirobrassinin evoked drops in thioflavin-T-based fluorescence; however, ferrofluid was more efficient in old controls (54-75 years old people) and spirobrassinin in multiple sclerosis patients, both compared to young controls. The results are discussed especially in relation to aggregated peptides/proteins and liposoluble fluorescent products of lipid peroxidation. Based on the significant effect of spirobrassinin in vitro, we suggest that spirobrassinin may be of therapeutic value in multiple sclerosis.


Subject(s)
Aging/cerebrospinal fluid , Chlorides/cerebrospinal fluid , Ferric Compounds/cerebrospinal fluid , Ferrous Compounds/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Spiro Compounds/cerebrospinal fluid , Thiazoles/cerebrospinal fluid , Adult , Aged , Benzothiazoles , Female , Fluorescence , Fluorescent Dyes/analysis , Humans , Male , Middle Aged , Multiple Sclerosis/diagnosis
2.
J Pharmacol Exp Ther ; 333(1): 152-60, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20065019

ABSTRACT

Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Autoradiography , Binding, Competitive , Biological Transport , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/blood , Bridged Bicyclo Compounds, Heterocyclic/cerebrospinal fluid , Cell Line , Chlorocebus aethiops , Female , Humans , Kinetics , Macaca mulatta , Male , Mice , Radioligand Assay , Receptors, Adrenomedullin , Receptors, Calcitonin/metabolism , Receptors, Calcitonin Gene-Related Peptide/physiology , Receptors, Islet Amyloid Polypeptide , Receptors, Peptide/metabolism , Spiro Compounds/blood , Spiro Compounds/cerebrospinal fluid , Vasodilation/drug effects
3.
J Pharmacol Exp Ther ; 294(3): 1112-9, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10945867

ABSTRACT

Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.


Subject(s)
Motor Activity/physiology , Nicotine/pharmacology , Receptors, Nicotinic/physiology , Animals , Bridged-Ring Compounds/cerebrospinal fluid , Bridged-Ring Compounds/pharmacology , Electrophysiology , Humans , In Vitro Techniques , Ligands , Male , Nicotinic Agonists/pharmacology , Oocytes/metabolism , Pyridines/pharmacology , Pyrrolidines/pharmacology , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, Nicotinic/drug effects , Reward , Self Administration , Spiro Compounds/cerebrospinal fluid , Spiro Compounds/pharmacology , Transfection , Xenopus laevis , alpha7 Nicotinic Acetylcholine Receptor
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