Yvette Michotte — Page 3

PubMed2002

Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures.

Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.

Action Potentials↗

PubMed2002

Cellular targets for angiotensin II fragments: pharmacological and molecular evidence.

Although angiotensin II has long been considered to represent the end product of the renin-angiotensin system (RAS), there is accumulating evidence that it encompasses additional effector peptides with diverse functions. In this respect, angiotensin IV (Ang IV) formed by deletion of the two N terminal amino acids, has sparked great interest because of its wide range of physiological effects. Among those, its facilitatory role in memory acquisition and retrieval is of special therapeutic relevance. High affinity binding sites for this peptide have been denoted as AT(4)- receptors and, very recently, they have been proposed to correspond to the membrane-associated OTase/ IRAP aminopeptidase. This offers new opportunities for examining physiological roles of Ang IV in the fields of cognition, cardiovascular and renal metabolism and pathophysiological conditions like diabetes and hypertension. Still new recognition sites may be unveiled for this and other angiotensin fragments. Recognition sites for Ang-(1-7) (deletion of the C terminal amino acid) are still elusive and some of the actions of angiotensin III (deletion of the N terminal amino acid) in the CNS are hard to explain on the basis of their interaction with AT(1)-receptors only. A more thorough cross-talk between in vitro investigations on native and transfected cell lines and in vivo investigations on healthy, diseased and transgenic animals may prove to be essential to further unravel the molecular basis of the physiological actions of these small endogenous angiotensin fragments.

Angiotensin I↗