Az Angiotenzin IV neuromoduláció és az AT4R/IRAP expresszió vizsgálata a prefrontális kéregben
Papp Zsolt Tamás
Pharmaceutical Sciences
Dr. Zelkó Romána
NET Farmakológiai és Farmakoterápiás Intézet, Knoll (Issekutz) terem
2025-11-12 14:00:00
Experimental and Clinical Pharmacology
Dr. Szökő Éva
Dr. Köles László
Dr. Szőke Éva
Dr. Ruisanchez Éva
Dr. Balla András
Dr. Mike Árpád
Dr. Magyar Máté
Physiologically, the prefrontal cortex may have a role in thinking and short term memory, in which glutamatergic neurotransmission and NMDA receptors are of particular importance. Pathological changes are observed in dementias and schizophrenia. Despite their frequency and severity, the pharmacological therapy is still not completely resolved in any of the diseases. Overactivity of the glutamate system leads to apoptosis and neurodegeneration, whereas complete inhibition of NMDA receptors causes severe side effects. Drug development is increasingly aimed at the fine tuning of the receptor. The brain renin angiotensin system has been recognized in recent decades and its role has been implicated in the neuromodulation of glutamatergic synapses, NMDA receptors. Ang IV stimulates memory in the healthy and improves or reverses memory impairments in cognitive disorders. Due to its peptide structure, it exhibits a poor pharmacokinetic profile. Efforts are being made to find its analogues by virtual and substance library screening and direct design. The clarification of Ang IV’s precise target and exact mechanism of action is of great relevance for drug development.
In our studies, we demonstrated that a wide concentration range of Ang IV, from 1 nM to 1 μM, exerts a negative allosteric modulatory effect on NMDA receptors in the layer V pyramidal cells of 9 12 days old rat PFC. The inhibition was mimicked by another IRAP inhibitor, LVVYP H7, consequently, the mechanism of action may be the suppression of aminopeptidase activity. The inhibition was not abolished by synaptic isolation, therefore a role for intercellular connectivity is excluded. Furthermore, our studies mapped the cell specific localization of Ang IV’s receptor, AT4R/IRAP. We detected both of its nucleic acid and protein levels in the PFC of rats of different ages. Marked expression was observed in cell layers II III. and V VI. Based on morphology and cell markers, we identified its expression in pyramidal neurons and GABAergic interneurons, but could not detect it in microgliae and astrocytes.
Our results may explain the nootropic and neuroprotective properties of Ang IV and the catalytic domain of IRAP may represent a suitable target for the pharmaceutical industry to develop NMDAR negative allosteric modulators for the treatment of PFC associated diseases.
