We investigated the molecular events triggered by NMDA and 3,5-dihydroxyphenylglycine (DHPG) preconditioning, that lead to neuroprotection against excitotoxic insults (AMPA or oxygen and glucose deprivation) in rat organotypic hippocampal slices, with particular attention on glutamate receptors and on cannabinoid system. We firstly evaluated the protein expression of NMDA and AMPA receptor subunits after preconditioning using western blot analysis performed in post-synaptic densities. We observed that following NMDA, but not DHPG preconditioning, the expression of GluA1 was significantly reduced and this reduction appeared to be associated with the internalization of AMPA receptors. Whole-cell voltage clamp recordings on CA1 pyramidal neurons of organotypic slices show that 24 hr after exposure to NMDA and DHPG preconditioning, AMPA-induced currents were significantly reduced. To clarify the mechanisms induced by DHPG preconditioning, we then investigated the involvement of the endocannabinoid system. Exposure of slices to the CB1 antagonist AM251 prevented the development of tolerance to AMPA toxicity induced by DHPG but not NMDA. Accordingly, the MAG-lipase inhibitor URB602, that increases arachidonoylglycerol (2-AG) content, but not the FAAH inhibitor URB597, that limits the degradation of anandamide, was also able to induce tolerance versus AMPA and OGD toxicity, suggesting that 2-AG is responsible for the DHPG-induced tolerance. In conclusion, preconditioning with NMDA or DHPG promotes differential neuroprotective mechanisms: NMDA by internalization of GluA1-AMPA receptors, DHPG by producing the endocannabinoid 2-AG. (Figure presented.).
Differential mechanisms of tolerance induced by NMDA and 3,5-dihydroxyphenylglycine (DHPG) preconditioning / E. Gerace, E. Zianni, E. Landucci, T. Scartabelli, R. Berlinguer Palmini, D. Iezzi, F. Moroni, M. Di Luca, G. Mannaioni, F. Gardoni, D.E. Pellegrini-Giampietro. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 155:6(2020 Dec), pp. 638-649.
|Titolo:||Differential mechanisms of tolerance induced by NMDA and 3,5-dihydroxyphenylglycine (DHPG) preconditioning|
ZIANNI, ELISA (Secondo)
GARDONI, FABRIZIO (Penultimo)
|Parole Chiave:||endocannabinoids; glutamate receptors; neuroprotection; organotypic hippocampal slices; post-synaptic densities; preconditioning; sEPSCs|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||dic-2020|
|Data ahead of print / Data di stampa:||mag-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/jnc.15033|
|Appare nelle tipologie:||01 - Articolo su periodico|