Effects of the Hybridization of Opioid and Neurotensin Pharmacophores on Cell Survival in Rat Organotypic Hippocampal Slice Cultures

Several neurotransmitter and neuromodulatory systems can control physiological glutamatergic activity. For example, opioid receptor ligands were shown to partially inhibit N-methyl-d-aspartic acid (NMDA) receptor-dependent glutamatergic excitotoxicity. Also, the endogenous tridecapeptide neurotensin (NT) was found to modulate excessive glutamate release and glutamate receptor activity in neurons. Alternatively to the one target-one drug approach, it has been well documented that hybrid compounds encompassing two pharmacophores in one molecular scaffold can represent more potent drugs. Moreover, such structures with dual activity can potentially enable a reduction of undesirable side effects and/or improved bioavailability. Herein, we describe the neuroprotective potential of an opioid-NT hybrid peptide (PK20), which was recently designed and synthesized within our group. The protective properties of PK20, assessed in an in vitro model of excitotoxic injury in organotypic hippocampal slice cultures subjected to NMDA, were compared to the effects caused by NT. Our results indicate that PK20 is a potent anti-neurodegenerative agent. Moreover, co-administered with NMDA, PK20 (25-100 ng/ml) dose-dependently reduced hippocampal cell death, determined by a decrease in the propidium iodide signal. We also report for the first time the significant NT-induced neuroprotective effect, as its application (50-100 ng/ml) to hippocampal slice cultures protected CA1 damage against neurotoxicity caused by NMDA.