Neuroprotective Potential of Biphalin, Multireceptor Opioid Peptide, Against Excitotoxic Injury in Hippocampal Organotypic Culture

Abstract

Biphalin is a dimeric opioid peptide that exhibits affinity for three types of opioid receptors (MOP, DOP and KOP). Biphalin is undergoing intensive preclinical study. It was recognized that activation of δ-opioid receptor elicits neuroprotection against brain hypoxia and ischemia. We compare the effect of biphalin and morphine and the inhibition of opioid receptors by naltrexone on survival of neurons in rat organotypic hippocampal cultures challenged with NMDA. Findings: (1) 0.025–0.1 μM biphalin reduces NMDA-induced neuronal damage; (2) biphalin neuroprotection is abolished by naltrexone; (3) reduced number of dead cells is shown even if biphalin is applied with delay after NMDA challenge.

The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

“…In vitro studies in hippocampal organotypic cultures demonstrated that biphalin possesses a much higher neuroprotective effect than morphine. In addition, these effects were partially reversed by naloxone, which may indicate opioid receptor involvement during the neuroprotective process [1]. Therefore, it was interesting to examine the antioxidative properties of morphine and biphalin in a "tube test" assay, without any receptor proteins present.…”

“…However, it should be considered that these "non-specific" distributions and interactions may have a biological function; furthermore, these activities may be physiologically important. Recent neurobiological studies have provided evidence for the neuroprotective effects of opioids [1,9]. A partial reversal of these effects using opioid antagonists indicated that, in addition to specific opioid receptor involvement, non-receptor effects should also be examined.…”

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

“…Chiba et al (2007) recently presented Colivelin as a novel neuroprotective peptide that contains an activity-dependent neurotrophic factor (ADNF) pharmacophore and the N-terminus of a potent Humanin derivative, AGA-(C8R)HNG17. In addition, Kawalec et al (2011) showed that a dimeric enkephalin, named biphalin, protects from NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures derived from rats. However, to date, there are no data describing any of the peptides that contain both opioid and NT pharmacophores as compounds able to modulate NMDA-induced neuronal cell death.…”

“…By use of the hippocampal slice/NMDA model, previous studies have shown that opioid ligands, including morphine and the peptide biphalin, express neuroprotective properties (Liu et al 2008;Kawalec et al 2011). Interestingly, both morphine and biphalin express a ceiling protective effect that was proposed to be directly related to the proportion of cells containing particular neuropeptide receptor types on their membranes.…”

“…Interestingly, both morphine and biphalin express a ceiling protective effect that was proposed to be directly related to the proportion of cells containing particular neuropeptide receptor types on their membranes. While biphalin-with a good affinity for mu-, delta-, and kappa opioid receptors-expressed protection in as much as 65 % of the cells, mu receptor selective ligands expressed a ceiling protective effect up to 50 % (Kawalec et al 2011). Therefore, we hypothesized that the activation of other neuropeptide receptors may result in independent protection and may result in additive or synergic effects when applied together with opioids.…”