Inhibition by Naloxone Stereoisomers of β-Amyloid Peptide (1–42)-induced Superoxide Production in Microglia and Degeneration of Cortical and Mesencephalic Neurons

Abstract

Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain. Recently we discovered that ␤-amyloid peptide A␤ (1-42) exhibited enhanced neurotoxicity toward both cortical and mesencephalic neurons through the activation of microglia and production of superoxide. The purpose of this study was to determine whether naloxone isomers had any effect on A␤ (1-42)-induced neurodegeneration. Pretreatment of either cortical or mesencephalic neuron-glia cultures with 1 to 10 M (Ϫ)-naloxone, prior to treatment for up to 11 days with 0.1 to 3 M A␤ (1-42), afforded significant neuroprotection as judged by neurotransmitter uptake, immunocytochemical analysis, and cell counting. More importantly, (ϩ)-naloxone, the ineffective enantiomer of (Ϫ)-naloxone in binding opioid receptors, was equally effective in affording neuroprotection. Mechanistically, inhibition of A␤ (1-42)-induced production of superoxide in microglia underlay the neuroprotective effect of naloxone stereoisomers. Moreover, neuroprotection and inhibition of A␤ (1-42)-induced superoxide production was also achieved with naloxone methiodide, a charged analog with quaternary amine, suggesting that the site of action for naloxone isomers is at the cell surface of microglia. These results demonstrated that naloxone isomers, through mechanisms unrelated to the opioid receptors, were capable of inhibiting A␤ (1-42)-induced microglial activation and degeneration of both cortical and mesencephalic neurons. Combined with our previous observations with inflammagen-induced neurodegeneration, naloxone analogs, especially (ϩ)-naloxone, may have potential therapeutic efficacy for the treatment of Alzheimer's and Parkinson's disease.

β-Funaltrexamine Inhibits Inducible Nitric-oxide Synthase Expression in Human Astroglial Cells

“…For example, both the MOR inactive stereoisomer (+)-naloxone and (−)-naloxone reduced inflammatoryinduced damage of rat dopaminergic neurons, suggesting a potential therapeutic role in the treatment of Parkinson's disease (Liu et al 2000). More recently, this same group determined that Aβ (1-42)-induced neurotoxicity was reduced by naloxone in an opioid receptor-independent mechanism (Liu et al 2002). It was determined that the neuroprotective effects of naloxone were due to reduced microglial superoxide production (Liu et al 2002).…”

“…More recently, this same group determined that Aβ (1-42)-induced neurotoxicity was reduced by naloxone in an opioid receptor-independent mechanism (Liu et al 2002). It was determined that the neuroprotective effects of naloxone were due to reduced microglial superoxide production (Liu et al 2002).…”

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

“…Taken together, the inhibition of microglia-generated superoxide might be the most efficient way to protect neurons from damage by Ab. Indeed, we have recently demonstrated that inhibition of superoxide release from Ab-activated microglia by naloxone affords significant protection both in cortical and mesencephalic neurons (Liu et al 2002).…”

Should we use naloxone epidurally?

“…La naloxone est administrée par les vétérinaires à de gros animaux sauvages anesthésiés avec du carfentanil. 2 Outre ces indications bien connues, la naloxone a été étudié chez des modèles animaux et lors d'essais cliniques comme traitement possible de certaines pathologies, y compris l'usage de drogues, l'alcoolisme, les troubles de l'alimentation, des lésions de la moelle épinière, un choc, l'ischémie cérébrale et cardiaque 3 et la constipation induite par la morphine périmédullaire.…”

“…7 Another mechanism by which Mu receptor antagonists could potentiate the antinociceptive action of morphine is by stimulating Mu receptor recirculation and increasing the number of Mu receptors available on neural cell surfaces. 8 It has been shown that naloxone can protect from brain damage induced by fentanyl and morphine 9,10 and can decrease superoxide production in microglia stimulated by Bamyloid peptide 3 and inflammatory processes; 11,12 this effect is stereoisomere-dependent, suggesting a possible beneficial action of naloxone in stroke and chronic cerebral pathologies such as Alzheimer's and Parkinson's disease.…”