RESUMEN
Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aß1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1ß to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aß1-42 in muscle or neurons, PNR502 rescued Aß-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aß1-42, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aß1-42 aggregation and prevent or reverse neurodegeneration.
RESUMEN
Morphine-6-O-sulfate (M6S) is as a mixed-action mu/delta (µ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule-controlled responding to assess abuse-liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3-O-acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine-like effects. Tolerance to response rate-decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food-reinforced operant sessions. At both unit doses, tolerance to M6S-elicited rate suppression developed more slowly than tolerance to morphine-induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food-reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist-precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine-maintained and M6S-maintained rats. In conclusion, the mixed µ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine-like subjective effects, perhaps implying a decreased abuse liability over µ agonists.