RESUMO
LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a-f) of EAAT2. Among them 4f, analyzed in comparison with 3 by different paradigms in a rat model of oxaliplatin-induced neuropathic pain, showed the better antihypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Piridazinas/química , Piridinas/farmacologia , Animais , Técnicas de Química Sintética , Transportador 2 de Aminoácido Excitatório , Masculino , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Fármacos Neuroprotetores/síntese química , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Piridazinas/síntese química , Piridazinas/farmacologia , Piridinas/química , Ratos Sprague-DawleyRESUMO
Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John's Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.