Naturally Derived Polyphenols Protect Against Corticosterone-Induced Changes in Primary Cortical Neurons.

BACKGROUND: Polyphenols are phytochemicals that have been associated with therapeutic effects in stress-related disorders. Indeed, studies suggest that polyphenols exert significant neuroprotection against multiple neuronal injuries, including oxidative stress and neuroinflammation, but the mechanisms are unclear. Evidence indicates that polyphenol neuroprotection may be mediated by activation of Nrf2, a transcription factor associated with antioxidant and cell survival responses. On the other hand, in stress-linked disorders, Fkbp5 is a novel molecular target for treatment because of its capacity to regulate glucocorticoid receptor sensitivity. However, it is not clear the role Fkbp5 plays in polyphenol-mediated stress modulation. In this study, the neuroprotective effects and mechanisms of the naturally derived polyphenols xanthohumol and quercetin against cytotoxicity induced by corticosterone were investigated in primary cortical cells. METHODS: Primary cortical cells containing both neurons and astrocytes were pre-incubated with different concentrations of quercetin and xanthohumol to examine the neuroprotective effects of polyphenols on cell viability, morphology, and gene expression following corticosterone insult. RESULTS: Both polyphenols tested prevented the reduction of cell viability and alterations of neuronal/astrocytic numbers due to corticosterone exposure. Basal levels of Bdnf mRNA were also decreased after corticosterone insult; however, this was reversed by both polyphenol treatments. Interestingly, the Nrf2 inhibitor blocked xanthohumol but not quercetin-mediated neuroprotection. In contrast, we found that Fkbp5 expression is exclusively modulated by quercetin. CONCLUSIONS: These results suggest that naturally derived polyphenols protect cortical cells against corticosterone-induced cytotoxicity and enhance cell survival via modulation of the Nrf2 pathway and expression of Fkbp5.

Characterization of the bupropion cue in the rat: lack of evidence for a dopaminergic mechanism.

Using a two-lever operant task rats were trained to discriminate 40 mg/kg IP of bupropion from saline. Despite bupropion's established dopaminergic activity in vitro and in vivo, it was found that the bupropion cue was neither mimicked by the dopaminergic drugs L-DOPA and bromocriptine nor blocked by a variety of neuroleptics (haloperidol, thioridazine, and thiothixene). In addition, bupropion was active in attenuating the behavior-suppressing effects of haloperidol, unlike amphetamine and the atypical antidepressants, nomifensine and viloxazine. The bupropion cue was not mimicked or disrupted by adrenergic or serotonergic drugs, but it did generalize to some stimulants (amphetamine, cocaine and caffeine) as well as to nomifensine and viloxazine. The generalizations were blocked by neuroleptics. These data indicate that bupropion's cue properties may not be based on its ability to modulate dopaminergic receptor activity. The possible involvement of phenylethylamine in the bupropion cue is also discussed.

Methcathinone intoxication in the rat: abrogation by dextrorphan.

STUDY OBJECTIVE: Methcathinone, a designer drug, has high abuse liability. In this study we characterized acute methcathinone toxicity in rats, attempting to determine whether the excitatory amino acid receptor antagonist dextrorphan can antagonize methcathinone intoxication. METHODS: Intoxication was produced with IV methcathinone infusion (5 mg/kg/minute; 100 mg/mL) in conscious rats. We studied pretreatment, in which dextrorphan or vehicle was injected 30 minutes before methcathinone infusion. In a second protocol, dextrorphan or saline solution was given immediately after the onset of convulsions. RESULTS: Methcathinone caused tachycardia (maximal increase, 131 +/- 10 beats/minute), hyperthermia (+2.3 degrees C), convulsions, and cardiorespiratory collapse in vehicle-pretreated rats (n = 9). Death occurred after 32.0 +/- 1.1 minutes of infusion. Dextrorphan pretreatment (25 mg/kg; n = 7) significantly reduced hyperthermia (+.1 degree +/- .3 degree C) and tachycardia and increased the convulsive (dextrorphan, 134 +/- 9 mg/kg; vehicle, 67 +/- 4 mg/kg) and lethal doses (dextrorphan, 204 +/- 9 mg/kg; vehicle, 160 +/- 5 mg/kg). Dextrorphan, given immediately after the initial methcathinone convulsion, reduced hyperthermic and tachycardic responses but not the lethality of methcathinone. CONCLUSION: Blockade of excitatory amino acid receptors by dextrorphan minimizes acute methcathinone intoxication.