Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death.

Lobeline attenuates the behavioral effects of psychostimulants in rodents and inhibits the function of nicotinic receptors (nAChRs), dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Monoamine transporters are considered valid targets for drug development for the treatment of methamphetamine abuse. In the current study, a series of lobeline analogs were evaluated for affinity and selectivity at these targets. None of the analogs was more potent than nicotine at the [ 3 H]methyllycaconitine binding site ‫ء7␣(‬ nAChR subtype). Lobeline tosylate was equipotent with lobeline in inhibiting [3 H]nicotine binding but 70-fold more potent in inhibiting nicotine-evoked 86 Rb ϩ efflux, demonstrating antagonism of ‫ء2␤4␣‬ nAChRs. Compared with lobeline, the defunctionalized analogs lobelane, mesotransdiene, and (Ϫ)-trans-transdiene showed dramatically reduced affinity at ‫ء2␤4␣‬ nAChRs and a 15-to 100-fold higher affinity (K i ϭ 1.95, 0.58, and 0.26 M, respectively) at DATs. Mesotransdiene and (Ϫ)-transtransdiene competitively inhibited DAT function, whereas lobelane and lobeline acted noncompetitively. 10S/10R-MEPP [N-methyl-2R-(2R/2S-hydroxy-2-phenylethyl)6S-(2-phenylethyl)piperidine] and 10R-MESP [N-methyl-2R-(2R-hydroxy-2-phenylethyl)6S-(2-phenylethen-1-yl)piperidine] were 2 to 3 orders of magnitude more potent (K i ϭ 0.01 and 0.04 M, respectively) than lobeline in inhibiting [3 H]serotonin uptake; 10S/10R-MEPP showed a 600-fold selectivity for this transporter. Uptake results using hDATs and human serotonin transporters expressed in human embryonic kidney-293 cells were consistent with native transporter assays. Lobelane and ketoalkene were 5-fold more potent (K i ϭ 0.92 and 1.35 M, respectively) than lobeline (K i ϭ 5.46 M) in inhibiting [ 3 H]methoxytetrabenazine binding to VMAT2 in vesicle preparations. Thus, structural modification (defunctionalization) of the lobeline molecule markedly decreases affinity for ‫ء2␤4␣‬ and ‫ء7␣‬ nAChRs while increasing affinity for neurotransmitter transporters, affording analogs with enhanced selectivity for these transporters and providing new leads for the treatment of psychostimulant abuse.Lobeline, an alkaloid from Indian tobacco, inhibits the behavioral and neurochemical effects of psychostimulant drugs of abuse. For example, lobeline attenuates d-amphetamine-, methamphetamine-and nicotine-induced hyperactivity (Green et al., 2001;Miller et al., 2001Miller et al., , 2002 and inhibits the discriminative stimulus effects of methamphetamine ). Although lobeline is not selfadministered, it decreases methamphetamine self-administration in rats, which is not surmounted by increasing methamphetamine unit doses (Harrod et al., , 2003. These results suggest that lobeline lacks abuse liability while decreasing the stimulant and rewarding effects of methamphetamine via a noncompetitive mechanism of action.Psychostimulant-induced behavioral activation and reinforcement are at least partly mediated via interaction with neurotransmitter transporters that r...

Ethanol preconditioning (EtOH-PC) refers to a phenomenon in which tissues are protected from the deleterious effects of ischemia/reperfusion (I/R) by prior ingestion of ethanol at low to moderate levels. In this study, we tested whether prior (24 hrs) administration of ethanol as a single bolus that produced a peak plasma concentration of 42-46 mg/dl in gerbils would offer protective effects on neuronal damage due to cerebral I/R. In addition, we also tested whether reactive oxygen species (ROS)-derived from NADPH oxidase played a role as an initiator of these putative protective effects. Groups of gerbils were administered either ethanol or the same volume of water by gavage 24 hrs prior to transient global cerebral ischemia induced by occlusion of both common carotid arteries (CCA) for 5 min. In some experiments, apocynin, a specific inhibitor of NADPH oxidase, was administered (5 mg/kg body wt, i.p.) 10 min before ethanol administration. EtOH-PC ameliorated behavioral deficit induced by cerebral I/R and protected the brain against I/R-induced delayed neuronal death (DND), neuronal and dendritic degeneration, oxidative DNA damage, and glial cell activation. These beneficial effects were attenuated by apocynin treatment coincident with ethanol administration. Ethanol ingestion was associated with translocation of the NADPH oxidase subunit, p67 phox , from hippocampal cytosol fraction to membrane, increased NADPH oxidase activity in hippocampus within the first hour after gavage, and increased lipid peroxidation (4-hydroxy-2-nonenal, HNE) in plasma and hippocampus within the first 2 hrs after gavage. These effects were also inhibited by concomitant apocynin treatment. Our data are consistent with the hypothesis that antecedent ethanol ingestion at socially-relevant levels induces neuroprotective effects in I/R by a mechanism that is triggered by ROS produced through NADPH oxidase. Our results further suggest the possibility that preconditioning with other pharmacological agents that induce a mild oxidative stress may have similar therapeutic value for suppressing stroke-mediated damage in brain.

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Pregnant women who are obese or have gestational diabetes mellitus have elevated leptin levels and their children have an increased risk for child and adult obesity. The goals of this study were to determine whether offspring weights are altered by maternal hyperleptinemia, and whether this occurs via behavioral changes that influence energy balance. We used 2 hyperleptinemic mouse models. The first was females heterozygous for a leptin receptor mutation (DB/+), which were severely hyperleptinemic, and that were compared with wild-type females. The second model was wild-type females infused with leptin (LEP), which were moderately hyperleptinemic, and were compared with wild-type females infused with saline (SAL). Total food consumption, food preference, locomotor activity, coordinated motor skills, and anxiety-like behaviors were assessed in wild-type offspring from each maternal group at 3 postnatal ages: 4-6, 11-13, and 19-21 weeks. Half the offspring from each group were then placed on a high-fat diet, and behaviors were reassessed. Adult offspring from both groups of hyperleptinemic dams weighed less than their respective controls beginning at 23 weeks of age, independent of diet or sex. Weight differences were not explained by food consumption or preference, because female offspring from hyperleptinemic dams tended to consume more food and had reduced preference for palatable, high-fat and sugar, food compared with controls. Offspring from DB/+ dams were more active than offspring of controls, as were female offspring of LEP dams. Maternal hyperleptinemia during pregnancy did not predispose offspring to obesity, and in fact, reduced weight gain.

Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Recently, bupropion has been reported to noncompetitively inhibit ␣3␤2, ␣3␤4, and ␣4␤2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native ‫ء2␤3␣‬ and ‫ء4␤3␣‬ nAChRs using functional neurotransmitter release assays, nicotine-evoked 3 H]NE overflow. Thus, bupropion acts as an antagonist at ‫ء2␤3␣‬ and ‫ء4␤3␣‬ nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function. The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.

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