Shoei-Yn Lin-Shiau

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Polydrug abuse has become a significant problem worldwide, and the combined use of methamphetamine (MA) and morphine (M) is now highly prevalent among addicts. In the present study, we investigated the neurobehavioral effects of repeated treatment regimens of these drugs (i.p. administration of 0.75 mg/kg/day MA, 5 mg/kg/day M, and their combination for five consecutive days followed by once weekly for five consecutive weeks) in mice. In addition, we used anin vivomicrodialysis technique to study the changes in extracellular concentrations of dopamine (DA) and its metabolites in the mouse striatum after challenge administration of these drugs. The results showed that systemic M increased MA‐induced conditioned place preference (CPP), as revealed by higher CPP values which were also maintained for a longer duration compared with those induced by an identical dose of MA or M alone. Subsequent to challenge with combined MA and M, mice exhibited an increase in stereotyped behavior, which appeared to be associated with an elevation of extracellular concentration of DA in the striatum. Our findings suggest that M not only produces synergistic effects on MA‐induced CPP, but also interacts with MA to induce stereotyped behavioral sensitization which is mediated by an increase in DA outflow in the striatum. These findings provide insight into the behavioral and neurochemical basis responsible for the combined abuse liability of MA and M.

NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca ²⁺ homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti‐inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3‐μL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na ⁺ , K ⁺ ‐ATPase and Mg ²⁺ ‐ATPase activity, reactive oxygen species production, mitochondrial membrane potential (ΔΨm), mitochondrial reductase activity (MTT test), and Ca ²⁺ concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (ΔΨm) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS‐sensitive Na ⁺ , K ⁺ ‐ATPase and Mg ²⁺ ‐ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na ⁺ , K ⁺ ‐ATPase and Mg ²⁺ ‐ATPase activity, the mitochondrial membrane potential (ΔΨm), the mitochondrial reductase activity, and the increased synaptosomal Ca ²⁺ concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.

Although the cytotoxic effects of mercuric chloride (HgCl₂) and methylmercury chloride (MeHg) have been extensively studied, the insoluble mercuric sulfide (HgS) has been the subject of fewer studies. Since the traditional Chinese mineral drug, cinnabar (containing >95% HgS) continues to be used as an ingredient for infant sedation, the pharmacological and toxicological effects of HgS need to be clarified. In previous experiments, HgS and cinnabar were shown to be absorbed from the gastrointestinal tract (GIT) and distributed in various tissues including the lungs. Thus, a preliminarily examination of whether HgS might exert any oxidative stress on a mouse lung was undertaken. HgS reduced GSH content and increased lipid peroxidation in the lung. Further studies on the cytotoxic effects and the possible mechanisms of action of HgS were compared with HgCl₂ and MeHg in cultured lung fibroblast V₇₉ cells. The results showed that HgS produced cytotoxicity at a concentration (400–1200 µM)in a dependent manner with IC₅₀ of 795.6 µM, as compared to HgCl₂ and MeHg, 8.1 µM and 5.9 µM, respectively. In addition, the HgS induced the phenomena of DNA fragmentation, increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential, accompanied by decreased levels of intracellular ATP and GSH and higher lipid peroxidation levels, similar to HgCl₂ and MeHg, but with different toxicokinetic properties. These findings provide evidence for understanding the mechanisms underlying the toxic effects of HgS.