Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity.
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-microL 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 (Delta Psi m), 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 (Delta Psi m) 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 (Delta Psi m), 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.
Chen
Chang-Mu
CM
Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Lin
Jen-Kun
JK
Liu
Shing-Hwa
SH
Lin-Shiau
Shoei-Yn
SY
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005419:Flavonoids / Q000008:administration & dosage* / Q000302:isolation & purification; D008297:Male; D008559:Memantine / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010636:Phenols / Q000008:administration & dosage* / Q000302:isolation & purification; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification; D059808:Polyphenols; D017382:Reactive Oxygen Species / Q000378:metabolism; D013662:Tea
D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D005419:Flavonoids; D018696:Neuroprotective Agents; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D017382:Reactive Oxygen Species; D013662:Tea; D008559:Memantine