Composition and method for neuroprotection against excitotoxic injury

Abstract

The present invention discloses the combined treatment of memantine (N-methyl-D-aspartate receptor antagonist) and tea polyphenol (an antioxidant and anti-inflammatory agent) is more effective (synergistic) 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 or treating clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation-in-part of the pending U.S. patent application Ser. No. 12 / 243,655 filed on Oct. 1, 2008, for which priority is claimed and is incorporated herein by reference in its entirety.[0002]Although incorporated by reference in its entirety, no arguments or disclaimers made in the parent application apply to this divisional application. Any disclaimer that may have occurred during the prosecution of the above-referenced application(s) is hereby expressly rescinded. Consequently, the Patent Office is asked to review the new set of claims in view of the entire prior art of record and any search that the Office deems appropriate.FIELD OF THE INVENTION[0003]The present invention relates to a composition and a method for synergistic neuroprotection against excitotoxic injury.BACKGROUND OF THE INVENTION[0004]Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS) and mediates ne...

AI Technical Summary

Benefits of technology

[0066]As shown in FIG. 7, memantine (10 mg/kg/day) for consecutive 14 days increased locomotor activities in the open field, TPM6 and TPM3 only slightly increased and TPM10 had no effect on the locomator activities. After icy injection of 3 μl of 8 mM NMDA markedly decreased locomotor activities which were prevented by pretreatment with M or TPM. Estimation of the neuroprotective potencies against NMDA-decreased locomotor activities (FIG. 8A), the orders of the potencies against NMDA neurotoxicities were TPM10>TPM6>TPM3>M. As to the neuroprotective effects against the decreased jump exploratory effect of NMDA (FIG. 8B), the order of the potencies are M>TPM6>TPM3>TPM10. However, after pretreatment with M and TPM alone for consecutive 14 days, the decrease in jump activity in orders are TPM6>M>TPM10 and TPM3 did not affect the jump activities (FIG. 8B). In addition, NMDA increased the retention time in the open field of elevated plus maze (FIG. 8C) but decreased rotarod motor equilibrium function which could be most efficiently prevented by TPM10. It was noted that prolonged use of M alone prominently increased retention time in the open field of elevated plus maze and reduced (FIG. 8C) the motor equilibrium function similarly to NMDA (FIG. 8C). Both TPM6 an

Problems solved by technology

However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity (Kemp J A, McKernan R M.

Potential neuroprotective agents that block virtually all NMDA receptor activity lead to unacceptable clinical side effects (drowsiness, hallucination, and even coma) because they block normal NMDA receptor activity (Palmer G C.

Under pathological conditions, however, overactivation of the receptor relieves the Mg2+ block and causes an excessive amount of Ca2+ influx into the nerve cell, which in turn triggers a variety of processes that can lead to necrosis, apoptosis, or dendritic / synaptic damage.

Energy depletion and increased oxidative damage to several synaptic proteins such as Na+, K+-ATPase may result in loss of local Ca2+ homeostasis and membrane depolarization.

Therefore, elevation of intracellular Ca2+ and increased ROS production are the major causes of neuronal death in excitotoxicity.

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