Abstract
An excessive release of glutamate is considered to be a molecular mechanism associated with several neurological diseases that causes neuronal damage. Therefore, searching for compounds that reduce glutamate neurotoxicity is necessary. In this study, the possibility that the natural flavone acacetin derived from the traditional Chinese medicine Clerodendrum inerme (L.) Gaertn is a neuroprotective agent was investigated. The effect of acacetin on endogenous glutamate release in rat hippocampal nerve terminals (synaptosomes) was also investigated. The results indicated that acacetin inhibited depolarization-evoked glutamate release and cytosolic free Ca2+ concentration ([Ca2+]C) in the hippocampal nerve terminals. However, acacetin did not alter synaptosomal membrane potential. Furthermore, the inhibitory effect of acacetin on evoked glutamate release was prevented by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker known as ω-conotoxin MVIIC. In a kainic acid (KA) rat model, an animal model used for excitotoxic neurodegeneration experiments, acacetin (10 or 50 mg/kg) was administrated intraperitoneally to the rats 30 min before the KA (15 mg/kg) intraperitoneal injection, and subsequently induced the attenuation of KA-induced neuronal cell death and microglia activation in the CA3 region of the hippocampus. The present study demonstrates that the natural compound, acacetin, inhibits glutamate release from hippocampal synaptosomes by attenuating voltage-dependent Ca2+ entry and effectively prevents KA-induced in vivo excitotoxicity. Collectively, these data suggest that acacetin has the therapeutic potential for treating neurological diseases associated with excitotoxicity.
Highlights
Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) and plays a critical role in numerous functions, such as cognition, movement, learning, and memory [1,2]
The purity of the compound was more than 98% on high-performance liquid chromatography (HPLC). 39, 39, 39-dipropylthiadicarbocyanine iodide [DiSC3(5)] and fura-2-acetoxymethyl ester (Fura-2-AM) were purchased from Invitrogen (Carlsbad, CA, USA). 4-aminopyridine (4-AP), vconotoxin MVIIC (v-CgTX MVIIC), dantrolene, 7-chloro-5-(2chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP371 57), kainic acid (KA), and all other reagents were purchased from Sigma-Aldrich
The experiments performed in this study demonstrated that acacetin inhibits glutamate release from hippocampal nerve terminals, supporting the hypothesis that acacetin produces a neuroprotective effect against exocytotoxic insults
Summary
Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) and plays a critical role in numerous functions, such as cognition, movement, learning, and memory [1,2]. In addition to the physiological role of glutamate, excessive glutamate release and activation of the glutamate receptors induce an increase in intracellular Ca2+ levels, which subsequently triggers a cascade of cellular responses, including enhanced oxygen free radical production, disturbed mitochondrial function, and protease activation, which kill the neurons [3,4,5] This process has been implicated as a pathophysiological factor in multiple neurological disorders, both acute, such as stroke and head trauma, and chronic, such as neurodegenerative disorders [6,7,8]. Several glutamatergic modulators are being developed, including N-methyl-D-aspartic acid (NMDA) receptor antagonists, and metabotropic glutamate receptor agonists and antagonists These drugs have been unsuccessful in clinical trials because of numerous side effects, such as ataxia and memory impairment [9,10]; the search for new drugs that target neurological disorders continues
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