Acacetin Inhibits Glutamate Release and Prevents Kainic Acid-Induced Neurotoxicity in Rats

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.

A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

“…Studies also suggest that a decrease in the activity of this enzyme may lead to an increase in Glu release mediated by NMDAR, resulting in an adverse effect on cellular integrity (Fig. 4) (Lin et al 2014;Volkow et al 2013). It has been demonstrated that intermittent ethanol treatment causes a decrease in the expression of the dopamine receptor type 2 (D2R) and a decrease in phosphorylation of 2B subunit of the NMDA receptor (NMDAR-2B) in the prefrontal cortex, hippocampus, NAc and only of D2R in the striatum (Pascual et al 2009).…”

Influence of seasonal variation on Thymus longicaulis C. Presl chemical composition and its antioxidant and anti-inflammatory properties

“…DFT studies revealed that the high antioxidant power of the molecule could be due to the abstraction of hydrogen atoms from the ortho hydroxyl groups, characterizing both its A and B rings (Cao et al, 2005). The sample Oct12 is the only one that contained as constituent acacetin, a well known antioxidant, anti-inflammatory and anticancer natural substance, recently proposed as a therapeutic agent for the treatment of neuropsychiatric disorders (Lin et al, 2014). The evaluation of the Fe 3+ reducing power strongly correlated with the TPC values (Table 3).…”

Echinacoside, an Active Constituent of <i>Cistanche Herba</i>, Exerts a Neuroprotective Effect in a Kainic Acid Rat Model by Inhibiting Inflammatory Processes and Activating the Akt/GSK3β Pathway

“…Fluoro-Jade B-positive cells in the CA3 region of hippocampus was determined as previously described. 30,31) Immunohistochemistry The sections were washed with 0.1 M PBS and blocked with 0.5% normal goat serum in 0.1 M PBS for 1 h at room temperature. Primary antibody (mouse monoclonal anti-OX-42 antibody, 1 : 1000; AbD Serotec, Oxford, U.K.) incubation was performed two overnight at 4°C.…”