Abstract
The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve terminals (synaptosomes). Echinacoside inhibited Ca2+-dependent, but not Ca2+-independent, 4-aminopyridine-evoked glutamate release in a concentration-dependent manner. Echinacoside also reduced the 4-aminopyridine-evoked increase in cytoplasmic free Ca2+ concentration but did not alter the synaptosomal membrane potential. The inhibitory effect of echinacoside on 4-aminopyridine-evoked glutamate release was prevented by ω-conotoxin MVIIC, a wide-spectrum blocker of Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but was insensitive to the intracellular Ca2+ release-inhibitors dantrolene and 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157). Furthermore, echinacoside decreased the 4-aminopyridine-induced phosphorylation of protein kinase C, and protein kinase C inhibitors abolished the effect of echinacoside on glutamate release. According to these results, we suggest that the inhibitory effect of echinacoside on evoked glutamate release is associated with reduced voltage-dependent Ca2+ entry and subsequent suppression of protein kinase C activity.
Highlights
Echinacoside is a major phenylenthanoid glycoside present in Herba Cistanche, a well-known traditional Chinese medicine used to treat forgetfulness, impotency, and chronic constipation [1]
We evaluated the effect of echinacoside on glutamate release, membrane potential, presynaptic Ca2+ influx, and protein kinase C activity
In synaptosomes incubated with 1 mM CaCl2, 1 mM 4-aminopyridine evoked a glutamate release of 7.4 ̆ 0.1 nmol/mg/5 min, which was reduced by 1, 5, 10, 30, and 50 μM echinacoside to 6.5 ̆ 0.2, 5.8 ̆ 0.3, 4.8 ̆ 0.2, 4.1 ̆ 0.1, or 2.3 ̆ 0.4 nmol/mg/5 min, respectively (F(5,24) = 67.1, p = 0.000)
Summary
Echinacoside is a major phenylenthanoid glycoside present in Herba Cistanche, a well-known traditional Chinese medicine used to treat forgetfulness, impotency, and chronic constipation [1]. Overactivation of glutamate receptors under high glutamate concentrations causes intracellular Ca2+ overload, mitochondrial dysfunction, free radical production, and neuronal death [14,15]. This pathological process is implicated in numerous brain disorders including cerebral ischemia, traumatic brain injury, epilepsy, and neurodegenerative disease [16,17]. Inhibitors blocking pathophysiological glutamatergic transmission are considered a potential neuroprotective drugs Notable examples of these are glutamate receptor antagonists [18,19]; clinical trials for these drugs have failed because of less effectivity and undesired, or even cytotoxic side effects [20,21]. Several neuroprotectants (e.g., memantine and riluzole) can reduce glutamate release in rat brain tissues [22,23,24]
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