Abstract
This study investigated the effects of enmein, an active constituent of Isodon japonicus Hara, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes) and evaluated its neuroprotective potential in a rat model of kainic acid (KA)-induced glutamate excitotoxicity. Enmein inhibited depolarization-induced glutamate release, FM1-43 release, and Ca2+ elevation in cortical nerve terminals but had no effect on the membrane potential. Removing extracellular Ca2+ and blocking vesicular glutamate transporters, N- and P/Q-type Ca2+ channels, or protein kinase C (PKC) prevented the inhibition of glutamate release by enmein. Enmein also decreased the phosphorylation of PKC, PKC-α, and myristoylated alanine-rich C kinase substrates in synaptosomes. In the KA rat model, intraperitoneal administration of enmein 30 min before intraperitoneal injection of KA reduced neuronal cell death, glial cell activation, and glutamate elevation in the hippocampus. Furthermore, in the hippocampi of KA rats, enmein increased the expression of synaptic markers (synaptophysin and postsynaptic density protein 95) and excitatory amino acid transporters 2 and 3, which are responsible for glutamate clearance, whereas enmein decreased the expression of glial fibrillary acidic protein (GFAP) and CD11b. These results indicate that enmein not only inhibited glutamate release from cortical synaptosomes by suppressing Ca2+ influx and PKC but also increased KA-induced hippocampal neuronal death by suppressing gliosis and decreasing glutamate levels by increasing glutamate uptake.
Highlights
In the kainic acid (KA) rat model of excitotoxicity, we evaluated the effects of enmein pretreatment on neuronal damage, glutamate elevation, glial cell activation, and the expression of excitatory amino acid transporters (EAATs) 2 and 3, which are responsible for glutamate clearance, synaptic plasticity-related proteins, synaptophysin and postsynaptic density protein 95 (PSD95), and hippocampal glial fibrillary acidic protein (GFAP) and CD11b
Incubation with enmein (30 μM) for 10 min before 4-AP administration did not have a significant effect on the basal release of glutamate but markedly reduced the glutamate release mediated by 4-AP [t(8) = 3.9, p < 0.001 vs. the control group]
Our results show for the first time the glutamate release-inhibiting and anti-excitotoxic properties of enmein, a diterpenoid extracted from Isodon japonicus Hara
Summary
Glutamate is an excitatory neurotransmitter that is involved in many physiological functions of the brain [1,2]. Changes in glutamate levels can disrupt glutamatergic neurotransmission, which can be a cause of neurological diseases such as stroke, epilepsy, traumatic brain injury, and psychiatric and neurodegenerative diseases [3,4]. Natural products are an invaluable source for novel drug research because of their safety and various biological functions [8]. The search for and discovery of active components in medicinal plants is a popular topic in pharmaceutical chemistry. Many natural constituents from medicinal plants have been reported to reduce synaptic glutamate release and thereby protect neurons, including baicalein, a flavonoid from
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