Abstract
The glutamatergic neurotransmitter system has received substantial attention in research on the pathophysiology and treatment of neurological disorders. The study investigated the effect of the polyphenolic compound chlorogenic acid (CGA) on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). CGA inhibited 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes. This inhibition was prevented in the absence of extracellular Ca2+ and was associated with the inhibition of 4-AP-induced elevation of Ca2+ but was not attributed to changes in synaptosomal membrane potential. In line with evidence observed through molecular docking, CGA did not inhibit glutamate release in the presence of P/Q-type Ca2+ channel inhibitors; therefore, CGA-induced inhibition of glutamate release may be mediated by P/Q-type Ca2+ channels. CGA-induced inhibition of glutamate release was also diminished by the calmodulin and Ca2+/calmodilin-dependent kinase II (CaMKII) inhibitors, and CGA reduced the phosphorylation of CaMKII and its substrate, synapsin I. Furthermore, pretreatment with intraperitoneal CGA injection attenuated the glutamate increment and neuronal damage in the rat cortex that were induced by kainic acid administration. These results indicate that CGA inhibits glutamate release from cortical synaptosomes by suppressing P/Q-type Ca2+ channels and CaMKII/synapsin I pathways, thereby preventing excitotoxic damage to cortical neurons.
Highlights
Glutamate is one of the most abundant excitatory neurotransmitters and performs vital physiological functions related to synaptic plasticity, memory, and learning [1,2]
In pathological conditions such as brain ischemia, seizures, and neurodegeneration, glutamate is released excessively, causing the over-activation of glutamate receptors. This process increases the concentrations of intracellular Ca2+, which can lead to neuronal damage or death [3,4]
To examine the effect of Chlorogenic acid (CGA) (Figure 1A) on glutamate release, synaptosomes were stimulated by 4-AP (1 mM), which increases Ca2+ influx and glutamate release [27]
Summary
Glutamate is one of the most abundant excitatory neurotransmitters and performs vital physiological functions related to synaptic plasticity, memory, and learning [1,2]. In pathological conditions such as brain ischemia, seizures, and neurodegeneration, glutamate is released excessively, causing the over-activation of glutamate receptors. This study evaluated the neuroprotective effect of CGA in a rat model of kainic acid (KA)-induced glutamate excitotoxicity [26]
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