Silymarin Inhibits Glutamate Release and Prevents against Kainic Acid-Induced Excitotoxic Injury in Rats

Abstract

Silymarin, a polyphenoic flavonoid derived from the seeds of milk thistle (Silybum marianum), exhibits neuroprotective effects. In this study, we used a model of rat cerebrocortical synaptosomes to investigate whether silymarin affects the release of glutamate, an essential neurotransmitter involved in excitotoxicity. Its possible neuroprotective effect on a rat model of kainic acid (KA)-induced excitotoxicity was also investigated. In rat cortical synaptosomes, silymarin reduced glutamate release and calcium elevation evoked by the K+ channel blocker 4-aminopyridine but did not affect glutamate release caused by the Na+ channel activator veratridine or the synaptosomal membrane potential. Decreased glutamate release by silymarin was prevented by removal of extracellular calcium and blocking of N- and P/Q-type Ca2+ channel or extracellular signal-regulated kinase 1/2 (ERK1/2) but not by blocking of intracellular Ca2+ release. Immunoblotting assay results revealed that silymarin reduced 4-aminopyridine-induced phosphorylation of ERK1/2. Moreover, systemic treatment of rats with silymarin (50 or 100 mg/kg) 30 min before systemic KA (15 mg/kg) administration attenuated KA-induced seizures, glutamate concentration elevation, neuronal damage, glial activation, and heat shock protein 70 expression as well as upregulated KA-induced decrease in Akt phosphorylation in the rat hippocampus. Taken together, the present study demonstrated that silymarin depressed synaptosomal glutamate release by suppressing voltage-dependent Ca2+ entry and ERK1/2 activity and effectively prevented KA-induced in vivo excitotoxicity.

Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

“…To date, no data documenting the effect of ISL on glutamate release was available. Several reports have indicated that natural products may effectively reduce the release of glutamate [20][21][22][23]. We examined whether ISL exhibited an effect on glutamate release in rat cerebrocortical nerve terminals.…”

“…Thus, reduced glutamatergic transmission through the inhibition of released glutamate has been proposed as a neuroprotective mechanism [17][18][19]. Studies have reported that several natural products with neuroprotective effects may reduce presynaptic glutamate release [20][21][22][23].…”

Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure

“…Fresh brain tissues from both the hippocampi were collected for synaptosomal preparation and Western blot analysis. The KA dose and administration schedule were chosen based on previous experiments [ 28 , 29 , 30 ].…”

“…Synaptosomes were prepared from male Sprague-Dawley rats as described previously [ 30 , 32 ]. Briefly, rats ( n = 3/group) were sacrificed through rapid decapitation, and the hippocampus was removed and homogenized in 0.32 M sucrose.…”

Eupafolin Suppresses P/Q-Type Ca2+ Channels to Inhibit Ca2+/ Calmodulin-Dependent Protein Kinase II and Glutamate Release at Rat Cerebrocortical Nerve Terminals

“…Thus, the glutamatergic system is a promising target for treatment of these diseases. Some studies have suggested that the inhibition of glutamate release by nerve terminals can help to prevent excitotoxic damage ( Wong et al ., 2015 ; Chang et al ., 2016 ; Lu et al ., 2020 ).…”