[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol, an indole-3-carbinol derivative, inhibits glutamate release in rat cerebrocortical nerve terminals by suppressing the P/Q-type Ca2+ channels and Ca2+/calmodulin/protein kinase A pathway
Introduction
Glutamate, an excitatory neurotransmitter, plays an crucial role in many functions in the central nervous system (CNS) (Zhou and Danbolt, 2014). However, high concentrations of glutamate causes the excessive activation of glutamate receptors, leading to neuronal death (Bano and Ankarcrona, 2018). This phenomenon, known as excitotoxicity, is a key pathogenic event in many neurological diseases, such as ischemic stroke, traumatic brain injury, epilepsy, and neurodegenerative diseases (Choi, 1988; Lewerenz and Maher, 2015; Olloquequi et al., 2018). Therefore, reducing the synaptic release of glutamate has neuroprotective potential. Several drugs that inhibit glutamate release can counteract glutamate excitotoxicity to provide neuroprotection (Chiu et al., 2019; Lin et al., 2013; Wong et al., 2015).
Indole-3-carbinol (I3C) is a natural compound found in cruciferous vegetables (Brassica sp.) such as cabbage, broccoli, cauliflower, and brussels sprouts (Licznerska and Baer-Dubowska, 2016). Studies have demonstrated that I3C possesses antioxidant, anti-inflammatory, anticancer, and antithrombotic properties (Bai et al., 2013; El-Naga et al., 2014; Fuentes et al., 2015; Katz et al., 2018; Lin et al., 2015). Moreover, I3C can protect against glutamate- or oxidative stress-induced neurotoxicity in cultured PC12 and HT22 cells (Jeong et al., 2015; Lee et al., 2019), attenuated neurological deficits and infarct volume in a rat model of cerebral ischemic stroke (Paliwal et al., 2018), and improved clonidine-induced depression-like behaviors and oxidative stress in rats (El-Naga et al., 2014). The I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM; Fig. 1A) has higher chemical stability and bioavailability than I3C (Weng et al., 2007, 2009, 2019). However, to the best of our knowledge, no study has reported on the efficacy of CIM in the CNS. Therefore, this study used isolated nerve terminals (synaptosomes) prepared from rat cerebral cortex to examine the effect and mechanism of action of CIM on glutamate release.
Section snippets
Chemicals
CIM (purity > 99%) was synthesized from Weng JR (Weng et al., 2007); 4-aminopyridine (4-AP), ethylene glycol bis(β-aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA), and general reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA); DL-threo-beta-benzyl-oxyaspartate (DL-TBOA), bafilomycin A1, dantrolene, 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), W7, and calmidazolium were
CIM inhibits the 4-AP-stimulated release of glutamate from purified rat cortical synaptosomes
First, to examine the effect of CIM on glutamate release, synaptosomes were incubated in the presence of increasing doses of CIM (1–50 μM) for 10 min, followed by the addition of the K+ channel blocker 4-AP (1 mM) to stimulate glutamate release (Nicholls, 1998). As shown in Fig. 1B, 4-AP-stimulated glutamate release was decreased in a dose-dependent manner by CIM (P < 0.001; n = 4–5). CIM did not alter the basal release of glutamate. Maximal inhibition was achieved at 50–100 μM (n = 5; Fig. 1C).
Discussion
The release of neurotransmitters from nerve terminals is a potential target for modulating excitability and synaptic transmission in central neurons (Wu and Saggau, 1997). Here, using isolated nerve terminals from rat cerebral cortex, we demonstrated that CIM, an I3C derivative, markedly decreased the release of glutamate induced by 4-AP. This is the first report, to our knowledge, of the effect of CIM on the central glutamate system.
Conclusion
This study is the first to demonstrate that the I3C derivative CIM suppresses the P/Q-type Ca2+ channels and Ca2+/calmodulin/PKA activation to inhibit glutamate release in rat cerebrocortical nerve terminals. Although our finding needs to be confirmed in vivo, they are crucial for understanding the role of CIM in the CNS and for exploiting its potential in therapeutic interventions.
Credit authorship contribution statement
Cheng Wei Lu: Conceptualization, Investigation, Formal analysis, Writing-original draft. Tzu-Yu Lin: Conceptualization, Investigation, Formal analysis, Writing-original draft. Hsiao Ching Yang: Investigation, Formal analysis, Writing-original draft. Chi Feng Hung: Investigation, Formal analysis. Jing Ru Weng: Investigation, Resources. Der Chen Chang: Writing-review& editing. Su Jane Wang: Conceptualization, Investigation, Formal analysis, Supervision, Writing-original draft, Writing-review&
Funding
This work was supported by the Far-Eastern Memorial Hospital (Grants 107-FEMH-FJU-01, FEMH-2018-C-008, FEMH-2018-C-034).
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Equal contribution to Tzu-Yu Lin and Cheng Wei Lu.