Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na+ and Ca2+ Overload in Motor Neuron-like NSC-34 Cells

Abstract

Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca 2? overload, and low expression of Ca 2? -buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 lM and rotenone 30 lM (O/R), or (2) phenylarsine oxide 1 lM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 lM (VTD) (to induce overload of Na ? and Ca 2? and to alter distribution of Ca 2? -buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on in vitro models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 lM and PAO at 10 lM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca 2? ] c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindinD28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na ? /Ca 2? overload, both of which are involved in ALS. Graphical Abstract Ca 2+ Ca 2+InsP 3 R UP CCVD CCVD mPTP Na + Ca 2+ VTD Na + Ca 2+

Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction

“…Daily administration of RES at a dose of 160 mg/kg for 4 weeks AMPK, adenosine monophosphate-activated protein kinase; Bak, B cell lymphoma 2 (Bcl-2) homologous antagonist killer; Bax, Bcl-2-associated X protein; cyt c, cytochrome c; GPx, glutathione peroxidase; HO-1, heme oxygenase-1; IMS, intermembrane space; MAC, mitochondrial apoptosisinduced channel; MCU, mitochondrial calcium uniporter; Mn-SOD (SOD2), manganese superoxide dismutase; MOMP, mitochondrial outer membrane permeabilization; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; mTOR, mechanistic (or mammalian) target of rapamycin; NCLX, the mitochondrial Na/Li/Ca exchanger; Nrf1/2, nuclear respiratory factor 1 and 2; O2 •−, superoxide radical; OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor coactivator-1α; PRx, peroxiredoxins (scavenger and antioxidant) ROS, reactive oxidative species; SIRT-1, sirtuin 1; SOD1/2, superoxide dismutase; TFAM, mitochondrial transcription factor A; ULK1, Unc-51 like kinase 1; VDAC, voltage-dependent anion-selective channel; α-syn, α-synuclein. -Ortega et al, 2016;Bozzo et al, 2017;Carrì et al, 2017) and utilization of mitochondrial protective agents like RES can be a favorable approach for restoring the function and dynamics of mitochondria resulting in improvements in different cellular aspects such as bioenergetic and redox status in patient with ALS.…”

Profiling donepezil template into multipotent hybrids with antioxidant properties

“…Compound 43 ( Figure 11 ) was selected for further pharmacological evaluation. It displayed voltage-gated calcium channel blockade 142 infarct volume reduction in a photothrombotic stroke-model in mice and neuroprotection against sodium and calcium overload in motor neuron-like NSC-34 cells, as a model of amyotrophic lateral sclerosis 143 , 144 .…”

The venom of jellyfish, Chrysaora pacifica, induces neurotoxicity via activating Ca2+-mediated ROS signaling in HT-22 cells

“…In normal or slightly toxic conditions, Ca 2+ plays a role in regulating cellular signaling associated with protein synthesis, cellular metabolism, ATP productions in mitochondria, and neuroprotective functions [13]. However, the excessive influx of extracellular Ca 2+ under neurotoxic conditions activates pathophysiological signaling, leading to a significant increase of ROS, which is due to the facilitated oxidative process of mitochondria [13][14][15][16]. Although we did not quantitively measure ROS production of mitochondria in this study, changes of Rhodamine123 fluorescence and cytochrome c expression demonstrate that CpV crucially induced mitochondrial dysfunction in HT-22 cells (Fig.…”