Table 1.

Summary of natural compounds and activities related to the treatment of amyotrophic lateral sclerosis (ALS).

Class of Pharmacological Activity and Compound Name	Evidence of Pharmacological Activity Related to ALS
Oxidative Stress
Curcumin and Dimethoxy Curcumin (DMC)	Activate Nrf2; protect cells against stress through the removal of free radicals and detoxication; eliminate the excitability induced by TDP-43. Inhibits DTT-induced SOD1 fibrillation and favors the formation of smaller and disordered SOD1 aggregates, reduction in SOD1-mediated toxicity; assessed in In vivo and in vitro studies, with clinical trials.
Resveratrol	Up-regulating SIRT1 expression in the mutant SOD1G93A-bearing motor neuron-like culture model of ALS, improving the cell viability and ATP levels and preventing cell apoptosis.
Epigallocatechin gallate (EGCG)	Inhibits most types of the apoptotic cell by up-regulation of Bcl-2, downregulating the Bax gene; protecting against lipid peroxidation; preventing OS-induced death of mutant SOD1; upregulating PI3K/Akt and GSK-3 pathways in G93A mutant cells; assess in In vivo and in vitro studies.
7,8-dihydroxyflavone (7,8-DHF)	Enhanced neuromuscular transmission via TrkB activation in diaphragm muscle preserves spinal motor neuron count, and dendritic spines; assessed in In vitro studies.
Quercetin	Prevents aluminum-induced translocation of cytochrome c, upregulates Bcl-2, down-regulates Bax, p53, and caspase-3 activation, and reduces DNA fragmentation; assess in In vivo and in vitro studies.
Firestin	Increased the expression of phosphorylated ERK, increased the expression of antioxidant factors, and reduce the levels of mutant and wild-type SOD1.
Ampelopsin	Prevented H2O2-induced p38 activation; Upregulation of HO-1 due to the activation of ERK and Akt signaling pathways; assessed in In vitro and in vivo studies.
Vitamin E	Using it as an adjuvant treatment with riluzole allowed us to verify changes in the levels of biochemical markers for oxidative stress; assessed in In vivo studies.
Astragaloside IV	Attenuate the H2O2-induced loss; Decrease apoptosis and attenuate ROS overproduction; Protects microglia from lipopolysaccharide-evoked death and down-regulated the release of pro-inflammatory mediators IL-1β, IL-6, TNF-α, and NO, and the expression of TLR4, MyD88, and NF-κB.
Madecassoside	Reduce neuronal damage caused by OS and inhibit apoptosis; reduce neurotoxicity, cognitive impairments, and the production of inflammatory cytokine agents (IL-1β, TNF-α, and IL-6 by activation of Nrf2 signaling); assessed in in vitro and in vivo studies.
Morronoside	Inhibitory effects on ROS formation and activation of caspase-3 and 9, up-regulate Bcl-2 in SH-SY5Y cells of a model of H2O2-induced toxicity. Reduce the intracellular accumulation of Ca2+ and decrease the mitochondrial membrane potential caused by the addition of H2O2.
Picroside-II	Increase in neurite outgrowth in PC-12 cells. Enable an increase in cell viability and a reduction in glutamate-induced ROS; assess in In vitro and In vivo studies.
Dially Trissufide	DATS treatment activated HO-1. Cause activation of Nrf2 and Nrf2 target gene in rat spinal cord, protected motor neurons against glutamate-induced excitotoxicity. Induces neuronal autophagy and lysosomal clearance of TDP-43 and C-terminal TDP-43 fragments.
Neuroinflammation
Celastrol	Down-regulates the expression of TNF-α and iNOS and the immunoreactivity of CD40 and GFAP; Inhibition of excessive production of NO, TNF-α, and IL-1β induced by lipopolysaccharide in BV-2 cells; attenuates cadmium-induced neuronal apoptosis via the calcium-dependent Akt/mTOR pathway.
Paeonol	Prevent cell death and mitochondrial injury; Reduces caspase-3 and p-ERK activity; Attenuates the overexpression of NO-synthase and cyclooxygenase 2; Reduced the production of ROS-upregulated HO-1.
Obovatrol	Inhibition of NO production, microglial expression of pro-inflammatory cytokines, multiple signaling pathways (NF-κB, STAT1, and MAPK); Protect neurons from microglial toxicity; inhibit neuroinflammation; assess in In vivo studies.
Isorhynchophylline	Attenuates proinflammatory cytokines production such as TNF-α and IL-1β as well as NO in mouse N9 microglial cells; Suppression of iNOS protein level, phosphorylation of ERK and p38 MAPKs, and degradation of IκBα.
Wogonin	Diminishes lipopolysaccharide-induced TNF-α, IL-1β, and NO production in a dose-dependent manner; Promotes the reduction in microglial cytotoxicity in PC-12 cells; Protective against experimental brain injury (in vivo).
Ginkgolide A	Inhibits NO production in lipopolysaccharide-stimulated microglia; Modulation of neuroinflammation caused by neurodegenerative processes.
Excitatory Amino Acid Toxicity
β-asarone	Neuroprotective action against NMDA or glutamate-induced excitotoxicity by blocking NMDA receptor function; Promotes a decrease in LDH leakage.
Catalpol	Suppress the down-regulation of Bcl-2 and up-regulation of Bax; Release mitochondrial cytochrome c to the cytosol; Attenuates the activation of caspase-3 and PARP cleavage and protects against apoptosis.
Huperzine-A	Reduces glutamate-mediated Ca2+ signaling; Attenuates excitatory amino acid toxicity; Modulates Ca2+ levels through the Cdk5 activation pathway.
Selaginellin	Acts against glutamate-induced toxicity in PC-12 cells, reducing ROS levels and regulating the Klotho gene.
Cryptotanshinone	Acts on glutamate-induced toxicity, protecting primary cortical neurons from neurotoxicity through activation of the phosphoinositide 3-kinase/Akt.
Ferulic Acid	Activated caspase-3 protein expression and PARP cleavage and inhibited the upregulation of glutamate-induced μ-calpain protein level; Inhibition of glutamate-induced reduction in Bcl-2 expression.
Anti-calcium Cytotoxicity
Paeoniflorin	Increases cell viability, inhibits apoptosis, decreases intracellular ROS and malondialdehyde levels, and increases SOD1 activity.
Gastrodin	Reduces intracellular Ca2+ level via voltage-gated Ca2+ channels.
Muscone	Inhibits Glu-induced apoptosis in PC-12 cells by a mechanism related to inhibition of intracellular Ca2+ overload and maintenance of mitochondrial membrane potential.
Ligustrazine	Inhibits L-type calcium current in SH-SY5Y human neuroblastoma.