Table 3.
Alkaloids as inhibitors of TNF-α and neuroinflammatory responses in neurodegenerative diseases
| Alkaloids | Source | Disease | Mechanism | IC50/dose | Model | Reference |
|---|---|---|---|---|---|---|
| Piperine | Piper nigrum | PD | Diminishes IL-1β and TNF-α | 20 mg/kg, p.o. | 6-OHDA-induced rats | Rinwa and Kumar, 2017 |
| Berberine | Coptis chinensis | PD | Activates AKT/GSK-3β/Nrf2-mediated regulation, cholinergic activity-mediated neurite outgrowth, induces NGF and BDNF secretion, and inhibits Cox2, TNF-α, NF-κB, IL-1β, and iNOS levels | 0.1–10 nM | SH-SY5Y cells | Hsu et al., 2013 |
| Tetrandrine | Stephania tetrandra | AD | Increase in NF-κB DNA binding activity, the over-expression in IL-1β and TNF-α | 20, 30, and 40 mg/kg | Aat model of AD | He et al., 2011 |
| Berberine | Coptis chinensis | ND | Decreases the expression of the proinflammatory cytokines Cox-2, IL-1β, and TNF-α and markedly restores levels of BDNF and CREB and reduced the escape latency, induced neuronal impairment and memory dysfunction | 20 mg/kg | Rats with scopolamine-induced memory impairments | Lee et al., 2012 |
| Higenamine | Aconite tuber | ND | Inhibits the production of TNF-α, IL-6, ROS as well as NO and PGE2 (mediated by COX2) | 1–100 μM | LPS-activated BV2 cells | Yang et al., 2020 |
| suppresses NF-κB and activates Nrf2/HO-1 signaling pathways | ||||||
| Gelsemine | Gelsemium elegans Benth | AD | Inhibites the over-expression of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α | 5–10 μg/kg | Rat model of AD | Chen et al., 2020 |
| Alleviates cognitive impairments induced by Aβ oligomer | ||||||
| Magnolol | Magnolia officinalis | Ischemic stroke | Attenuates IL-1β, TNF-α, IL-6 and ROS production and upregulates AKT and NF-κB levels | 10 and 30 mg/kg |
Rat global ischemic stroke model | Sacks et al., 2018 |
| Berberin | Coptis chinensis | AD | Activation of AKT/GSK-3 β/Nrf2-mediated regulation, cholinergic activity mediated neurite outgrowth, induces NGF and BDNF secretion, and inhibits COX2, TNF-α, NF-κB, IL-1β, and iNOS levels | 1,2.5,5,10 and µM 0.1–50 µM 100 mg/kg/d |
HeEK293 cell line, SH-SY5Y and microglia human neuroglioma H4 cells Raw 264.7 Transgenic mouse model |
Hirsch and Hunot, 2009; Bassani et al., 2015; Gopalakrishna and Alexander, 2015; Moon and Paek, 2015; Shahpiri et al., 2016 |
| Ginkgolide B | Ginkgo biloba | AD | Activates Trk/MAPK/ERK-mediated neurite outgrowth, induces NGF and BDNF secretion, reduces AChE, TNF-α, NF-κB, IL-1β, and MDA levels, and increases SOD, GSH-Px, Cat, Bcl-2, Bcl-xL, and TGF-β level | 1, 10 or 50 M 40 μM | PC12 cells and SH-SY5Y cells | Zhang et al., 2011; Li et al., 2013 |
| Berberine | Coptis chinensis | AD | Activates AKT/GSK-3b/Nrf2-mediated regulation, induces NGF and BDNF secretion, and inhibits COX-2, TNF-α, NF-kB, IL-1β, and iNOS levels | 20 mg/kg | Murine primary microglia cells and cultured BV2 microglia cells Rat | Jia et al., 2012; Lee et al., 2012 |
| Huperzine A | Huperzia serrata | AD | Activates Trk/MAPK/ERK-mediated neurite outgrowth, induces NGF and BDNF secretion, reduces AChE, TNF-α, NF-κB, IL-1β, and MDA levels, and increases SOD, GSH-Px, Cat, Bcl-2, Bcl-xL, and TGF-α level | 1 µM 0.1 mg/kg | NSCs and microglia Rat | Wang et al., 2010; Zhu et al., 2015 |
AChE: Acetylcholinesterase; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; Aβ: amyloid-β peptide; BDNF: brain-derived neurotrophic factor; Cat: Catalase; CCL5: C-C Motif Chemokine Ligand 5; COX-2: cyclooxygenase-2; CREB: cAMP response element-binding protein; CX3CR1: C-X3-C Motif Chemokine Receptor 1; ERK: extracellular signal-regulated kinase; FADD: fas-associated death domain protein; GDNF: glial cell line-derived neurotrophic factor; GFAP: glial fibrillary acidic protein; GSH-Px: glutathione peroxidase; GSK-3: glycogen synthase kinase 3; HIF-a: hypoxia-inducible factor 1-alpha; HO-1: heme oxygenase-1; IKK: IκB kinase; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinases; JNKK1: c-Jun N-terminal kinase kinase 1; MEK: mitogen-activated protein kinase kinase; MEKK1: mitogen-activated protein kinase kinase kinase 1; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS: multiple sclerosis; mTORC1: mechanistic target of rapamycin complex 1; ND: neurodegenerative disease; NGF: nerve growth factor; Nrf2: nuclear factor erythroid 2 related factor 2; PD: Parkinson’s disease; PI3K: phosphoinositide 3-kinase; PKB: protein kinase B; ROS: reactive oxygen species; SOD: superoxide dismutase; TLR-2: Toll-like receptor-2; TNFR: tumor necrosis factor alpha receptor; TNFα: tumor necrosis factor alpha; TREM2: triggering receptor expressed on myeloid cells 2; TYROBP: tyrosine kinase-binding protein.