TABLE 1.
Effects of triptolide and celastrol on neurological diseases.
| Disease | Component | In vivo/In vitro | Effects | References |
|---|---|---|---|---|
| Alzheimer’s disease | Triptolide | in vivo; Aβ 1-40-induced AD rats | attenuates the degeneration of dendritic spines in hippocampal neurons | Wan et al. (2014) |
| in vivo; APP/PS1 double transgenic AD murine model | improves cognitive function, accompanied by reduced neuroinflammation and Aβ deposition | Cheng et al. (2014) | ||
| in vivo; APP/PS1 double transgenic AD murine model | reduces astrocyte proliferation and microglia activation in the hippocampal region | Li et al. (2016) | ||
| in vivo; APP/PS1 double transgenic AD murine model | improves spatial memory deficits by inhibiting of BACE1 | Wang et al. (2014) | ||
| in vivo; APP/PS1 double transgenic AD murine model | improves spatial memory deficits by inhibiting inflammatory responses and MAPKs activity | Cui et al. (2016) | ||
| in vitro; SH-SY5Y cell lines | exerts neuroprotective effects by inhibiting CXCR2 activity and reducing Aβ production | Wang et al. (2013b) | ||
| in vitro; Aβ 1-42-treated cultured rat microglia | exerts protective effects by inhibiting TNF-α and IL-1β expression levels | Jiao et al. (2008) | ||
| in vitro; glutamate-stimulated PC12 cells | inhibits the level of ROS, attenuating apoptosis | He et al., 2003; Gu et al., 2004 | ||
| in vitro; Aβ 25-35-treated differentiated PC12 cells | promotes autophagy and inhibits oxidative stress, exerting neuroprotective effects | Xu et al., 2015; Xu et al., 2016 | ||
| in vitro; Aβ 1-42-treated differentiated PC12 cells | nanoparticles loaded with triptolide reduces oxidative stress and inhibits cytotoxicity | Jia et al. (2021) | ||
| in vitro; primary astrocytes from rats | increases synthesis and release of nerve growth factor | Xue et al. (2007) | ||
| in vitro; hippocampal neurons | increases the expression of synaptophysin | Nie et al. (2012) | ||
| in vivo; APP/PS1 double transgenic AD murine model | increased hippocampal neuroligin-1 expression through epigenetic mechanisms | Lu et al. (2019) | ||
| Celastrol | in vivo; LPS rat model | improves performance in memory and learning activity tests | Allison et al. (2001) | |
| in vivo; double transgenic Tg PS1/APPsw AD mice | attenuates the accumulation of pathological plaque and microglial activation | Paris et al. (2010) | ||
| in vivo; diabetes mellitus rat model | improves cognitive function and decreases amyloid substance | Liao et al. (2018) | ||
| in vivo; Aβ 25-35-microinjected rats | improves learning and memory deficits by inhibiting NF-kB activity, improving synaptic function and increasing glucose metabolism | Xiao et al. (2021) | ||
| In vivo and vitro; P301S microtubule associated protein tau mice and 3XTg mice, N2a cells | activates transcription factor EB-mediated autophagy and lysosome biogenesis, reduce the accumulation of neurofibrillary tangles, thereby attenuating disease severity | Yang et al. (2022b) | ||
| in vitro; human monocytes and macrophages, microglia, endothelial cells | inhibits the production of TNF-α and IL-1β by human monocytes and macrophages, the expression of MHC II molecules of microglia, and the production of inducible nitric oxide in endothelial cells | Allison et al. (2001) | ||
| in vitro; HEK293 cells | attenuates NF-kB activity | Paris et al. (2010) | ||
| in vitro; 7 W CHO cells overexpressing wild-type human APP | inhibits amyloid-β production by inhibiting BACE-1 | Paris et al. (2010) | ||
| in vitro; IMR-32 cells | exerts neuroprotective effects by inhibiting IKK | Veerappan et al. (2017) | ||
| in vitro; LPS-treated H4-APP cells | celastrol inhibits the production of Aβ, attenuates NF-kB activity and suppresses COX-2 expression. In addition, celastrol increases the expression of Hsp70 and Bcl-2 | Zhao et al. (2014) | ||
| in vitro; Aβ 1-42-treated SH-SY5Y cells | no effect on the expression of Hsp70, while inhibits the expression of Hsp90 | Cao et al. (2018) | ||
| Parkinson’s disease | Triptolide | in vivo; LPS rat model | exerting neuroprotective effects by protecting dopaminergic neurons and reducing the expression of pro-inflammatory cytokines (TNF-α and IL-1β) | Zhou et al. (2005) |
| in vivo; LPS rat model | protecting dopaminergic neurons and inhibiting microglia activation | Li et al. (2006b) | ||
| in vivo; MPP + -induced rat model | improving behavioral performance by protecting dopaminergic neurons and inhibiting microglial activation | Gao et al. (2008) | ||
| in vitro; LPS-induced primary mesencephalic neuron/glia mixed culture | decreases [3H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons, inhibits microglial activation, and attenuates TNF-α and NO production | Li et al. (2004) | ||
| in vitro; MPP + -induced primary mesencephalic neurons | tripchlorolide; promotes axonal elongation and protects dopaminergic neurons, as well as increases BDNF mRNA expression | Li et al. (2003) | ||
| in vivo; partially lesioned PD rat model | tripchlorolide; protects dopaminergic neurons and inhibits the overproduction of TNF-α and IL-2 | Cheng et al. (2002) | ||
| in vivo; MPTP-induced PD mouse model | tripchlorolide; improves behavioral performance, protects dopaminergic neurons and inhibits astroglial responses | Hong et al. (2007) | ||
| in vitro; preformed fibrils of human wild-type α-synuclein-induced mouse primary microglia | inhibits microglial activation by suppressing NF-κB activity via targeting the miR155–5p/SHIP1 pathway | Feng et al. (2019) | ||
| in vivo and vitro; LPS-induced PD model | inhibits microglial activation by upregulating metabotropic glutamate receptor 5 | Huang et al. (2018) | ||
| in vitro; MN9D cell line | enhances autophagy in neuronal cells, promoting the clearance of α-synuclein | Hu et al. (2017) | ||
| Celastrol | in vivo; Drosophila DJ-1A PD model | inhibits the reduction of dopaminergic neurons and increases brain dopamine content | Faust et al. (2009) | |
| in vivo; MPTP-induced mouse PD model | attenuates the loss of dopaminergic neurons, increases Hsp70 within dopaminergic neurons, and decreases the levels of NF-kB and TNF-α | Cleren et al. (2005) | ||
| in vivo; MPTP-induced mouse PD model | exerts neuroprotective effects by promoting mitophagy | Lin et al. (2019) | ||
| in vivo; AAV-mediated human α-synuclein overexpression PD model and the MPTP-induced PD mouse model | improve motor deficits by modulating the Nrf2-NLRP3-caspase-1 pathway | Zhang et al. (2021) | ||
| in vivo and vitro; lactacystin-induced Wistar rats, SH-SY5Y cells and mouse primary cortical neurons | no neuroprotective effects | Konieczny et al. (2014) | ||
| in vitro; rotenone-induced SH-SY5Y PD model | exerts neuroprotection by inducing autophagy, preserving mitochondrial function and inhibiting p38 MAPK | Deng et al., 2013; Choi et al., 2014 | ||
| in vitro; dendritic cells | mediates antigen trafficking in DCs, thus attenuating α-synuclein-specific T cell responses | Ng et al. (2022) | ||
| Multiple sclerosis | Triptolide | in vivo; C57 BL/6 mouse EAE model | delays the onset of EAE, attenuates the degree of inflammation and demyelination, improves behavirol deficits, and inhibits NF-kB-DNA binding activity | Wang et al. (2008) |
| in vivo; C57 BL/6 mouse EAE model | LLDT-8; suppresses the severity of EAE by inhibiting T-cell activation | Fu et al. (2006) | ||
| in vivo; SJL/J mouse EAE model | increases expression levels of Hsp70 and stabilisation of the NF-kB/IkBα complex | Kizelsztein et al. (2009) | ||
| in vivo; cuprizone-induced toxic model | improves behavioral deficits and attenuates neuroinflammation by inhibiting NF-kB activation and promoting intrinsic myelin repair | Sanadgol et al. (2018) | ||
| Celastrol | in vivo; relapsing-remitting EAE rat model | inhibits relapses and reduces clinical scores by modulating the Th1/Th2 cytokines profile (increases IL-10 expression but reduces TNF-α expression), inhibiting NF-κB and TLR2 expression, and reducing CD3+ T lymphocytic count | O'Brien et al., 2001; Abdin and Hasby, (2014) | |
| in vivo; EAE mouse model | exerts neuroprotective effects by inhibiting Th17 cell responses and attenuating cytokine production | Wang et al. (2015) | ||
| in vivo; EAE mouse model | affects T-cell responses through the MAPK pathway, inhibiting SGK1 expression and incresing BDNF expression | Venkatesha and Moudgil, (2019) | ||
| in vivo; EAE rat model | inhibiting the expression of iNOS and NF-kB and attenuating MS and optic neuritis | Yang et al. (2017) | ||
| Huntington’s diseases | Celastrol | in vivo; 3-nitropropionic acid-induced HD rat models | decreases striatal lesion voulme, increases the expression of Hsp70 in the striata, and attenuates astrogliosis | Cleren et al. (2005) |
| in vitro; cell lines expressing mutant | inhibits polyglutamine aggregation by inducing HSF1 and increasing the expression of Hsp70 | Zhang and Sarge, (2007) | ||
| polyglutamine protein | ||||
| in vitro; HdhQ111/Q111 knock-in mouse-derived striatal cell line | inhibits mutant huntingtin aggregation, and reverses the abnormal cellular localization of full-length mutant huntingtin | Wang et al. (2005) | ||
| Amyotrophic lateral sclerosis | Celastrol | in vivo; G93A SOD1 transgenic ALS mouse model | delays disease onset, improves motor deficits, increases the number of neurons, promotes Hsp70 expression, and reduces TNF-α and iNOS levels | Kiaei et al. (2005) |
| in vitro; staurosporin or H2O2-induced primary motoneurons | activates the heat shock response (i.e. increases Hsp70 expression) | Kalmar and Greensmith, (2009) | ||
| in vitro; H2O2-treated G93A SOD1 transfected NSC34 cells | reduces cell death by activating MEK/ERK and PI3K/AKT signaling pathways | Li et al. (2017) | ||
| Cerebral ischemia | Triptolide | in vivo; focal cerebral ischemia reperfusion rat model | improves neural function, attenuates neuronal apoptosis, and suppresses infiltration of neutrophils | Wei et al. (2004) |
| in vivo; focal cerebral ischemia reperfusion rat model | exerts neuroprotection by inhibiting NF-kB activity | Jin et al., 2015; Bai et al., 2016a; Bai et al., 2016b | ||
| in vivo; focal cerebral ischemia reperfusion rat model | exerts neuroprotective effects by inhibiting NF-kB/PUMA signaling pathway | Zhang et al. (2016) | ||
| in vivo and vitro; focal cerebral ischemia reperfusion rat model, and OGD and TNF-α-stimulated SH-SY5Y cells | inhibits NF-kB and p38 MAPK signaling pathways, exerting neuroprotection | Hao et al. (2015) | ||
| in vivo; focal cerebral ischemia reperfusion rat model | upregulates autophagy and downregulates apoptosis | Yang et al. (2015) | ||
| in vivo; focal cerebral ischemia reperfusion rat model | downregulating apoptosis by activating the PI3K/AKT/mTOR signaling pathway | Li et al. (2015) | ||
| in vivo; focal cerebral ischemic mouse model | improves cerebral ischemia by triggering BDNF-AKT signaling pathway and autophagy | Du et al. (2020) | ||
| in vivo; focal cerebral ischemia reperfusion rat model | improves neurobehavioral scores, reduces brain damage, reduces levels of malondialdehyde and ROS, increases superoxide dismutase level, involving inhibition of Wnt/β-catenin signaling pathway | Pan and Xu, (2020) | ||
| in vivo and vitro; chronic cerebral hypoperfusion mouse model, and OGD-stimulated primary oligodendrocytes and BV2 cells | alleviates white matter injury, protects against oligodendrocyte apoptosis directly, and inhibits microglial inflammation indirectly, involving increase of phosphorylation of the Src/AKT/GSK 3β singnaling pathway | Wan et al. (2022) | ||
| Celastrol | in vivo; permanent middle cerebral artery occlusion mouse model | improves neurological function and reduces infarct volume in by attenuating the expression of NF-kB, p-c-Jun, and p-JNK | Li et al. (2012) | |
| in vivo; transient global cerebral ischemia reperfusion rat model | exerts neuroprotection, inhibits the expression of pro-inflammatory cytokines and MDA and elevates the levels of GSH and SOD, which is mediated by inhibiting HMGB1/NF-kB signaling pathway | Zhang et al. (2020) | ||
| in vivo and vitro; focal cerebral ischemia reperfusion rat model and OGD-stimulated primary rat cortical neuron | directly binds to HMGB1, thus inhibiting the binding of HMGB1 to its downstream inflammatory components; inhibits NF-kB activity | Liu M et al. (2021) | ||
| in vivo and vitro; permanent focal ischemia rat model and OGD-stimulated rimary neurons and microglia | exerts neuroprotective effects through an IL-33/ST2 axis-mediated M2 microglia/macrophage polarization | Jiang et al. (2018) | ||
| in vivo; focal cerebral ischemia reperfusion mouse model | attenuates glycolysis and exerts neuroprotection by inhibiting HIF-1α/PDK1 | Chen et al. (2022) | ||
| in vivo and vitro; cerebral ischemia reperfusion mouse model and OGD-stimulated HT-22 cells | inhibits AK005401/MAP3K12 and activates PI3K/AKT signaling pathway, thus exerting neuroprotective effects | Wang et al. (2021) | ||
| Traumatic brain injury | Triptolide | in vivo; TBI rat model | improves neurological deficits and attenuates contusion volume, edema, cell apoptosis, decreases expressions of pro-inflammatory cytokines while increases level of anti-inflammatory cytokines | Lee et al. (2012) |
| Celastrol | in vivo; TBI mouse model | improves neurobehavioral functions and protects neuronal cells by inducing Hsp70/Hsp110 expression | Eroglu et al. (2014) | |
| Spinal cord injury | Triptolide | in vivo and vitro; SCI rat model and LPS-stimulated primary astrocytes | promotes spinal cord repair, inhibits inflammation, and attenuates astrogliosis and glial scar by inhibiting the JAK2/STAT3 pathway | Su et al. (2010) |
| in vivo; SCI rat model | exerts neuroprotection by targeting the miR-96/IKKβ/NF-κB pathway and thus inhibiting microglial activation | Huang et al. (2019) | ||
| in vivo; SCI mouse model | enhances autophagy and inhibits MAPK/ERK1/2 signaling pathway | Zhu et al. (2020) | ||
| Celastrol | in vitro; SCI spinal cords model | reduces motorneuron death by inducing Hsp70 expression, while exerts limited protection on the lumbar motor network | Petrović et al. (2019) | |
| in vivo and vitro; SCI rat model and LPS + ATP-induced BV2 cells | attenuates microglial activation in the spinal cord, inhibits the expression of NF-kB, thus inhibiting the expression of NLRP3, caspase-1, GSDMD and inflammatory cytokines, while increases the levels of anti-inflammatory cytokines | Dai et al. (2019) | ||
| Epilepsy | Triptolide | in vivo; kainic acid-induced epilepsy rat model | protects neurons, which is associated with increased expression of neuron kv1.1 in the CA3 region of the hippocampus | Pan et al. (2012) |
| in vitro; kainic acid-stimulated BV2 microglia | inhibits microglial activation, decreases MHC II expression in microglia by inhibiting AP-1/class II transactivator, which is related to neuronal death | Sun et al. (2018) | ||
| Celastrol | in vivo; multiple-hit rat model | has a therapeutic effect by inhibiting NF-kB | Schiavone et al. (2021) | |
| in vivo and vitro; kainic acid-induced rats and hippocampal slices | inhibits NOX activation and rapid H2O2 release, thus alleviating epileptic seizure | Malkov et al. (2019) | ||
| in vivo; mouse amygdala-kindling model | increases microglial activation in hippocampal CA1 and CA3 regions and reduces postkindling seizure thresholds | von Rüden et al. (2019) |