Table 1.

The detailed experimental studies of celastrol on CNS cells and neurodegenerative diseases.

Effects of celastrol on CNS cells and diseases	In vitro or in vivo	Models	Mechanisms of action of celastrol	Refs.
Microglia activation	Microglia cell line MG6	dsRNA [poly(I:C)]-induced activation	preventing F-actin rearrangement, preventing cytoskeletal alteration, attenuating the expression of proinflammatory cytokines and chemokines	10
	BV-2 microglia cells	LPS-stimulated activation	inhibiting LPS-induced phosphorylation of MAPK/ERK1/2 and NF-κB activation	11
	Female SD rats	SCI model	inhibiting the activation of microglia and microglia pyroptosis, down-regulating the release of pro-inflammatory cytokines and up-regulating the expression of anti-inflammatory cytokine and reducing the expression of NLRP3 inflammasome by inhibiting the expression of NF-κB/p-p65	12
	BV-2 microglia cells	LPS/ATP induced microgliosis
Inflammatory responses of astrocytes	CRT-MG human astroglial cells	HIV-1 Tat (trans-activator of transcription)-induced inflammatory responses	inhibiting JNK, AP-1 and NF-κB activation and inducing expression of HO-1	16
		Poly (I:C) activated neuro-inflammation	suppressing ICAM-1/VCAM-1, chemokines expression and activation of JNK-STAT1 and NF-κB signaling pathways	17
Neuronal apoptosis and neuro-inflammation	PC12, SH-SY5Y cells and primary neurons	Cells were treated with Cd (10 μM and/or 20 μM) for 24 h	(1) inactivating JNK and Akt/mTOR signaling pathway and elevating PTEN activity; (2) inhibiting CaMKII-dependent Akt/mTOR pathway; (3) suppressing mitochondrial ROS-dependent AMPK-mTOR signaling pathway; (4) targeting NOX2-derived ROS-dependent PP5-JNK signaling pathway.	22-25
BBB dysfunction	Murine brain endothelial bEnd3 cells	OGD model	inducing activation of MAPKs and PI3K/Akt/mTOR pathways	30
AD	Male SD rats	i.p. injection of STZ, and inhale 3% sevoflurane for 2 h	All these dementias like pathology were reversed after celastrol treatment.	37
	Male SD rats	Aβ25-35-induced rat model of AD	Celastrol attenuated hippocampal inflammation, improved synaptic function, and maintained hippocampal energy metabolism.	38
	CHO cell line	A CHO cell line overexpressing Aβ	Celastrol inhibited Aβ1-40 and Aβ1-42 production by reducing the β-cleavage of APP, and reduced BACE-1 expression by preventing NF-κB activation.	18
	Transgenic mouse model of AD	A transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw)	Celastrol reduced the levels of Aβ, decreased the microgliosis in the cortex, and reduced the levels of both soluble and insoluble Aβ1-38, Aβ1-40 and Aβ1-42.
	SH-SY5Y cells	Tau hyperphosphorylation induced by Aβ1-42	Aβ1-42 induced Tau hyperphosphorylation and HSP90 expression were inhibited by celastrol	39
	SH-SY5Y cells, C57BL/6J and APP23 mice primary hippocampal neurons	None	In addition to increased expression of HSP40, HSP70 and HSP90, celastrol induced activation of HSF1 and promoted the TTR transcription in SH-SY5Y cells.	40
	C57BL/6J, transgenic mouse model of AD	APP23 AD model mice, APP23/Ttr-/-(APP23 mice on Ttr knock-out background) mouse strains
	H4 human neuroglioma cells stably transfected to overexpress human full length APP	LPS induced neuroinflammation	Celastrol increased HSP-70 and Bcl-2 expression, decreased NF-κB, COX-2, phosphorylated GSK-3β expression and ROS production.	43
PD	Drosophila	A Drosophila DJ-1A RNAi model of PD	Celastrol prevented the loss of DN and restored dopamine content to near normal levels.	45
	Swiss Webster mice	Dopaminergic neurotoxin MPTP-induced PD model	Celastrol attenuated the loss of dopaminergic neuron in the SNpc and reduced depletion of striatal dopamine levels, increased HSP70 expression to attenuate inflammation by preventing TNF-α and NF-κB activation.	19
	Male C57BL/6 mice and genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO)	MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model	Celastrol relieved motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway.	46
	SH-SY5Y cells	Rotenone-induced PD model	Celastrol suppressed oxidative stress, provided antiapoptotic effects to maintain the mitochondrial function and induced autophagy to clear damaged mitochondria.	47
	SH-SY5Y cells	SH-SY5Y cells were treated with 1 mM MPP+ for 24 h to induced about 50% neuronal death.	Celastrol treatment suppressed MPP+-induced injuries by activating autophagy through MAPK/p38, MAPK/ERK, MAPK/Akt, or MAPK/JNK signaling pathways.	26
	Male C57BL/6 mice	Mice received i.p. injections of MPTP (10 mg/kg/day for 3 days) 24 h after the last celastrol injection	Celastrol increased Bcl-2 expression in the substantia nigra by enhancing mitophagy to clear impaired mitochondria and further inhibiting dopaminergic neuronal apoptosis
MS	Female C57BL/6 mice	EAE animal model	Celastrol suppressed pathogenic Th17 polarization in the peripheral lymph nodes, downregulated cytokine production in BMDCs and inhibited T cells infiltration into the CNS and Th17 cell responses in the CNS.	51
	Male SD rats	EAE animal model	Celastrol attenuated demyelination and inflammatory infiltration in spinal cord. Celastrol also attenuated optic neuritis by inhibiting cytokines and microgliosis production, expression of iNOS and activation of NF-κB in optic nerve, and attenuating ganglion cells apoptosis in the retina of EAE rats.	52
	Male C57BL/6 mice	EAE animal model	Celastrol modulated MAPK (p38, ERK) to regulate the downstream genes encoding SGK1, so as to restore the Th17/Treg balance and enhance BDNF expression in T cells, and lead to protection against EAE.	53
	Female SD rats	EAE animal model	Celastrol transformed cytokines profile from Th1 to Th2 pattern, with decreasing TNF-α and increasing IL-10 correspondingly. Celastrol also decreased NF-κB expression, nitrites levels, and immune-histochemical expression of TLR2 and CD3+ T-lymphocytic count.	54
ALS	Transgenic ALS mice	G93A transgenic familial ALS mice (high expresser line)	Celastrol inhibited proinflammatory cytokine and glial activation through reducing TNF-α, iNOS, CD40, GFAP and increasing HSP70 immunoreactivity in lumbar spinal cord neurons.	56
	Primary motoneuron cultures	Cellular stress, such as staurosporin and H2O2, to induce apoptosis and oxidative stress	Celastrol did not appear any neuroprotective effect and exhibited neurotoxic.	57, 58
Polyglutamine expansion diseases	HD Male Lewis rats	Succinate dehydrogenase inhibitor 3-NP-induced HD	Celastrol reduced neurotoxicity by decreasing the striatal lesion volumes, inducing HSP70 in the striata, and reducing astrogliosis.	19
	Polyglutamine aggregation and toxicity HeLa cells, PC12 cells, HSF1+/+ and HSF1-/- mouse embryo fibroblast (MEF) cells	Polyglutamine aggregation and toxicity is transfection of a Q57-YFP fusion protein into cell lines	Celastrol effectively decreased the aggregation and toxicity of polyglutamine expression in vitro via stimulating HSF1 activity to lead to inducible HSP70 gene expression pathway.	60, 61
SCA14	SH-SY5Y, CHO, and COS-7 cells, primary cultured Purkinje cells	Adenovirus infection	Celastrol induced upregulation of HSP70 and HSP40 to synergistic diminish aggregation formation of mutant PKCγ and cells death. Celastrol activated autophagy also benefited for clearing the PKCγ aggregates.	63
	Male C57BL/6N mice	Pharmacological induction of HSPs	Celastrol treatment upregulated HSP70 by penetrating the mouse cerebellum.
Stroke	Male SD rats	pMCAO model	Celastrol downregulated the expression of p-JNK, p-c-Jun and NF-κB.	67
	AIS patients	Clinical samples	Celastrol treatment increased IL-33 and IL-10 expression, and decreased IL-1β, IL-6, and TNF-α level in vitro and in vivo. The neuroprotective and anti-inflammatory effects of celastrol for ischemic stroke were derived from promoting growth ST2/IL-33 activation in microglia.	13
	Male SD rats	pMCAO model
	Primary rats neurons and microglia	OGD model
	Primary microglia-enriched cultures	Microglial polarization: microglia were transfected with a ST2 interference vector before pretreatment with OGD for 3 h, then treated with 50 ng/mL IL-33
	Primary rats neuronal	Neurons underwent OGD for 3 h after which they were treated with different concentrations of IL-33
	Male SD rats	Transient global cerebral ischemia reperfusion	Celastrol inhibited HMGB1/NF-κB signaling pathway.	69
	Primary rats neuronal	OGD model	Celastrol directly bound to HMGB1 to inactivate it, up-regulated HSP70 and down-regulated NF-κB expression to play neuroprotective effect in cerebral ischemia reperfusion injury in vitro and in vivo.	27
	Male SD rats	MCAO model
	Male C57BL/6 mice	MCAO model	Celastrol exhibited neuroprotection and anti-apoptosis effects partially by modulating lipid metabolites.	70
	Hippocampal cell line (HT-22) cells	OGD model	Celastrol significantly attenuated I/R-induced hippocampal injury by inhibiting the AK005401/MAP3K12 signaling and activating the PI3K/Akt pathway.	71
	Male C57BL/6 mice	Bilateral common carotid clip reperfusion
	Male SD rats	SAH endovascular perforation model	Celastrol attenuated brain swelling and protected BBB integrity after rats SAH by decreasing MMP-9 expression and attenuating pro-inflammatory cytokines expression.	31
TBI	hsp110-deficient mice, hsp70.1 and hsp70.3 (named hsp70i)-deficient mouse lines with C57BL/6 genetic background	Controlled Cortical Impact (CCI)	By increasing the levels of HSP70/HSP110, celastrol treatment in wild-type mice exhibited lower levels of brain injury, decreased cellular apoptosis, inflammatory cells infiltration and gliosis, and increased Ki-67-positive cells and improved behavior.	74