Celastrol: A Potential Natural Lead Molecule for New Drug Design, Development and Therapy for Memory Impairment

Figures & data

Figure 1 An illustration of a degenerative disease of the brain as a result of gradual neuronal cell damage. Created with BioRender.com.

Table 1 A Summary of in-vivo Studies Investigated the Efficacy of Celastrol on Memory Impairment

Animal, Sex	MI Models	Dose of Celastrol	Route of Administration	Testing Procedures	Remarks	Effect	References
G93A transgenic mice	ALS	2, 8 mg/kg	P.O.	Rotarod, histological analysis	Enhanced motor performance, attenuated neuronal loss and extended mice lifespan	Prevention of MI	Kiaei et al^Citation9
Swiss Webster mice, male	3-NP & MPTP	3 mg/kg	i.p.	HPLC, ELISA, histological analysis	Attenuate loss of DA and dopaminergic neurons, increase in HSP70, reduce inflammation	Prevention of MI	Cleren et al^Citation10
Tg PS1/APPsw mice	β-amyloid	1, 2.5 mg/kg	1 mg/kg: i.p. 2.5 mg/kg: s.c.	Histological analysis	Reduce β-amyloid formation	Prevention of MI	Paris et al^Citation11
Sprague-Dawley rats, male	tGCI/R	1, 2, 4 mg/kg	i.p.	MWM, ELISA, estimation of MDA, GSH, SOD and CAT levels, Western blot, immunofluorescent staining, Nissl and TUNEL staining	Attenuate inflammation, mitigate oxidative stress, reduce apoptosis	Treatment of MI	Zhang et al^Citation12

Abbreviations: ALS, amyotrophic lateral sclerosis; 3-NP, 3-nitropropionic acid; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; tGCI/R, transient global cerebral ischemia reperfusion; P.O., oral administration Per os; i.p., intraperitoneal injection; s.c., subcutaneous; HPLC, high performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay; MWM, Morris Water Maze; MAD, malondialdehyde; GSH, glutathione; SOD, superoxide dismutase; CAT, catalase; TUNEL, Terminal Deoxynucleotidyl Transferase-Mediated dUTP-Biotin Nick End Labelling; DA, dopamine; HSP70, 70 kilodalton heat shock protein.

Table 2 A Summary of in-vitro Studies Investigated the Efficacy of Celastrol on Memory Impairment

Cell Culture	MI Models	Dose of Celastrol	Testing Procedures	Remarks	References
Rat pheochromocytoma (PC12) cell line	Cd	0.1–10 µM	DAPI staining, Western blotting	Prevent cadmium-induced neuronal apoptosis	Chen et al^Citation13
SH-SY5Y cells	Rotenone	200, 500, 1000, 5000 nM	Apoptosis analysis, measurement of SOD and GSH, measurement of ROS and MMP, immunofluorescent staining, immunoblotting, electron microscopy	Ameliorate rotenone-induced SH-SY5Y cell death	Deng et al^Citation14
H4 human neuroglioma cells stably transfected to overexpress full-length APP (H4-APP)	LPS	10 nM	Measurement of intracellular ROS, immunofluorescent staining. Western blotting, ELISA	Reduced LPS-induced cell death and LPS-induced β-amyloid production	Zhao et al^Citation15

Abbreviations: Cd, cadmium; LPS, lipopolysaccharides; DAPI, 4’,6-diaminido-2-phenylindole; SOD, superoxide dismutase; GSH, glutathione; ROS, reactive oxygen species; MMP, mitochondria membrane potential; ELISA, enzyme-linked immunosorbent assay.

Figure 2 The neurotoxic rotenone induces mitochondrial dysfunction, which leads to neurodegenerative diseases. Reactive oxygen species (ROS) are generated as a result of rotenone’s inhibition of the MRC complex I. Overproduction of ROS reduces the levels of ATP and GSH, which sets off a series of events that lessen its permeability and ultimately lead to the death of brain cells. Created with BioRender.com.

Abbreviations: HMGB, high mobility group box 1 protein; TLR4, Toll-like receptor 4; MRC complex I, mitochondrial complex I; ATP, adenosine triphosphate; GSH, glutathione.

Figure 3 Future perspectives on strategies for the delivery of celastrol using nanocarriers. Celastrol can be loaded onto or conjugated to nanocarriers, boosting its ability to pass across blood-brain barriers and increasing its solubility and bioavailability through the digestive tract. Created with BioRender.com.

Figure 4 Continued.

Figure 4 (A-D) Structurally relevant molecules of celastrol. The main body text contains information on the numbered molecules.

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Zhang B, Zhong Q, Chen X, et al. Neuroprotective effects of celastrol on transient global cerebral ischemia rats via regulating HMGB1/NF-kB signaling pathway. Front Neurosci. 2020;14:1–17. doi:10.3389/fnins.2020.00001

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Chen S, Gu C, Xu C, et al. Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. J Neurochem. 2013;128:256–266. doi:10.1111/jnc.12474

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Deng Y-N, Shi J, Liu J, Qu Q-M. Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int. 2013;63(1):1–9. doi:10.1016/j.neuint.2013.04.005

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