Oxidative Medicine and Cellular Longevity / 2020 / Article / Tab 1

Review Article

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Table 1

Key pharmacological effects and mechanisms of action of DG and its major derivatives in neurological diseases.

EntryActive ingredientExperimental modelPharmacological effectMechanisms of actionRef

1Diosgenin5XFAD transgenic mouse model of AD;
Rat cortical neurons and mouse cortical neuron primary culture
Increased memory and decreased axonal degeneration;
Reduced amyloid plaques and neurofibrillary tangles in the cerebral cortex and hippocampus
1,25D₃-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS)[65]
2DiosgeninNormal mouseImproved memory and axonal density;
Increased c-Fos expression in the medial prefrontal and perirhinal cortices
1,25D3-MARRS-triggered axonal growth[66]
3DiosgeninTrimethyltin- (TMT-) injected transgenic 2576 (TG) miceDecreased the number of Aβ-stained plaques and dead cells in the granule cell layer of the dentate gyrus;
Reduced acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression; increased expression of nerve growth factor (NGF) and superoxide dismutase (SOD) activity
Increased phosphorylation of downstream members in TrkA signaling;
Evaluated p75(NTR) expression and JNK phosphorylation in the NGF signaling pathway
4Compound 6Memory-impaired Long-Evans rats induced by infusion of Fe2+, Aβ42, and buthionine-sulfoximine (FAB) into the left cerebral ventricle for 4 weeksEnhanced cognitive function;
Decreased amyloid deposits, astrogliosis, and Tau protein phosphorylation in hippocampus
5Compound 6Aβ-induced neurotoxicity in rat PC12 and human NT2N neuronal cellsProtected against 0.1 μM Aβ in PC12 cells;
Reversed 0.1-10 μM Aβ-induced decrease in ATP levels
Physicochemical interaction with Aβ inhibited the formation of neurotoxic amyloid-derived diffusible ligands[70, 71]
6Compound 6Aβ1-42-induced SK-N-AS cellsProtected MPT and inhibited accumulation of the Aβ1-42 in the mitochondrial matrixDirectly targeting complexes IV and the mitochondrial respiratory chain[72]
7Compound 8A cellular AD model using MC65 neuroblastoma cells from TC withdrawal-induced cytotoxicityAntioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formationBind directly to Aβ[56]
8Compound 9A cellular AD model using MC65 neuroblastoma cells from TC withdrawal-induced cytotoxicity;
Neuronal N2a cells and rat primary cortical neurons
Significant stimulating activity on neurotic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondriaInterfere with glutamate uptake or its redox reaction[27]
9Diosgenin-rich yam extractsSenescent mice induced by D-galactoseImprove their learning and memory abilities;
Increase the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and decrease malondialdehyde (MDA) level
Enhancing endogenous antioxidant enzymatic activities[56, 58]
10DiosgeninPD model using Sprague-Dawley rats using intrastriatal injection of lipopolysaccharide (LPS)Attenuate the inflammatory and oxidative stress response;
Restore LPS-induced motor deficits;
Decrease the expression levels of TLR2, TLR4, and NF-κB
Inhibiting the TLR/NF-κB pathway[26]
11DiosgeninIn vitro model of HIV-induced dementia using human neuronal cultures with E4 allele of ApoEProtected against the neurotoxicity of Tat+morphine;
Tat-induced oxidative stress impaired morphine metabolism
12DiosgeninA rat model with brain aging through subcutaneous injection of D-galactoseImprove learning and memory;
Upregulating Rheb and downregulating mTOR
Rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway
13Compound 3Neuroinflammation induced by intraperitoneal injection of LPSEnhanced the serotonergic system and produced the antidepressant effectProtects the hippocampus from LPS-induced neuroinflammation by the neurotransmitter 5-HT and the HMGB-1/TLR4 signaling pathway[80]
14Compound 2Neuroinflammation model using rat microglia and BV2 cells induced by LPSSuppressed the expression levels of proinflammatory M1 markers, such as NO, IL-6, and TNF-α;
Repressed IκB-α, ERK, MAPK, and p38 MAPK phosphorylation
Inhibiting NF-κB, ERK/MAP, and p38/MAPK signaling[81]
15Compound 7Neuroinflammation model using BV2 cells induced by LPSInhibition of the inflammatory mediators such as NO, iNOS, COX-2, IL-6/1b, and TNF-α in protein and mRNA levels;
Suppressed the NF-κB activity and phosphorylation level of JNK
Inactivation of NF-κB and JNK MAPK signaling[82]
16Compound 4Neuroinflammation model using BV2 cells or mice by I.C.V. injection of LPSImproved the cognitive function impaired by LPS and attenuated LPS-impaired neurogenesis;
Suppressed the production of proinflammatory cytokines in hippocampal DG
Blocking microglial activation;
Underlying NF-κB and JNK MAPK;
Signaling in LPS-induced adult mice
17DiosgeninC57BL/6J mice model of experimental autoimmune encephalomyelitisInhibit the activation of microglia and macrophages, suppress CD4+ T cell proliferation, and hinder Th1/Th17 cell differentiation[84]
18DiosgeninRat primary oligodendrocyte progenitor cell (OPC) culture model, a cuprizone-induced demyelination C57BL/6J mice modelSignificantly and specifically promotes OPC differentiation;
Enhances remyelination;
Increases the number of mature oligodendrocytes in the corpus callosum
Differentiation of OPC into mature oligodendrocytes through an ER-mediated ERK1/2 activation pathway to accelerate remyelination[85]
19Compound 2Sprague-Dawley rats with traumatic spinal cord injurySignificantly less tissue injury and edema;
Functional recovery
Significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway due to the downregulation of miR-155-3p[87]
20Compound 3Ischemic stroke rat modelImproved infarct volume and neurological scores;
Reduced inflammatory responses, and suppressed the expression of TLR4, MyD88, NF-κB, TGF-β1, HMGB-1, IRAK1, and TRAF6
Inhibition of TLR4/MyD88/NF-κB induced inflammation[89]
21Compound 5Thrombosis model using male balb/C miceProlonging the bleeding time;
Inhibited platelet aggregation, prolonged partial thromboplastin time (APTT), and inhibited factor VIII activities
22DiosgeninTransient focal cerebral ischemia-reperfusion (I/R) injury model by middle cerebral artery occlusion (MCAO) using the intraluminal thread for 90 minInhibited the death rate and improved the impaired neurological functions, neurological deficit scores, and cerebral infarct size;
Reduced cell apoptosis in the hippocampus CA1 and cortex;
Suppressed the production of proinflammatory cytokines TNF-α, IL-1β, and IL-6 in blood serum
Antiapoptosis, anti-inflammation, and intervening NF-κB signaling pathway[92]
23Compound 3In vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) modelPrevented OGD/R insult and cerebral I/R injury;
Inhibition in the expression and the nuclear-to-cytosolic translocation of HMGB-1;
Blockade of the TLR4/MyD88/TRAF6 signaling pathway;
Inhibited NF-κB and AP-1 transcriptional activities, inhibited MAPK and STAT3 phosphorylation, inhibited proinflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors
HMGB-1/TLR4 signaling[93]
24Compound 3Cerebral ischemia-reperfusion model by middle cerebral artery occlusion (MCAO) ischemic miceEnhanced spatial learning memory in ischemic mice;
An improvement in deficient ability and reduction in infarct volume
25DiosgeninOvariectomized (OVX) female Wistar ratsDose-dependently influences IL-2 levels in the brain of OVX rats and affects depressive behavior in OVX with high-anxiety rats[95]
26DiosgeninNeuropathic pain model induced by chronic constriction injury (CCI) in ratsReversed the mechanical withdrawal threshold and thermal withdrawal latency;
Inhibited the expression levels of proinflammatory cytokines TNF-α, IL-1β, and IL-2;
Suppressed oxidative stress
Inhibiting activation of p38 MAPK and NF-κB signaling pathways[96]
27DiosgeninDiabetic neuropathy mice modelIncreased NGF levels in the sciatic nerve, enhanced neurite outgrowth in PC12 cells, and improved nerve conduction velocities;
Reduced disarrangement of the myelin sheath, increased area of myelinated axons, and an improvement in the damaged axons
Increased the nerve conduction velocity by induction of NGF[97]
28DiosgeninPeripheral nerve injury model using male Sprague-Dawley rat to crush the right sciatic nerve for 30 secIncreased sciatic function index (SFI) value;
Suppressed nerve injury-induced c-Fos expression in the ventrolateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN);
Increased expression levels of BDNF, TrkB, COX-2, and iNOS
29DiosgeninC6 rat glioma cellsReduced the dosage regimen of TMZ and overcome temozolomide resistance in TMZ-resistant GBM cells;
Underwent apoptosis and early cell cycle arrest with significant reduction in MMP-2 levels
Upregulation of MMP-2 level and apoptosis signaling pathway[103]
30Compound 3In vitro study using GBM, U87MG, A172, LN18, NBRC, T98G, and LN229 cell linesInhibited proliferation of C6 glioma cells, ROS generation caused mitochondrial damage and cell apoptosis;
Inhibited tumor size and extended the life cycle of rats
Increase in ROS accumulation, DNA damage, and mitochondrial-mediated apoptosis signaling[104]