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| Entry | Active ingredient | Experimental model | Pharmacological effect | Mechanisms of action | Ref |
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| 1 | Diosgenin | 5XFAD 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] |
| 2 | Diosgenin | Normal mouse | Improved memory and axonal density;
Increased c-Fos expression in the medial prefrontal and perirhinal cortices | 1,25D3-MARRS-triggered axonal growth | [66] |
| 3 | Diosgenin | Trimethyltin- (TMT-) injected transgenic 2576 (TG) mice | Decreased 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 | [67] |
| 4 | Compound 6 | Memory-impaired Long-Evans rats induced by infusion of Fe2+, Aβ42, and buthionine-sulfoximine (FAB) into the left cerebral ventricle for 4 weeks | Enhanced cognitive function;
Decreased amyloid deposits, astrogliosis, and Tau protein phosphorylation in hippocampus | | [68] |
| 5 | Compound 6 | Aβ-induced neurotoxicity in rat PC12 and human NT2N neuronal cells | Protected 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] |
| 6 | Compound 6 | Aβ1-42-induced SK-N-AS cells | Protected MPT and inhibited accumulation of the Aβ1-42 in the mitochondrial matrix | Directly targeting complexes IV and the mitochondrial respiratory chain | [72] |
| 7 | Compound 8 | A cellular AD model using MC65 neuroblastoma cells from TC withdrawal-induced cytotoxicity | Antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation | Bind directly to Aβ | [56] |
| 8 | Compound 9 | A 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 mitochondria | Interfere with glutamate uptake or its redox reaction | [27] |
| 9 | Diosgenin-rich yam extracts | Senescent mice induced by D-galactose | Improve 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] |
| 10 | Diosgenin | PD 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] |
| 11 | Diosgenin | In vitro model of HIV-induced dementia using human neuronal cultures with E4 allele of ApoE | Protected against the neurotoxicity of Tat+morphine;
Tat-induced oxidative stress impaired morphine metabolism | | [76] |
| 12 | Diosgenin | A rat model with brain aging through subcutaneous injection of D-galactose | Improve learning and memory;
Upregulating Rheb and downregulating mTOR | Rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway | |
| 13 | Compound 3 | Neuroinflammation induced by intraperitoneal injection of LPS | Enhanced the serotonergic system and produced the antidepressant effect | Protects the hippocampus from LPS-induced neuroinflammation by the neurotransmitter 5-HT and the HMGB-1/TLR4 signaling pathway | [80] |
| 14 | Compound 2 | Neuroinflammation model using rat microglia and BV2 cells induced by LPS | Suppressed 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] |
| 15 | Compound 7 | Neuroinflammation model using BV2 cells induced by LPS | Inhibition 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] |
| 16 | Compound 4 | Neuroinflammation model using BV2 cells or mice by I.C.V. injection of LPS | Improved 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 | [57] |
| 17 | Diosgenin | C57BL/6J mice model of experimental autoimmune encephalomyelitis | Inhibit the activation of microglia and macrophages, suppress CD4+ T cell proliferation, and hinder Th1/Th17 cell differentiation | | [84] |
| 18 | Diosgenin | Rat primary oligodendrocyte progenitor cell (OPC) culture model, a cuprizone-induced demyelination C57BL/6J mice model | Significantly 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] |
| 19 | Compound 2 | Sprague-Dawley rats with traumatic spinal cord injury | Significantly 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] |
| 20 | Compound 3 | Ischemic stroke rat model | Improved 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] |
| 21 | Compound 5 | Thrombosis model using male balb/C mice | Prolonging the bleeding time;
Inhibited platelet aggregation, prolonged partial thromboplastin time (APTT), and inhibited factor VIII activities | | [90] |
| 22 | Diosgenin | Transient focal cerebral ischemia-reperfusion (I/R) injury model by middle cerebral artery occlusion (MCAO) using the intraluminal thread for 90 min | Inhibited 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] |
| 23 | Compound 3 | In vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model | Prevented 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] |
| 24 | Compound 3 | Cerebral ischemia-reperfusion model by middle cerebral artery occlusion (MCAO) ischemic mice | Enhanced spatial learning memory in ischemic mice;
An improvement in deficient ability and reduction in infarct volume | | [94] |
| 25 | Diosgenin | Ovariectomized (OVX) female Wistar rats | Dose-dependently influences IL-2 levels in the brain of OVX rats and affects depressive behavior in OVX with high-anxiety rats | | [95] |
| 26 | Diosgenin | Neuropathic pain model induced by chronic constriction injury (CCI) in rats | Reversed 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] |
| 27 | Diosgenin | Diabetic neuropathy mice model | Increased 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] |
| 28 | Diosgenin | Peripheral nerve injury model using male Sprague-Dawley rat to crush the right sciatic nerve for 30 sec | Increased 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 | | [99] |
| 29 | Diosgenin | C6 rat glioma cells | Reduced 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] |
| 30 | Compound 3 | In vitro study using GBM, U87MG, A172, LN18, NBRC, T98G, and LN229 cell lines | Inhibited 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] |
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