# Review of neuroprotective potential of natural products against hypoxia-induced neuronal injury **Authors:** Yuman Zhang, Xingyu Yi, Dingzhong Wang, Cunlong Kong, Yan Xu, Jianping Xie PMC · DOI: 10.3389/fphar.2026.1746683 · Frontiers in Pharmacology · 2026-02-11 ## TL;DR This review explores how natural products like curcumin and quercetin may protect neurons from hypoxia-related damage, offering potential treatments for neurological diseases. ## Contribution The paper systematically reviews the neuroprotective potential of specific natural products against hypoxia-induced injury and their underlying mechanisms. ## Key findings - Natural products like curcumin and quercetin show neuroprotective effects against hypoxia-induced injury. - These products may act through mechanisms such as reducing oxidative stress and neuroinflammation. - They offer potential therapeutic approaches for diseases like Alzheimer’s and Parkinson’s. ## Abstract Neurological disorders such as neurodegenerative diseases (NDDs) and stroke have become a major global health burden. Evidences from several studies suggest that their pathogenesis is related to hypoxia. However, there are certain limitations and adverse effects associated with the current treatments for neurological disorders. Studies have shown that some natural products and their extracts—such as (−)-epigallocatechin-3-gallate, Centella asiatica, ginkgolides, quercetin, berberine, and curcumin, which are the focus of this paper, along with briefly mentioned resveratrol and compounded preparations—have some neuroprotective effects in hypoxia-induced neurological injury. Owing to their favorable safety profile and minimal adverse effects, they have attracted widespread attention. Moreover, their primary mechanisms of action possibly stem from oxidative stress inhibition, neuroinflammation attenuation, and neuronal apoptosis reduction, providing potential approaches for the prevention and treatment of neurological diseases. In this review, we searched the PubMed and Web of Science databases for relevant literature collected over the past 35 years. Overall, we summarized the neuroprotective effects of these natural products against hypoxia-related neurological injury, focusing on the molecular mechanisms and signaling pathways, thereby offering a theoretical basis for further research on the specific neuroprotective mechanisms and drug targets of their observed preventive and therapeutic effects on NDDs, primarily Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) in this review. ## Linked entities - **Chemicals:** (−)-epigallocatechin-3-gallate (PubChem CID 65064), quercetin (PubChem CID 5280343), berberine (PubChem CID 2353), curcumin (PubChem CID 969516), resveratrol (PubChem CID 5056) - **Diseases:** stroke (MONDO:0005098), Alzheimer’s disease (MONDO:0004975), Parkinson’s disease (MONDO:0005180), Huntington’s disease (MONDO:0007739) ## Full-text entities - **Genes:** Hif1a (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 29560] {aka HIF1-alpha, MOP1}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, MME (membrane metalloendopeptidase) [NCBI Gene 4311] {aka CALLA, CD10, CMT2T, NEP, SCA43, SFE}, Sirt1 (sirtuin 1) [NCBI Gene 309757] {aka Sir2}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, HSP90AB1 (heat shock protein 90 alpha family class B member 1) [NCBI Gene 3326] {aka D6S182, HSP84, HSP90B, HSPC2, HSPCB}, Gfap (glial fibrillary acidic protein) [NCBI Gene 24387], STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, H19 (H19 imprinted maternally expressed transcript) [NCBI Gene 283120] {aka ASM, ASM1, BWS, D11S813E, GMRSP, LINC00008}, Hmox1 (heme oxygenase 1) [NCBI Gene 24451] {aka HEOXG, Heox, Hmox, Ho-1, Ho1, hsp32}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 116554] {aka JNK}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Ephb1 (Eph receptor B1) [NCBI Gene 24338] {aka Ephb2, Erk, elk}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, IREB2 (iron responsive element binding protein 2) [NCBI Gene 3658] {aka ACO3, IRE-BP 2, IRE-BP2, IRP2, IRP2AD, NDCAMA}, Mme (membrane metallo-endopeptidase) [NCBI Gene 24590] {aka CD10, Nep, SFE}, Tlr4 (toll-like receptor 4) [NCBI Gene 29260], NLRX1 (NLR family member X1) [NCBI Gene 79671] {aka CLR11.3, DLNB26, NOD26, NOD5, NOD9}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, YWHAG (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma) [NCBI Gene 7532] {aka 14-3-3GAMMA, DEE56, EIEE56, PPP1R170}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 25464] {aka CD54, ICAM, RICAM-I}, Ikbkb (inhibitor of nuclear factor kappa B kinase subunit beta) [NCBI Gene 84351] {aka AIM-1, IKK2}, Il1b (interleukin 1 beta) [NCBI Gene 24494] {aka IL-1F2}, Ireb2 (iron responsive element binding protein 2) [NCBI Gene 64831] {aka Irp2}, Cat (catalase) [NCBI Gene 24248] {aka CS1, Cas1, Cat01, Catl, Cs-1}, Nlrx1 (NLR family member X1) [NCBI Gene 315599] {aka RGD1311293}, Keap1 (Kelch-like ECH-associated protein 1) [NCBI Gene 117519] {aka Inrf2}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 25125], Hmgb1 (high mobility group box 1) [NCBI Gene 25459] {aka Ac2-008, Hmg1}, Myd88 (MYD88, innate immune signal transduction adaptor) [NCBI Gene 301059], Hmox1 (heme oxygenase 1) [NCBI Gene 15368] {aka D8Wsu38e, HO-1, HO1, Hemox, Hmox, Hsp32}, Casp8 (caspase 8) [NCBI Gene 64044] {aka CASP-8}, Trpm2 (transient receptor potential cation channel, subfamily M, member 2) [NCBI Gene 294329] {aka Trpm2-predicted}, Aqp4 (aquaporin 4) [NCBI Gene 25293] {aka AQP-4, Miwc, WCH4}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Pik3cg (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma) [NCBI Gene 298947] {aka Pi3k}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, Crebbp (CREB binding lysine acetyltransferase) [NCBI Gene 54244] {aka CBP, RSTS, RTS}, Nod2 (nucleotide-binding oligomerization domain containing 2) [NCBI Gene 291912] {aka Card15}, FNDC5 (fibronectin type III domain containing 5) [NCBI Gene 252995] {aka FRCP2, irisin}, Nfkbia (NFKB inhibitor alpha) [NCBI Gene 25493] {aka RL/IF-1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, Syt1 (synaptotagmin 1) [NCBI Gene 25716] {aka P65}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, Casp9 (caspase 9) [NCBI Gene 58918] {aka Apaf3, Casp-9-CTD, Casp9_v1, Ice-Lap6, Mch6}, App (amyloid beta precursor protein) [NCBI Gene 11820] {aka Abeta, Abpp, Adap, Ag, Cvap, E030013M08Rik}, Anxa3 (annexin A3) [NCBI Gene 25291] {aka Anx3, LC3, LRRGT00047}, PPARGC1A (PPARG coactivator 1 alpha) [NCBI Gene 10891] {aka LEM6, PGC-1(alpha), PGC-1alpha, PGC-1v, PGC1, PGC1A}, Fndc5 (fibronectin type III domain containing 5) [NCBI Gene 260327], Nefh (neurofilament heavy chain) [NCBI Gene 24587] {aka Nfh}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb} - **Diseases:** cerebral ischemic diseases (MESH:D002539), cerebral hypoperfusion (MESH:D002547), I/R injury (MESH:D015427), ALS (MESH:D000690), excitotoxic injury (MESH:D014947), NDDs (MESH:D019636), inflammation (MESH:D007249), arthritis (MESH:D001168), HIV-associated dementia (MESH:D015526), nerve damage (MESH:D000080902), PD (MESH:D010300), brain cell damage (MESH:D001925), atherosclerosis (MESH:D050197), MCAO (MESH:D020244), mitochondrial and synaptic damage (MESH:D028361), hypoxic neurological damage (MESH:D020196), brain injury (MESH:D001930), death (MESH:D003643), cerebral ischemic injury (MESH:D017202), HD (MESH:D006816), cerebral ischemia (MESH:D002545), diabetes (MESH:D003920), cancer (MESH:D009369), cerebral infarct (MESH:D002544), AD (MESH:D000544), neurotoxic (MESH:D020258), venous insufficiency (MESH:D014689), infection (MESH:D007239), OGD (MESH:C536050), central nervous system disorders (MESH:D002493), anxiety (MESH:D001007), neuroinflammation (MESH:D000090862), BBB damage (MESH:C536830), cerebrovascular diseases (MESH:D002561), TBI (MESH:D000070642), HAD (MESH:C535310), hypoxic (MESH:D002534), neurological disease (MESH:D020271), bleeding (MESH:D006470), OSA (MESH:D020181), brain edema (MESH:D001929), ischemic neuronal damage (MESH:D009410), sensorimotor (MESH:D020233), WMI (MESH:D056784), AIDS (MESH:D000163), glutamate excitotoxicity (MESH:C537425), acute stroke (MESH:D020521), dementia (MESH:D003704), HI (MESH:C538424), loss of neurological function (MESH:D003291), liver toxicity (MESH:D056486), spinal cord injury (MESH:D013119), acute hypoxia (MESH:D000208), pheochromocytoma (MESH:D010673), AIS (MESH:D000083242), neuroblastoma (MESH:D009447), HIE (MESH:D020925), Neurological disorders (MESH:D009461), hypoxic ischemia (MESH:D007511), HINS (MESH:C535466) - **Chemicals:** Curcumin (MESH:D003474), NO (MESH:D009614), PC (-), (-)-epigallocatechin-3-gallate (MESH:C045651), GM (MESH:C469722), chrysin (MESH:C043561), O2 (MESH:D010100), AA (MESH:C017032), rhamnetin (MESH:C063423), GB (MESH:C045856), NADPH (MESH:D009249), isoquercitrin (MESH:C016527), Ginkgolides (MESH:D046934), 3,3',4',5,7-pentahydroxyflavone (MESH:D011794), amino acid (MESH:D000596), Asp (MESH:D001224), MS (MESH:C093443), MDA (MESH:D008315), KCN (MESH:D011190), rutin (MESH:D012431), AS (MESH:C004446), triterpenoids (MESH:D014315), free radicals (MESH:D005609), GSH (MESH:D005978), GC (MESH:C058295), S1P (MESH:C060506), ATP (MESH:D000255), water (MESH:D014867), polyphenol (MESH:D059808), essential oils (MESH:D009822), Catechins (MESH:D002392), terpenoids (MESH:D013729), LPS (MESH:D008070), iron (MESH:D007501), lipid (MESH:D008055), GK (MESH:C481151), GL (MESH:C481152), epigallocatechin (MESH:C057580), Glu (MESH:D018698), glycolipid (MESH:D006017), iron oxide (MESH:C000499), GABA (MESH:D005680), Resveratrol (MESH:D000077185), MA (MESH:C001669), Gly (MESH:D005998), excitatory amino acids (MESH:D018846), ROS (MESH:D017382), glycosides (MESH:D006027), BBR (MESH:D001599), GA (MESH:C477042), GJ (MESH:C075228), calcium (MESH:D002118), flavonol (MESH:C041477), glucose (MESH:D005947), CoCl2 (MESH:C018021), Flavonoids (MESH:D005419) - **Species:** Centella asiatica (Asiatic pennywort, species) [taxon 48106], Rhodiola rosea (rose-root, species) [taxon 203015], Coptis chinensis (species) [taxon 261450], Danio rerio (leopard danio, species) [taxon 7955], Ginkgo biloba (ginkgo, species) [taxon 3311], Malus domestica (apple, species) [taxon 3750], Centella (genus) [taxon 43068], Mus musculus (house mouse, species) [taxon 10090], Hippophae rhamnoides (sallowthorn, species) [taxon 193516], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Camellia sinensis (black tea, species) [taxon 4442], Curcuma longa (turmeric, species) [taxon 136217], Coptis japonica (Japanese goldthread, species) [taxon 3442], Allium cepa (onion, species) [taxon 4679], Prunus dulcis (almond, species) [taxon 3755] - **Cell lines:** PC12 — Rattus norvegicus (Rat), Rat adrenal gland pheochromocytoma, Cancer cell line (CVCL_0481), HT22 — Mus musculus (Mouse), Transformed cell line (CVCL_0321), SH-SY5Y — Homo sapiens (Human), Neuroblastoma, Cancer cell line (CVCL_0019), PC 12 — Mus musculus (Mouse), Hybridoma (CVCL_J992), GT1-7 — Mus musculus (Mouse), Transformed cell line (CVCL_0281), BV2 — Mus musculus (Mouse), Transformed cell line (CVCL_0182), NB7 — Homo sapiens (Human), Neuroblastoma, Cancer cell line (CVCL_8824), C6 — Rattus norvegicus (Rat), Rat malignant glioma, Cancer cell line (CVCL_0194) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12932467/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12932467/full.md ## References 233 references — full list in the complete paper: https://tomesphere.com/paper/PMC12932467/full.md --- Source: https://tomesphere.com/paper/PMC12932467