Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury
Simple Summary
Abstract
1. Introduction
Feature | Ischemic Stroke | TIA | I/R Injury | Representative References |
---|---|---|---|---|
Duration | >24 h | <24 h | Variable (depends on insult) | [1,2] |
Recovery | Often incomplete (permanent damage) | Complete recovery | Variable, but often worsens with reperfusion | [3,4] |
Pathological Outcome | Infarction, necrosis | No infarction | Infarction, oxidative stress, BBB disruption | [2,4,5] |
Main Cause | Thrombosis, embolism | Thrombosis, embolism (transient) | Reperfusion after ischemia | [2,3] |
Treatment | Thrombolysis, thrombectomy | Risk reduction (e.g., anticoagulants) | Antioxidants, anti-inflammatory therapies | [6,7,8] |
2. Pathophysiology of Brain I/R Injury
2.1. Oxidative Stress
2.2. Inflammation
2.3. Excitotoxicity
2.4. Mitochondrial Dysfunction
2.5. Apoptosis and Necrosis
2.6. BBB Disruption
Pathophysiological Mechanism | Key Features | Representative References |
---|---|---|
Oxidative stress | ROS overproduction, lipid peroxidation, DNA/protein damage; Nrf2/ARE activation counters injury | [6,15,16,17,18,19,20,21,22,23,24,25] |
Inflammation | Cytokine release (TNF-α, IL-1β), microglial activation, NF-κB pathway, astrocyte gliosis | [5,7,8,12,26,27,28,29,30,31,32] |
Excitotoxicity | Glutamate accumulation, NMDA/AMPA overactivation, Ca2+ influx, oxidative stress, synaptic loss | [1,33,34,35,36,37,38,39] |
Mitochondrial dysfunction | ATP depletion, mPTP opening, cytochrome c release, Drp1-mediated fission, impaired mitophagy | [2,40,41,42,43,44,45,46,47,48] |
Apoptosis and necrosis | Caspase cascade (3, 8, 9), Bcl-2/Bax ratio shift, intrinsic/extrinsic apoptosis, SIRT1 signaling | [5,49,50,51,52,53,54,55,56] |
BBB disruption | Tight junction protein loss, MMP-9 upregulation, astrocyte endfeet detachment, IgG/albumin leakage | [4,57,58,59,60,61,62,63,64,65,66,67,68,69,70] |
3. Natural Compounds with Therapeutic Potential for Brain I/R Injury
3.1. Resveratrol
3.2. Curcumin
3.3. Quercetin
3.4. Berberine
3.5. Ginkgolide B
3.6. Baicalin
3.7. Naringin
3.8. Fucoidan
3.9. Astaxanthin
Compound | Formula | Key Functions | Post-I/R Benefits | Key Pharmacokinetic Features | Oral Absorbed Bioavailability (%) | Representative References |
---|---|---|---|---|---|---|
Resveratrol | C14H12O3 | Antioxidant, anti-inflammatory, SIRT1/Nrf2 activator | Reduces infarct size, suppresses oxidative damage (30–50 mg/kg, mouse MCAO model) | Rapid absorption; however, extensive first-pass metabolism (glucuronidation/sulfation) reduces systemic bioavailability | <1% (unmetabolized), absorbed ~70% (human) ~20% (metabolized form) (rat) | [79,80,81,82,83,84,86,87] |
Curcumin | C21H20O6 | NF-κB/NLRP3 inhibition, antioxidant | Improve neurological outcomes post-I/R (50–100 mg/kg, rat 150 mg/kg, mouse MCAO model) | Poor solubility and permeability; undergoes rapid conjugation and systemic elimination | <1% (human) | [5,88,89,91] |
Quercetin | C15H10O7 | PI3K/Akt/NF-κB modulation, promotes M2 microglia | Improves neuronal survival, reduces inflammation (30–60 mg/kg, rat MCAO model) | Low solubility; undergoes extensive phase II metabolism (glucuronidation/sulfation) | <0.5% (pig) | [12,93,94,96] |
Berberine | C20H18NO4+ | Reduces ER stress, mitochondrial protection | Attenuates apoptosis and ER stress post-I/R (10–50 mg/kg, rat MCAO model) | Limited absorption due to P-gp efflux, low permeability, and hepatic first-pass metabolism | <0.4% (rat) | [97,98,99,101] |
Ginkgolide B | C20H24O10 | PAF antagonist, promotes neurogenesis | Enhance recovery, supports plasticity (20 mg/kg, rat MCAO model) | Well absorbed (Tmax ~1.5–2 h); limited BBB penetration despite lipophilicity | ~88% (human) | [102,103,104,106] |
Baicalin | C21H18O11 | Anti-inflammatory, modulates Bcl-2/Bax, cytokine suppression | Suppresses IL-1β, TNF-α, reduces infarct size (50–100 mg/kg, rat MCAO model) | Poor permeability; hydrolyzed to baicalein in gut before limited absorption | ~2.2% (rat) | [7,109] |
Naringin | C27H32O14 | BDNF upregulation, supports neurogenesis | Mitigates cognitive deficits post-I/R (100 mg/kg, rat MCAO model) | Hydrolyzed to naringenin by gut flora; undergoes enterohepatic recirculation | ~34.4% (dog) ~44.1% (rat) | [110,111,113] |
Fucoidan | Variable | Reduces ROS/inflammation, protects BBB | Improves oxidative and inflammatory status (50 mg/kg, rat 4VO model) | Bioavailability increases with lower molecular weight; polysaccharide with poor permeability | ~28.3% (Low Molecular Weight Fucoidan) (rat) | [66,114,115] |
Astaxanthin | C40H52O4 | Antioxidant, stabilizes mitochondria, reduces lipid peroxidation | Reduces stroke volume, restores oxidant/caspase levels (25–50 mg/kg, rat MCAO model) | Lipophilic; bioavailability increases with fat-rich meals | ~10% (standard form), ~17–37% (lipid-based formulations) (human) | [16,116,118] |
4. Mechanisms of Therapeutic Neuroprotection of the Compounds in Brain I/R Injury
4.1. Antioxidant Effects
4.2. Anti-Inflammatory Actions
4.3. Anti-Apoptotic Activity
4.4. BBB Protection
4.5. Neurogenesis and Plasticity
4.6. Inhibition of Mitochondrial Dysfunction
4.7. Extracellular Vesicles as Neuroprotective Mediators
5. Mechanistic Comparison of the Compounds and Insights
6. Challenges and Opportunities in Translating Natural Compounds for Brain I/R Therapy
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Akt | Protein kinase B |
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
ATP | Adenosine triphosphate |
BBB | Blood-brain barrier |
BCCAO | Bilateral common carotid artery occlusion |
Bax | Bcl-2-associated X protein |
Bcl-2 | B-cell leukemia/lymphoma 2 |
BDNF | Brain-derived neurotrophic factor |
CNPY2 | Canopy FGF signaling regulator 2 |
EVs | Extracellular vesicles |
HO-1 | Heme oxygenase-1 |
IL | Interleukin |
IgG | Immunoglobulin G |
I/R | Ischemia-Reperfusion |
Keap1 | Kelch-like ECH-associated protein 1 |
MCAO | Middle cerebral artery occlusion |
MMPs | Matrix metalloproteinases |
mPTP | Mitochondrial permeability transition pore |
NF-κB | Nuclear factor kappa B |
NLRP3 | NOD-, LRR- and pyrin domain-containing protein 3 |
NMDA | N-methyl-D-aspartate |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
PAF | Platelet-activating factor |
PI3K | Phosphatidylinositol 3-kinase |
ROS | Reactive oxygen species |
SOD | Superoxide dismutase |
TIA | Transient ischemic attack |
TNF-α | Tumor necrosis factor alpha |
TUNEL | TdT-mediated dUTP nick end labeling |
4VO | four-vessel occlusion |
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Yoo, K.-Y.; Won, M.-H.; Ahn, J.H.; Park, J.H. Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury. Biology 2025, 14, 1153. https://doi.org/10.3390/biology14091153
Yoo K-Y, Won M-H, Ahn JH, Park JH. Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury. Biology. 2025; 14(9):1153. https://doi.org/10.3390/biology14091153
Chicago/Turabian StyleYoo, Ki-Yeon, Moo-Ho Won, Ji Hyeon Ahn, and Joon Ha Park. 2025. "Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury" Biology 14, no. 9: 1153. https://doi.org/10.3390/biology14091153
APA StyleYoo, K.-Y., Won, M.-H., Ahn, J. H., & Park, J. H. (2025). Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury. Biology, 14(9), 1153. https://doi.org/10.3390/biology14091153