Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury

Abstract

Brain ischemia-reperfusion (I/R) injury, commonly occurring in ischemic stroke and post-cardiac arrest scenarios, results in complex secondary damage involving oxidative stress, inflammation, apoptosis, and blood-brain barrier (BBB) breakdown. Despite decades of research, no pharmacological agent has yet been clinically approved for post-I/R neuroprotection. Natural compounds have recently gained attention for their multimodal therapeutic potential, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroregenerative effects. This review highlights nine promising candidates-resveratrol, curcumin, quercetin, berberine, ginkgolide B, baicalin, naringin, fucoidan, and astaxanthin-that exhibit efficacy in experimental models of I/R injury when administered after the insult. Their chemical structures, pharmacokinetics, and mechanisms of action are described in detail, focusing on key signaling pathways such as nuclear factor erythroid 2-related (Nrf2), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and brain-derived neurotrophic factor (BDNF). Importantly, we outline the selection criteria for these compounds, including demonstrated neuroprotective efficacy, mechanistic clarity, and translational feasibility. While several challenges remain-such as limited bioavailability, BBB penetration, and species-specific metabolism-emerging strategies like nanoparticle delivery, synthetic analogs, and drug combinations offer potential solutions. By emphasizing the therapeutic versatility and mechanistic diversity of these natural agents, this review supports their clinical potential and encourages further preclinical optimization and biomarker-guided human trials.

Keywords: antioxidant therapy; blood-brain barrier; ischemic stroke; natural product; neuroinflammation; neuroprotection; reperfusion injury.

Figure 1

Representative imaging of brain I/R injury in humans and animal models. (A): Diffusion-weighted MRI (DWI) from a human patient with focal cerebral I/R injury reveals hyperintense regions (asterisks) indicating acute infarction in the middle cerebral artery territory [9]. (B): 2,3,5-triphenyltetrazolium chloride (TTC)-stained coronal brain sections from a rat subjected to MCAO, a model of focal I/R injury [10]. White regions (asterisk) indicate infarcted tissue, while red areas represent viable brain. (C): Cresyl violet-stained hippocampal sections from a gerbil following global cerebral I/R injury show significant neuronal loss (asterisk) in the CA1 region, a hallmark of delayed pyramidal cell death [11].

Figure 2

Pathophysiological mechanisms underlying brain I/R injury. The I/R event initiates a cascade of interrelated cellular and molecular responses, including oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, apoptosis/necrosis, and BBB disruption. These pathological processes interact to promote neuronal death and neurological deficits. Understanding these mechanisms is essential for identifying therapeutic targets and developing interventions to mitigate I/R-induced brain damage.

Figure 3

Chemical structures of nine natural compounds with demonstrated post-I/R therapeutic effects. (A–C): resveratrol, curcumin, quercetin. (D–F): row: berberine, ginkgolide B, baicalin. (G–I): ow: naringin, fucoidan (a representative sulfated fucose unit, reflecting its polysaccharide nature), astaxanthin. These compounds represent diverse chemical classes and exhibit antioxidant, anti-inflammatory, and anti-apoptotic activities relevant to therapeutic neuroprotection in brain I/R injury.

Figure 4

Schematic illustration of the neuroprotective mechanisms exerted by natural compounds following brain I/R injury. These compounds act via multiple pathways, including: activation of the Nrf2/HO-1 antioxidant system; suppression of NF-κB and NLRP3 inflammasome for anti-inflammatory effects; modulation of the Bcl-2/Bax ratio and caspase inhibition for anti-apoptotic effects; protection of the BBB by stabilizing tight junction proteins; promotion of neurogenesis and synaptic plasticity through BDNF signaling; inhibition of mitochondrial dysfunction and autophagy regulation; and therapeutic roles of extracellular vesicles in reducing inflammation and promoting neurogenesis.

Figure 5

Schematic overview of future strategies to enhance the therapeutic application of natural compounds for brain I/R injury. This diagram outlines four major future directions aimed at overcoming current limitations in the clinical translation of natural compounds. These strategies, supported by formulation science and precision medicine, are critical for advancing natural compounds from preclinical promise to clinical impact.