Glycyrrhizic Acid's Potential to Protect the Brain After Stroke: How It Works and Treatment Possibilities

HMGB1, a non-histone DNA-binding nuclear protein, plays a crucial role in the pathology of CI/RI. Recognized as a damage-associated molecular pattern (DAMP), HMGB1 is actively secreted by immune cells or passively released from necrotic cells during ischemic events. Its binding to pattern recognition receptors, such as Toll-like receptor 2/4 (TLR2/4) and the receptor for advanced glycation end-products (RAGE), triggers innate immune responses that promote the release of pro-inflammatory cytokines and exacerbate tissue damage, amplifying the inflammatory cascade in affected brain regions [35,36]. When HMGB1 binds to the RAGE, it activates several downstream signaling pathways, including JAK/STAT, ERK1/2, JNK/SAPK, and MAPK. These pathways are crucial for the activation of transcription factors such as nuclear factor kappa B (NF-κB) and STAT3, which facilitate the translocation of inflammatory cells and the production of inflammatory mediators, exacerbating systemic inflammatory responses [37].

Under ischemic conditions, HMGB1 binds to the TLR4 receptor, initiating a critical inflammatory response. This binding activates microglia, the resident immune cells of the central nervous system, which play a pivotal role in responding to ischemic damage [38,39,40]. Typically, during ischemic conditions, activated microglia adopt a pro-inflammatory (M1) state, releasing cytokines such as TNF-α and IL-6 through intracellular pathways such as MyD88 and TRIF, which in turn activate NF-κB. The activation of NF-κB, particularly its p65 subunit, further intensifies the inflammatory response, significantly contributing to neuronal damage and cell death [41,42].

In pathological conditions, such as those induced by CI/RI, activated microglia often adopt a pro-inflammatory (M1) phenotype, characterized by the release of inflammatory chemokines and cytokines, including CD16 and iNOS, which contribute significantly to neuronal damage. Conversely, M2 microglia, marked by indicators such as CD206 and Arg-1, play a crucial role in tissue repair and debris clearance, mediating anti-inflammatory effects essential for recovery [43,44].

GA, the principal bioactive component of licorice, acts as a potent inhibitor of HMGB1 by directly binding to the HMG box domains, forming a complex that effectively inhibits HMGB1’s phosphorylation, secretion, and translocation from the nucleus to the cytoplasm. This direct inhibition contrasts with HMGB1 antibodies, which primarily block HMGB1’s interaction with the RAGE receptor and thus possess a narrower scope of action [7,25,45,46]. GA’s ability to inhibit HMGB1 expression has also been shown to reduce memory deficits and alleviate neurological impairments in animal models of neuroinflammation induced by lipopolysaccharide (LPS), highlighting its potential for managing inflammation-related neurological conditions [47]. By blocking the interaction between HMGB1 and RAGE, GA prevents NF-κB activation, reduces its transcriptional activity, and subsequently lowers the production of inflammatory cytokines, ultimately suppressing the overall inflammatory response [25]. GA also modulates microglial dynamics by promoting a shift from the pro-inflammatory M1 state to the reparative M2 state, thereby reducing inflammation and enhancing recovery processes within the brain following a stroke. This GA-induced shift minimizes ischemic damage and supports long-term neurological function, underscoring GA’s potential as a neuroprotective agent (Figure 3) [11,14].

Studies indicate that enriched housing conditions after a stroke promote neurogenesis and functional recovery by inhibiting calpain 1 activity and activating the STAT3/HIF-1α/VEGF signaling pathway. GA further enhances these recovery processes by modulating HMGB1-related pathways, which are critical in neurogenesis and neuroinflammation. Through the inhibition of HMGB1, GA plays a neuroprotective role by reducing inflammatory responses and supporting cellular repair mechanisms, illustrating its therapeutic potential for improving post-stroke outcomes in ischemic stroke models [48].

HMGB1 triggers pyroptosis, a form of programmed inflammatory cell death, through inflammasome activation. This process exacerbates neuronal injury by releasing additional pro-inflammatory cytokines, thereby amplifying neuroinflammation and tissue damage in ischemic stroke [49]. Research by Xiong et al. demonstrates that GA mitigates these effects by targeting HMGB1-mediated T cell activity, significantly reducing CD4 and CD8 T cell infiltration and lowering levels of pro-inflammatory cytokines, such as IFNγ. This dual action of inhibiting pyroptosis and modulating T cell infiltration aligns with GA’s role in reducing neuroinflammation and highlights its neuroprotective potential in cerebral ischemia models through immune regulation [12].

Glycyrrhizin also plays a crucial role in modulating the HMGB1-TLR4-IL-17A signaling pathway, which mediates inflammatory responses and neuronal apoptosis during ischemic stroke. Recent studies have demonstrated that GA significantly alleviates neurotoxicity by inhibiting HMGB1 phosphorylation. This inhibition prevents HMGB1 from translocating to the cytoplasm, thereby reducing the activation of downstream inflammatory pathways, including NF-κB [50]. By inhibiting this pathway, glycyrrhizin significantly reduces IL-17A secretion, decreases infarct size, improves neurological outcomes, and reduces neuronal apoptosis, highlighting its therapeutic potential in stroke management [17,20].

Post-treatment with Glycyrrhizae Radix et Rhizoma (GRex), particularly its methanolic extract, has shown neuroprotective effects in ischemic stroke models. These include reducing cerebral infarction, alleviating cerebral edema, and modulating inflammatory responses through the regulation of microglia and astrocytes [51]. Specifically, GRex dampens inflammatory responses by inhibiting TLR4 and NF-κB signaling pathways, mechanisms closely aligned with GA’s known anti-inflammatory actions. Furthermore, GA exhibits protective effects against hemorrhagic transformation (HT), notably in models of delayed thrombolytic therapy. When administered alongside delayed tissue plasminogen activator (t-PA) treatments, GA inhibits peroxynitrite-mediated HMGB1/TLR2 signaling cascades, thereby reducing blood-brain barrier (BBB) permeability, preserving key structural proteins such as collagen IV and claudin-5, and suppressing matrix metalloproteinase-9 (MMP-9) activation. These actions decrease the likelihood of HT, lower mortality, and improve neurological recovery, highlighting GA’s potential as an effective adjuvant to thrombolytic therapy by mitigating the adverse effects commonly associated with delayed t-PA administration [15,52].

Gualou Guizhi granules (GLGZG) and Trichosanthes kirilowii cassia twig particles, both containing GA, have also shown promising neuroprotective effects in ischemia/reperfusion (I/R) injury models. GLGZG administration enhances BBB integrity, reduces infarct volume, and alleviates neurological deficits in MCAO-induced I/R injury [53]. Likewise, Trichosanthes kirilowii cassia twig particles cross the BBB, allowing active components such as paeoniflorin, albiflorin, and liquiritin to reduce neurological deficits, BBB permeability, and infarct size [54]. These findings highlight the potential of GA and its derivatives to modulate BBB permeability and deliver multifaceted neuroprotective actions in ischemic conditions, suggesting their promise in combination therapies for ischemic stroke recovery.

In cerebral ischemia models, particularly in diabetic mice, post-treatment with GA has been found to significantly suppress the expression of key components in the HMGB1/TLR4-Myd88/NF-κB p65 signaling pathway. This suppression effectively reduces ischemic brain damage and improves neurological outcomes [16]. Additionally, recent research has underscored the critical role of the HMGB1–TLR2/4 axis in microglial activation following cortical spreading depression—a phenomenon that exacerbates neuronal injury in conditions such as stroke. Glycyrrhizin’s inhibition of this pathway has been shown to prevent microglial hypertrophy and mitigate associated neuroinflammatory damage, further highlighting its potential as a neuroprotective agent in ischemic conditions [27].

In studies of neonatal HIBD, GA has been shown to inhibit additional inflammatory pathways, such as the HMGB1/GPX4 pathway. By inhibiting HMGB1 expression and ectopia, GA blocks the p38 MAPK signaling pathway, which is involved in cell proliferation, differentiation, apoptosis, necrosis, and cell cycle regulation. These actions suggest that GA can effectively mitigate neuronal damage and provide neuroprotection in conditions characterized by heightened inflammation [21,28].

HMGB1 also plays a role in neurovascular repair by influencing the paracrine functions of endothelial progenitor cells (EPCs) after ischemic stroke [55]. HMGB1 released from activated microglia can stimulate IL-8 production in EPCs, thereby enhancing their angiogenic potential and supporting neurovascular remodeling. By inhibiting HMGB1, GA may attenuate this EPC-driven angiogenesis, suggesting that GA’s therapeutic scope extends beyond inflammation control to modulation of neurovascular repair mechanisms, enriching its neuroprotective profile in stroke management.

While primarily known for its role in neuroinflammation, HMGB1 also functions as a critical autocrine trophic factor for oligodendrocytes (OLs) under ischemic stress, especially in white matter stroke models [56]. HMGB1 released by damaged OLs activates TLR2 signaling in nearby OLs, promoting cell survival and supporting myelin integrity. In this context, GA’s inhibition of HMGB1 may inadvertently interfere with this protective mechanism in white matter, potentially exacerbating demyelination and related functional deficits under ischemic conditions. This complexity suggests that although GA’s inhibition of HMGB1 provides significant anti-inflammatory benefits in gray matter regions, its effects on white matter injury might be more nuanced, as it could disrupt OL-specific autocrine support essential for myelin preservation and structural stability during ischemic stress.

In addition to its effects in ischemic stroke, glycyrrhizin has shown promising results in models of traumatic brain injury (TBI). Glycyrrhizin’s inhibition of HMGB1 reduces brain edema, astrocyte and microglia activation, and cognitive deficits in models of pediatric TBI, suggesting that glycyrrhizin can provide long-term neuroprotection by mitigating neuroinflammatory responses [57]. Furthermore, studies on TBI models provide additional evidence of GA’s neuroprotective effects via modulation of the HMGB1/TLR4/RAGE/NF-κB pathway. Research by Gu et al. demonstrated that GA administration in TBI significantly reduced the expression of HMGB1 and its receptors TLR4 and RAGE, thereby downregulating NF-κB activity and reducing levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 [58]. These results highlight GA’s potential in mitigating secondary brain injury by modulating inflammation and apoptosis, reinforcing its therapeutic applicability in ischemic and traumatic neural injuries. This aligns with findings that glycyrrhizin effectively reduces HMGB1–RAGE interactions, leading to decreased expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which are critical mediators of inflammation in TBI [25].

Beyond cerebral ischemia, glycyrrhizin’s efficacy extends to other injury models, such as spinal cord injuries and thermal burns. In spinal cord injury models, GA treatment significantly decreases pro-inflammatory markers such as iNOS and CD86 while simultaneously increasing anti-inflammatory markers such as CD206 and Arg-1 within microglia [59,60]. These findings suggest that GA effectively inhibits the polarization of microglia towards the pro-inflammatory M1 phenotype and promotes their shift toward the reparative M2 phenotype. This modulation is crucial in treating spinal cord injuries and offers a new direction for using GA in managing CI/RI by leveraging its broad anti-inflammatory and neuroprotective capabilities.

In models of thermal burns, glycyrrhizin suppresses systemic inflammation by inhibiting HMGB1 and reducing pro-inflammatory cytokine levels, thereby protecting vital organs from damage [61]. Additionally, glycyrrhizin inhibits T cell proliferation and reduces markers such as CD68 and MPO, further controlling inflammation at the molecular level by preventing inflammasome activation [12].

In myocardial ischemia-reperfusion injury models, glycyrrhizin blocks the HMGB1-dependent phospho-JNK/Bax pathway, reducing apoptosis and highlighting its potential across ischemic conditions [30]. In hyperglycemic and diabetic stroke models, glycyrrhizin alleviates ischemic damage by preserving the blood-brain barrier and reducing neuroinflammation, making it a promising therapeutic agent for stroke patients with complicating conditions such as diabetes [62,63].

Diammonium glycyrrhizinate (DG), a derivative of GA, has also demonstrated significant neuroprotective effects. In a mouse model of ischemia-reperfusion injury, DG was shown to reduce the expression of inflammatory mediators such as IL-1, TNF-α, COX-2, iNOS, and NF-κB, leading to improved neurological outcomes and reduced brain injury [64]. Recent studies further indicate that DG exhibits neurovascular protective effects in cerebral I/R models by upregulating tight junction proteins such as Rac-1, Claudin-5, and VE-Cadherin, thereby reducing BBB permeability and supporting neurovascular stability [65]. This dual action, which includes both the suppression of inflammatory mediators and enhancement of BBB integrity, aligns with GA’s known effects on neuroinflammation and suggests that GA and its derivatives may be valuable therapeutic agents for managing ischemic injuries and supporting neurovascular stability.

GA has demonstrated significant neuroprotective effects across various models of neurological injury by inhibiting the release and activity of HMGB1. The role of HMGB1 in ischemic stroke has been extensively documented, with its release contributing to neuroinflammation and blood-brain barrier disruption—processes that glycyrrhizin effectively mitigates. In focal cerebral ischemia, GA reduces brain infarction by inhibiting T cell functions and preventing the release of HMGB1, thus dampening subsequent inflammatory responses [66]. This is further supported by evidence highlighting HMGB1’s dual role in the early inflammatory response and neurovascular remodeling during stroke recovery, underscoring the potential of targeting HMGB1 as a therapeutic strategy to reduce stroke-induced damage [67,68].

Apoptosis, or programmed cell death, is essential for maintaining cellular homeostasis. However, during ischemic stroke, excessive apoptosis exacerbates neuronal loss and contributes to further brain damage. This process is distinct from necrosis, which typically induces inflammation. In apoptosis, cells undergo controlled degradation involving caspase activation, nuclear condensation, and DNA fragmentation [69]. In contrast, necrosis triggers the release of DAMPs, such as HMGB1, which activate inflammatory responses [70].

During ischemic stroke, neurons release HMGB1, a key DAMP that exacerbates inflammation and promotes apoptosis. HMGB1 activates microglia, leading to additional inflammatory responses that damage surrounding neurons [71,72]. Targeting HMGB1 signaling, specifically through the TLR4 receptor, has been shown to reduce neuronal death. GA, by inhibiting HMGB1, can reduce neuronal apoptosis in ischemic conditions by modulating the HMGB1/TLR4 axis [18,73].

DG, a derivative of GA, reduces apoptosis by modulating key signaling pathways such as Akt and caspase-3, which are crucial for cell survival and programmed cell death during ischemic events [74]. Targeting these pathways is relevant not only for stroke but also for neurodegenerative diseases such as Alzheimer’s disease [75]. Furthermore, HMGB1 released during ischemia impairs astrocytic glutamate clearance, leading to excitotoxicity. GA mitigates this process by inhibiting the HMGB1/TLR4 axis [76].

In ischemic stroke, the balance between pro-apoptotic and anti-apoptotic proteins, Bax and Bcl2, respectively, is critical. A higher Bax/Bcl2 ratio promotes apoptosis, while an increased Bcl2/Bax ratio has been shown to protect neurons and reduce infarct size [77,78]. GA effectively modulates this balance by increasing Bcl2 expression and reducing Bax expression, thereby inhibiting apoptosis [19,79]. Studies on neonatal mice subjected to ischemia/hypoxia confirm that GA regulates Bax and Bcl2 protein levels, preventing neuronal apoptosis in the hippocampus [23].

Mitochondrial dysfunction is a key factor in ischemic stroke-induced apoptosis. The release of cytochrome c from mitochondria into the cytoplasm triggers caspase-3 activation, leading to apoptosis [80]. GA inhibits cytochrome c release, preventing downstream activation of apoptotic pathways [26]. In ischemia-reperfusion injury models, GA also inhibits the JNK and p38-MAPK pathways, reducing oxidative stress and inflammation and ultimately decreasing apoptosis [22].

These findings are consistent with other research where roasted licorice ethanol extract (rLee) demonstrated significant neuroprotective effects in a gerbil model of transient forebrain ischemia, preserving neuronal density in the hippocampal CA1 region by reducing ischemic damage [81]. Additionally, DG has been shown to improve survival outcomes in ischemic models, such as random skin flaps in rats, through mechanisms that reduce inflammation and oxidative stress and promote angiogenesis [82].

In spinal cord injuries, inhibiting HMGB1 with GA has been shown to reduce edema and astrocyte activation, providing protection against secondary injury [79]. Similarly, GA reduces apoptosis in ischemic stroke by preventing HMGB1-induced excitotoxicity and inflammation [22]. This ability to inhibit HMGB1’s pro-apoptotic effects extends beyond stroke, as demonstrated in TBI models, where GA mitigates brain edema and reduces the activation of microglia and astrocytes [57].

GA has also shown efficacy in chronic cerebral ischemia models by improving cognitive function and reducing apoptosis. GA achieves these effects by regulating the PI3K/Akt/GSK3β pathway, reducing oxidative stress, and inhibiting cytochrome c release [26]. Furthermore, in neonatal brain injury models, GA prevents neuronal loss and preserves myelin integrity, which is essential for proper brain function [23].

While GA primarily reduces apoptosis through caspase-dependent pathways, it also modulates cell death through non-caspase-dependent mechanisms [83,84]. For example, GA has demonstrated anti-proliferative and pro-apoptotic effects in non-neurological conditions, such as cancer, suggesting broader therapeutic applications beyond ischemic stroke [85].

GA shows significant potential in modulating oxidative stress and autophagy, both critical factors in ischemic stroke. Studies indicate that licorice treatment in ischemic models significantly increases superoxide dismutase (SOD) activity and reduces lactate dehydrogenase (LDH) release, supporting the antioxidant properties of GA and its derivatives [26,81]. Research by Namik et al. on 18β-glycyrrhetinic acid (18β-GA), a GA metabolite, highlighted its protective effects against oxidative damage induced by global cerebral I/R injury. This study demonstrated that 18β-GA significantly attenuates lipid peroxidation, increases SOD, catalase (CAT), and glutathione (GSH) activity, and reduces neuronal apoptosis in I/R-injured brain tissue, underscoring the neuroprotective potential of GA and its derivatives in managing oxidative stress [86]. Additionally, carbenoxolone (CBX) [58], a semisynthetic GA derivative, exhibits protective effects against I/R injury by reducing oxidative damage. CBX decreases malondialdehyde (MDA) levels, a marker of lipid peroxidation, in both hippocampal and skeletal muscle tissues during ischemic events, mitigating cellular damage. These antioxidant properties highlight the therapeutic scope of GA derivatives in reducing oxidative stress and promoting neuroprotection in ischemic stroke models.

ROS exacerbate ischemic injury by promoting cellular apoptosis, calcium overload, and pro-inflammatory cytokine secretion. In neonatal HIBD, GA regulates HMGB1 expression through microglial polarization, inhibiting ROS generation and reducing neuronal damage [14]. GA’s inhibitory effects on HMGB1 also attenuate spinal cord edema and astrocyte activation in injury models [87]. Furthermore, GA demonstrates antioxidant properties in models of neurodegenerative diseases, such as Huntington’s disease, by downregulating the HMGB1/TLR4/NF-κB pathway, reducing markers of oxidative stress such as MDA, and increasing antioxidant defenses such as GSH and SOD, underscoring GA’s broad neuroprotective potential [29].

Oxidative stress, driven by ROS, plays a central role in ischemia-reperfusion injury, where elevated ROS production leads to tissue damage, apoptosis, calcium overload, and pro-inflammatory cytokine secretion, all of which exacerbate ischemic injury. The NRF2 (Nuclear factor erythroid 2–related factor 2) and KEAP1 (Kelch-like ECH-associated protein 1) signaling pathway is essential in cellular responses to oxidative stress by regulating the production of antioxidants and detoxification enzymes. Under normal conditions, NRF2 is bound to KEAP1 in the cytoplasm, where KEAP1 promotes NRF2 degradation. However, during oxidative stress, KEAP1 releases NRF2, enabling it to translocate to the nucleus. In the nucleus, NRF2 activates antioxidant response elements (AREs), which enhance the expression of cytoprotective enzymes such as heme oxygenase-1 (HO-1), SOD, and CAT. These enzymes collectively reduce ROS and mitigate cellular damage [35,88]. GA’s modulation of the KEAP1/NRF2 pathway enhances its antioxidant capacity, positioning it as a neuroprotective agent in ischemic conditions by reducing ROS levels, protecting mitochondrial integrity, and improving cellular resilience. However, persistent NRF2 activation can lead to nuclear accumulation and binding to the Klf9 promoter, which can inadvertently increase ROS and lead to cell death under certain pathological conditions [31,32,89,90]. This dual role of NRF2 highlights the complexity of its regulation, particularly as it pertains to neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) [91,92].

Beyond antioxidant protection, GA’s influence on the KEAP1/NRF2 pathway aligns with its broader effects on mitochondrial health through pathways such as PINK1/Parkin-dependent mitophagy, a selective autophagic process critical for removing damaged mitochondria. Autophagy is a crucial cellular mechanism for maintaining homeostasis by degrading and recycling damaged organelles and proteins, especially under ischemic conditions. In ischemic stroke, mitochondrial damage results in increased ROS production, which in turn promotes further cell death. Through the PINK1/Parkin-dependent pathway, GA promotes mitophagy, removing dysfunctional mitochondria and shielding cells from oxidative damage [93]. Under ischemic conditions, PINK1 accumulation on the outer mitochondrial membrane signals the initiation of mitophagy, which not only reduces ROS production but also prevents cellular apoptosis [94]. GA’s activation of this pathway has demonstrated neuroprotective effects during cerebral ischemia-reperfusion injury and in neurodegenerative diseases such as Parkinson’s disease, where it regulates PINK1 and parkin expression levels, further supporting neuronal survival [95].

Additionally, GA’s regulatory impact extends to interactions between HMGB1 and Beclin-1, a critical autophagy regulator, enhancing protective autophagy while limiting excessive cell death. Endogenous HMGB1 functions as a pro-autophagic protein by binding to Beclin-1, thereby maintaining autophagic activity crucial for cell survival. GA’s ability to inhibit the MEK/ERK signaling pathway through its interaction with HMGB1 also helps prevent excessive autophagy-induced cell death, which is particularly relevant in neuroinflammatory and neurodegenerative contexts [33,34,35,76,96]. This nuanced regulation of autophagy underscores GA’s potential in supporting neuronal survival, highlighting its broader therapeutic application in both ischemic and neurodegenerative diseases.

Ferroptosis, a form of iron-dependent lipid peroxidation-induced cell death, plays a crucial role in ischemic brain injury. GA effectively inhibits ferroptosis via the HMGB1/GPX4 pathway, especially in neonatal hypoxic-ischemic brain injury. GPX4, an enzyme that reduces lipid peroxides using GSH, is vital in protecting cells from oxidative stress-induced damage. By enhancing GPX4 activity, GA mitigates lipid peroxidation accumulation and preserves mitochondrial integrity, thereby reducing neuronal injury [21]. GA’s inhibition of ferroptosis is particularly important, as ferroptotic cell death is associated with mitochondrial dysfunction, ROS accumulation, and iron dysregulation, all of which are exacerbated during ischemic events. GA also enhances antioxidant enzyme activity, further reducing oxidative damage and preventing ferroptosis-induced neurodegeneration [21,29]. These studies underscore GA’s protective effects in ischemic brain injuries, extending beyond its antioxidant properties to include inhibition of ferroptosis, a critical factor in mitigating neuronal death and promoting recovery in ischemic conditions (Figure 4).

In addition to its effects in stroke models, GA has been shown to activate the Sirtuin3 (Sirt3) pathway in juvenile epilepsy models, promoting mitophagy and reducing oxidative stress. This regulation of mitochondrial autophagy not only mitigates neuronal damage but also preserves hippocampal function [97]. Moreover, the metabolite of glycyrrhizin, 18β-GA, has demonstrated the ability to inhibit apoptosis and activate protective autophagy through suppression of the JAK2/STAT3 pathway in cerebral ischemia-reperfusion injury models [13]. These findings underscore the broader therapeutic potential of GA, not only in stroke but also in managing other neuroinflammatory and neurodegenerative diseases through its dual regulation of autophagy and oxidative stress.

The clinical relevance of GA has also been validated in trials. Ravanfar et al. conducted randomized, double-blind, placebo-controlled trials demonstrating that the oral administration of licorice extract significantly improved neurological outcomes in patients with acute ischemic stroke. Patients treated with licorice extract exhibited greater reductions in NIHSS (National Institutes of Health Stroke Scale) and modified Rankin scale (MRS) scores compared to the control group, providing robust clinical evidence for GA’s neuroprotective effects. These findings underscore GA’s efficacy in reducing inflammation and oxidative stress in clinical settings, further supporting its potential as a therapeutic agent for stroke recovery [98].

A study also demonstrated that DG, a derivative of GA, significantly reduced oxidative stress and prevented histological damage in brain tissue during global ischemia-reperfusion injury, further bolstering GA’s therapeutic prospects in ischemic stroke treatment [74]. GA’s ability to reduce HT following ischemic stroke has also been explored. HT, a severe complication of thrombolysis therapy using t-PA, can be mitigated by targeting key inflammatory pathways such as HMGB1, TLR4, and NF-κB. Glycyrrhizin, by downregulating these pathways, has been shown to reduce the risk of HT and improve neurological outcomes in ischemic stroke patients [99].

GA’s neuroprotective potential extends to preventing excitotoxicity and neuronal damage by mitigating ischemia/reperfusion-induced impairment of astrocytic glutamate clearance, which is regulated through the HMGB1/TLR4 signaling axis [76]. These findings highlight the broad therapeutic potential of GA, not only in stroke treatment but also in managing other neuroinflammatory and neurodegenerative diseases.