Levetiracetam Reduces Early Inflammatory Response After Experimental Intracerebral Hemorrhage by Regulating the Janus Kinase 2 (JAK2)–Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

Xiong, Jing; Zhou, Han; Lu, Dong-Lin; Wang, Zixuan; Liu, Heng-Jian; Sun, Yuqi; Xu, Jinxiang; Feng, Yali; Xing, Ang

doi:10.12659/msm.922741

Cited by 7 publications

(3 citation statements)

References 28 publications

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“…In one of those studies and LEV inhibited microglial activation, suppressed TNFα and Il-1β levels, and promoted angiogenesis after cerebral ischemia in rats (Yao et al, 2021). Xiong et al (2020) showed that in lipopolysaccharide-treated microglia cells, LEV treatment significantly decreased inflammatory factors levels and reduced NF-κB and STAT3 protein expressions. In an intracerebral hemorrhage (ICH) rat model, LEV treatment improved neurological function, alleviated brain edema, and decreased NF-κB, JAK2, and STAT3 protein expressions, indicating that LEV can repress early inflammatory responses induced by ICH.…”

Section: Figurementioning

confidence: 97%

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

et al. 2023

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Introduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline of M2 microglia in the diabetic rats indicates that high glucose promotes the differentiation of microglia into the M1 type to trigger neuroinflammatory responses. Moreover, there is a lack of strong evidence for treatments of diabetes-associated cognitive impairment in addition to controlling blood glucose.Methods: Diabetic rats were established by intraperitoneal injection of one dose of streptozotocin (60 mg/kg). Polarization transitions of microglia were induced by high glucose treatment in BV2 cells. Levetiracetam was orally administered to rats 72 h after streptozotocin injection for 12 weeks.Results: In STZ-induced diabetic rats, the results demonstrated that levetiracetam improved rat cognitive function (Morris water maze test) and hippocampus morphology (Hematoxylin-eosin staining), and the effect was more evident in the high-dose levetiracetam group. Microglia activation in the hippocampus was inhibited by levetiracetam treatment for 12 weeks. Serum levels of TNF-α, IL-1β, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1β level was obviously reduced in the LEV-H group. In vitro, we found that levetiracetam 50 µM attenuated high-glucose induced microglial polarization by increasing IL-10 level and decreasing IL-1β and TNF-α levels. Moreover, levetiracetam 50 µM increased and decreased the proportion of CD206+/Iba1+ and iNOS+/Iba1+cells, respectively. Western blot analysis illustrated that LEV 50 µM downregulated the expression of MyD88 and TRAF6, and phosphorylation of TAK1, JNK, p38, and NF-κB p65. The effect of levetiracetam on the anti-polarization and expression of p-JNK and p-NF-κB p65 were partly reversed by anisomycin (p38 and JNK activators).Discussion: Together, our data suggest that levetiracetam attenuates streptozotocin-induced cognitive impairment by suppressing microglia activation. The in vitro findings also indicate that the levetiracetam inhibited the polarization of microglia via the JNK/MAPK/NF-κB signaling pathway.

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Section: Figurementioning

confidence: 97%

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

et al. 2023

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“…LEV is widely used for the treatment of focal and systemic epilepsy, which has a favorable efficacy and low profile of toxicity in epilepsy treatment [3, 7, 8]. As a second‐generation antiepileptic drug, LEV has a novel structure of acetyl pyrrolidine that is structurally unrelated to existing antiepileptic drugs [9–11]. The action mechanism of LEV has not been understood completely, but it may bind to a synaptic vesicle protein 2A which could reduce the synaptic release of Glutam by preventing presynaptic calcium (Ca 2+ ) ion release and accumulation, resulting in the prevention of epileptic seizures [7, 8, 12–16].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation to determine levetiracetam in epileptic patient serum and its application in therapeutic drug monitoring

Yin

et al. 2021

J of Separation Science

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Levetiracetam is an antiepileptic drug that is primarily approved by the Food and Drug Administration for the treatment of focal and generalized seizures. This study describes the development and validation of a highly selective and sensitive liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation to determine levetiracetam in epileptic patient serum. After simple protein precipitation, the analytes were separated on a short reversed‐phase column (Agilent Poroshell 120 SB‐C18 column, 4.6 × 50 mm, 2.7 μm) using isocratic elution with 25% 0.1% formic acid in water (solvent A) and 75% methanol (solvent B) at a flow rate of 0.8 ml/min. The linear range is 0.5–50 μg/mL (R2 > 0.99). All the validation data, such as lower limit of quantification, linearity, specificity, recoveries, matrix effects, and other parameters, fit the request of biological method validation guidance. Passing–Bablok regression coefficients demonstrated that there is no constant bias and no proportional bias between the liquid chromatography‐tandem mass spectrometry methods with triple‐stage fragmentation and liquid multiple reaction monitoring. Bland–Altman plot showed that the developed liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation method is reliable and accurate to determine levetiracetam in human serum.

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“… 38 Another drug that shows repurposable potential is levetiracetam, an antiepileptic drug that alleviates inflammation, and in experimental ICH inhibits IL-1β and TNF-α expression. 41 …”

Section: Introductionmentioning

confidence: 99%

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation

Crilly

Withers

Allan

et al. 2020

International Journal of Stroke

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Intracerebral hemorrhage is a devastating global health burden with limited treatment options and is responsible for 49% of 6.5 million annual stroke-related deaths comparable to ischemic stroke. Despite the impact of intracerebral hemorrhage, there are currently no effective treatments and so weaknesses in the translational pipeline must be addressed. There have been many preclinical studies in intracerebral hemorrhage models with positive outcomes for potential therapies in vivo, but beyond advancing the understanding of intracerebral hemorrhage pathology, there has been no translation toward successful clinical application. Multidisciplinary preclinical research, use of multiple models, and validation in human tissue are essential for effective translation. Repurposing of therapeutics for intracerebral hemorrhage may be the most promising strategy to help relieve the global health burden of intracerebral hemorrhage. Here, we have reviewed the existing literature to highlight repurposable drugs with successful outcomes in preclinical models of intracerebral hemorrhage that have realistic potential for development into the clinic for intracerebral hemorrhage.

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Levetiracetam Reduces Early Inflammatory Response After Experimental Intracerebral Hemorrhage by Regulating the Janus Kinase 2 (JAK2)–Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

Cited by 7 publications

References 28 publications

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

Development and validation of a liquid chromatography‐tandem mass spectrometry method with triple‐stage fragmentation to determine levetiracetam in epileptic patient serum and its application in therapeutic drug monitoring

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation

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