Inhibition of protease-activated receptor 1 ameliorates behavioral deficits and restores hippocampal synaptic plasticity in a rat model of status epilepticus

Semenikhina, Marharyta; Bogovyk, R.I.; Fedoriuk, Mykhailo; Nikolaienko, Oksana; Kury, Lina T. Al; Savotchenko, Alina; Krishtal, O. A.; Isaeva, Elena

doi:10.1016/j.neulet.2018.10.058

Cited by 19 publications

(14 citation statements)

References 32 publications

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“…Semenikhina et al report that inhibition of PAR-1 ameliorates behavioral deficits and restores hippocampal synaptic plasticity in a rat model of status epilepticus [41], and PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia in mice [13]. These results indicate that activation of thrombin/PAR-1 pathway in brain likely through PAR-1 up-regulation triggers the cognitive behavioral deficits in diabetes condition.…”

Section: Discussionmentioning

confidence: 96%

Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through inhibiting thrombin/PAR-1 pathway

Kong

Liu

Zhang

et al. 2020

Preprint

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Background: Sarsasapogenin (Sar), a natural steroidal compound, shows neuroprotective, promoting cognition, anti-inflammatory, anti-thrombosis effects, etc. However, whether Sar can ameliorate diabetes-associated cognitive impairment and whether it is related to the anti-inflammatory and anti-thrombosis effects of Sar, it remains unknown. Methods: Streptozotocin-induced diabetic rats were treated orally with Sar (20 and 60 mg/kg), and normal rats was orally administrated of Sar (60 mg/kg). Cognitive tests were performed using Morris water maze. Nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome (NLRP1, cleaved caspase 1, IL-1β, and IL-18), as well as thrombin and its receptor protease-activated receptor 1 (PAR-1) pathway and advanced glycation endproducts (AGEs) and its receptor RAGE axis were examined in the brain of diabetic rats. Meanwhile high glucose-cultured human SH-SY5Y cells were used to further investigate the effects of Sar (0.2, 1, 5 μM) on central neurons and deeply explore the mechanism. Results: Sar markedly increased numbers of crossing platform and percentage of time spent in the target quadrant in Morris water maze tests in diabetic rats, accompanied by inhibitions of NLRP1 inflammasome, PAR-1 upregulation, and AGEs/RAGE axis in cerebral cortex. Moreover, Sar mitigated neuronal damages, NLRP1 inflammasome activation, and PAR-1 upregulation in high glucose-cultured SH-SY5Y cells, and the effects were similar to those of the PAR-1 inhibition with a selective PAR-1 antagonist vorapaxar. But Sar also did not affect thrombin activity in the brain of diabetic rats and high glucose-cultured SH-SY5Y cells. Further studies indicated that the key molecules of NLRP1 inflammasome and the phosphorylated NF-kappaB p65 were remarkably decreased in SH-SY5Y cells cultured with high glucose after PAR-1 knockdown by using F2R (the gene symbol of PAR-1) shRNA, and these effects were confirmed by using Sar addition in such condition. Conclusions: These findings demonstrated that Sar could improve memory impairment caused by diabetes, which was achieved through suppressing neuroinflammation from the activated NLRP1 inflammasome and NF-kappaB mediated by thrombin/PAR-1 activation in brain. Moreover, Sar was proved to be a pleiotropic neuroprotective agent and memory enhancer.

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Section: Discussionmentioning

confidence: 96%

Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through inhibiting thrombin/PAR-1 pathway

Kong

Liu

Zhang

et al. 2020

Preprint

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“…Таким чином, актуальною постає проблема пошуку нових молекулярних мішеней, вплив на які не тільки забезпечить антиепілептичну дію, а і знизить імовірність розвитку супутніх поведінкових розладів надалі. Однією з таких перспективних мішеней є протеазаактивовані рецептори 1 (ПАР1), блокада яких під час епілептогенезу призводить до покращення стану тварин у пілокарпіновій та літій-пілокарпіновій моделях епілептичного статусу (ЕС) [6][7][8].…”

Section: вступunclassified

The Effect of Protease-Activated Receptors 1 Inhibition on Depressive-Like Behavior in the Latent Stage of Formation of Temporal Lobe Epilepsy

Semenikhina¹,

Fedoryuk²,

Bogovik³

2020

Fiziol Zh

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Here we investigate the effect of pharmacological blockade of protease-activated receptors 1 (PAR1) on depressive-like behavioral impairments following status epilepticus (SE). Behavioral tests were performed during the latent stage of formation of temporal lobe epilepsy two weeks after SE induced using lithium-pilocarpine model. The PAR1 blocker (SCH 79797) was injected for 10 days after SE. The results indicate a partial normalization of depressive-like behavior in the forced swim test: the climbing time was 180 s after PAR1 inhibition, and 87 s after SE). We also observed behavioral normalization after PAR1 inhibition in the sucrose test. PAR1 inhibition led to the normalization of climbing time in the forced swim test, as well as normalized the behavior in the sucrose preference test. At the same time, the swimming time in the forced swim test decreased due to the PAR1 inhibition compared to the control group, while the floating time increased.

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“…Для травматичної епілепсії висуваються ідеї відносно терапевтичного втручання в першу годину після травми [10], а результати щодо блокування ПАР1 гіпотетично можуть бути використані для посттравматичної терапії пацієнтів. Також у попередніх працях ми показали, що блокування ПАР1 під час епілептогенезу призводить до нормалізації рівня тривожності у латентній та хронічній стадіях скроневої епілепсії, нормалізації формування афективної пам'яті та синаптичної пластичності гіпокампа, але не впливає на просторову пам'ять та соціальну поведінку [2,11,12].…”

Section: результати та їх обговоренняunclassified

Pharmacological Blockade of Protease-Activated Receptors 1 Normalizes Behavioral Hyperexcitability of Rats in the Latent Stage of the Experimental Model of Temporal Lobe Epilepsy

Semenikhina¹,

Bogovik²,

Fedoryuk³

et al. 2019

Fiziol Zh

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Inhibition of protease-activated receptor 1 ameliorates behavioral deficits and restores hippocampal synaptic plasticity in a rat model of status epilepticus

Cited by 19 publications

References 32 publications

Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through inhibiting thrombin/PAR-1 pathway

Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through inhibiting thrombin/PAR-1 pathway

The Effect of Protease-Activated Receptors 1 Inhibition on Depressive-Like Behavior in the Latent Stage of Formation of Temporal Lobe Epilepsy

Pharmacological Blockade of Protease-Activated Receptors 1 Normalizes Behavioral Hyperexcitability of Rats in the Latent Stage of the Experimental Model of Temporal Lobe Epilepsy

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