A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex

Ni, Ming; Zhang, Jigang; Huang, Lin; Gao-lin, Liu; Li, Qin

doi:10.1016/j.jphs.2018.08.012

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…Long-term cerebral ischemia causes neuronal apoptosis, neurodegeneration, and structural damage in brain tissue, resulting in a decline in cognitive capability, eventually developing into VaD [ 30 ]. In the present study, 2VO injury caused apparent pathological abnormalities, characterized by the significantly increased number of degenerative neurons in the brain, as indicated by FJB staining.…”

Section: Discussionmentioning

confidence: 99%

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p‐CaMKII/ERK/CREB and ox‐CaMKII‐Dependent MAPK/NF‐κB Pathways

Jiang

Ashraf

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

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Section: Discussionmentioning

confidence: 99%

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p‐CaMKII/ERK/CREB and ox‐CaMKII‐Dependent MAPK/NF‐κB Pathways

Jiang

Ashraf

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Therefore, we adopted these two doses (30 and 15 mg/kg per day) to explore the effects of apatinib on BP over a 15-day period. In addition, we studied effect of Y27632 on apatinib-induced hypertension, using previously reported doses [ 9 , 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension

Wang

et al. 2021

Journal of Hypertension

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Objectives: Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated.Methods: Normotensive female Wistar-Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed.Results: Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dosedependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes. Conclusion:These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

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“…[72] Rho kinase inhibitors exert neuroprotective effects against cerebral ischemia, and their main mechanism is to reverse learning and memory deficits in a rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex. [74] Table 2 Main effects and mechanisms of NMDAR on cerebral IRI.…”

Section: Nmdar-mediated Downstream Survival Pathwaysmentioning

confidence: 99%

Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review

Liao,

Wen,

Yang

et al. 2023

Medicine

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There is an urgent need to find common targets for precision therapy, as there are no effective preventive therapeutic measures for combined clinical heart-brain organ protection and common pathways associated with glutamate receptors are involved in heart-brain injury, but current glutamate receptor-related clinical trials have failed. Ischemia-reperfusion injury (IRI) is a common pathological condition that occurs in multiple organs, including the heart and brain, and can lead to severe morbidity and mortality. N-methyl-D-aspartate receptor (NMDAR), a type of ionotropic glutamate receptor, plays a crucial role in the pathogenesis of IRI. NMDAR activity is mainly regulated by endogenous activators, agonists, antagonists, and voltage-gated channels, and activation leads to excessive calcium influx, oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, and necrosis in ischemic cells. In this review, we summarize current research advances regarding the role of NMDAR in myocardial and cerebral IRI and discuss potential therapeutic strategies to modulate NMDAR signaling to prevent and treat IRI.

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A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex

Cited by 13 publications

References 35 publications

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p‐CaMKII/ERK/CREB and ox‐CaMKII‐Dependent MAPK/NF‐κB Pathways

Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p‐CaMKII/ERK/CREB and ox‐CaMKII‐Dependent MAPK/NF‐κB Pathways

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension

Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review

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