Inhibition of protease-activated receptor 1 (PAR1) ameliorates cognitive performance and synaptic plasticity impairments in animal model of Alzheimer’s diseases

Zare, Daruoosh; Rajizadeh, Mohammad Amin; Maneshian, Marzieh; Jonaidi, Hossein; Sheibani, Vahid; Asadi-Shekaari, Majid; Yousefi, Maryam; Esmaeilpour, Khadijeh

doi:10.1007/s00213-021-05798-8

Cited by 14 publications

(11 citation statements)

References 80 publications

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“…Moreover, PAR‐1 antagonism attenuates the clinical symptoms of experimental autoimmune encephalomyelitis by blocking breakdown of blood–brain barrier [13], and blocking PAR‐1 promotes repair of demyelinated lesions in the adult brain [21]. Further, PAR‐1 suppression ameliorates cognitive performance and synaptic plasticity impairments in rat model of Alzheimer's diseases [14] and diabetes‐associated cognitive impairment in rats [15]. These studies indicate that inhibition or downregulation of PAR‐1 provides a promising therapeutic strategy for decreasing neuronal damage and common neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, brain PAR‐1 signaling is activated in a mouse model of amyotrophic lateral sclerosis [12]. On the other hand, PAR‐1 antagonism attenuates the clinical symptoms of experimental autoimmune encephalomyelitis by blocking the breakdown of blood–brain barrier [13], and PAR‐1 inhibition ameliorates cognitive performance and synaptic plasticity impairments in animal model of Alzheimer's diseases [14]. Together, hyperactivation of PAR‐1 contributes to the neurological deficit including cognitive dysfunctions.…”

Section: Introductionmentioning

confidence: 99%

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High glucose upregulates PAR‐1 in SH‐SY5Y cells via deficiency of miR‐20a and miR‐190a

Kong

Tang

et al. 2021

Fundamemntal Clinical Pharma

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Thrombin activity enhancement and its receptor protease‐activated receptor 1 (PAR‐1) activation play vital roles in neurologic deficits in the central nervous system. Our recent study showed that PAR‐1 upregulation stimulated by chronic high glucose (HG) caused central neuron injury through neuroinflammation; however, the molecular mechanisms are far from clear. In the present study, we found that HG resulted in neuronal injury of SH‐SY5Y cells as evidenced by decreased cell viability and increased lactate dehydrogenase release and elevated the mRNA level of PAR‐1. Moreover, we predicted and determined several potential microRNAs (miRs) combining with the 3′‐UTR of PAR‐1 mRNA, finding that miR‐20a‐5p, miR‐93‐5p, and miR‐190a‐5p were significantly decreased in HG‐cultured SH‐SY5Y cells compared with control. Further, SH‐SY5Y cells stably transfected with miR‐20a‐5p or miR‐190a‐5p mimic were established, and overexpression efficiency were confirmed. It was found that miR‐20a‐5p or miR‐190a‐5p overexpression markedly decreased PAR‐1 mRNA level and protein expression in SH‐SY5Y cells cultured with HG and normal glucose, indicating that miR‐20a or miR‐19a deficiency contributed to HG‐induced PAR‐1 upregulation. Together, our findings demonstrated that PAR‐1 upregulation mediated HG‐induced neuronal damage in central neurons, which was achieved through miR‐20a or miR‐190a deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High glucose upregulates PAR‐1 in SH‐SY5Y cells via deficiency of miR‐20a and miR‐190a

Kong

Tang

et al. 2021

Fundamemntal Clinical Pharma

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“…Moreover, it improved synaptic plasticity by restricting the noxious effects of PAR 1 on the N-methyl-D-aspartate (NMDA) receptors. 66 In one study, it has been confirmed that SCH-79797 significantly inhibited the production of proinflammatory molecules, including TNF-α and IL-1β, and decreased the generation of nitric oxide (NO) and other ROS molecules induced by α-synuclein in primary microglia cells. This finding proposes the potential of SCH-79797 for inhibiting microglia activation in PD.…”

Section: Sch-79797mentioning

confidence: 97%

“…It augmented the learning and memory impairment in the AD rats by improving long‐term potentiation (LTP) generation in the hippocampal CA1 regions. Moreover, it improved synaptic plasticity by restricting the noxious effects of PAR 1 on the N‐methyl‐ d ‐aspartate (NMDA) receptors 66 . In one study, it has been confirmed that SCH‐79797 significantly inhibited the production of proinflammatory molecules, including TNF‐α and IL‐1β, and decreased the generation of nitric oxide (NO) and other ROS molecules induced by α‐synuclein in primary microglia cells.…”

Section: Synthetic Antiplatelet Molecules For Nddsmentioning

confidence: 97%

Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases

Beura

Dhapola

Panigrahi

et al. 2023

Medicinal Research Reviews

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The blood platelet plays an important role but often remains under‐recognized in several vascular complications and associated diseases. Surprisingly, platelet hyperactivity and hyperaggregability have often been considered the critical risk factors for developing vascular dysfunctions in several neurodegenerative diseases (NDDs) like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, platelet structural and functional impairments promote prothrombotic and proinflammatory environment that can aggravate the progression of several NDDs. These findings provide the rationale for using antiplatelet agents not only to prevent morbidity but also to reduce mortality caused by NDDs. Therefore, we thoroughly review the evidence supporting the potential pleiotropic effects of several novel classes of synthetic antiplatelet drugs, that is, cyclooxygenase inhibitors, adenosine diphosphate receptor antagonists, protease‐activated receptor blockers, and glycoprotein IIb/IIIa receptor inhibitors in NDDs. Apart from this, the review also emphasizes the recent developments of selected natural antiplatelet phytochemicals belonging to key classes of plant‐based bioactive compounds, including polyphenols, alkaloids, terpenoids, and flavonoids as potential therapeutic candidates in NDDs. We believe that the broad analysis of contemporary strategies and specific approaches for plausible therapeutic treatment for NDDs presented in this review could be helpful for further successful research in this area.

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“…10 Inhibition of PAR1 improves cognitive performance and alleviates synaptic plasticity impairments in a rat model of AD. 11 With the increased use of edoxaban in Taiwan in recent years, the study comprehensively assesses the vascular, heart failure, bleeding, and neurological outcomes in Taiwanese AF patients treated with edoxaban or warfarin, considering their cancer history.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular and Neurological Outcomes in Patients Treated with Edoxaban for Atrial Fibrillation and Characteristics in Patients with Cancer

Cheng,

Tu,

Cheng

et al. 2023

Preprint

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BACKGROUND: Direct oral anticoagulants (DOACs) outperform warfarin in vascular and bleeding events in atrial fibrillation (AF) patients. Yet, effects of DOACs on congestive heart failure (CHF) and Alzheimer's disease (AD) remain less explored. METHODS: Using the Taiwan National Health Insurance Research Database, a nationwide retrospective cohort study was conducted. The study matched 5,683 non-valvular atrial fibrillation (NVAF) edoxaban patients with 11,366 warfarin patients, and 703 NVAF with cancer (NVAF-C) edoxaban patients with 1,406 warfarin patients. Vasular and non-vascular outcomes, with focuses on CHF and AD, were compared between the edoxaban and warfarin users. RESULTS: Edoxaban significantly lowered adjusted hazrad ratio (aHR) of all-cause mortality, hospitalization for gastrointestinal bleeding, and CHF (0.37, 0.74, and 0.26, respectively, in NVAF; 0.39, 0.67, and 0.31, respectively, in NVAF-C, all p < 0.05), compared to warfarin. Edoxaban was associated with significantly lower aHRs of acute myocardial infarction, peripheral artery disease, venous thromboembolism, pulmonary embolism, and AD (0.71, 0.48, 0.55, 0.20, and 0.66, respectively; all p < 0.05) in NVAF patients versus warfarin. However, edoxaban had higher aHR of hospitalized bleeding (1.19, p = 0.002) than warfarin in NVAF patients, but not in NVAF-C patients. CONCLUSIONS: Edoxaban demonstrated lowered CHF risks in both NVAF and NVAF-C patients, and reduced AD occurrence in NVAF patients versus warfarin. These findings advocate for edoxaban's use in AF cases.

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Inhibition of protease-activated receptor 1 (PAR1) ameliorates cognitive performance and synaptic plasticity impairments in animal model of Alzheimer’s diseases

Cited by 14 publications

References 80 publications

High glucose upregulates PAR‐1 in SH‐SY5Y cells via deficiency of miR‐20a and miR‐190a

High glucose upregulates PAR‐1 in SH‐SY5Y cells via deficiency of miR‐20a and miR‐190a

Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases

Cardiovascular and Neurological Outcomes in Patients Treated with Edoxaban for Atrial Fibrillation and Characteristics in Patients with Cancer

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