Molecular mechanisms of cognitive impairment associated with stroke

Over two thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

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The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms20143420 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3420 ◽

Cited By ~ 13

Author(s):

Gniewomir Latacz ◽

Annamaria Lubelska ◽

Magdalena Jastrzębska-Więsek ◽

Anna Partyka ◽

Małgorzata Anna Marć ◽

...

Keyword(s):

Cognitive Impairment ◽

Serotonin Receptors ◽

Serotonin Receptor ◽

Molecular Mechanisms ◽

Binding Properties ◽

Piperazine Derivatives ◽

Behavioral Studies ◽

Triazine Derivatives

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

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Baicalin Ameliorates Cognitive Impairment and Protects Microglia from LPS-Induced Neuroinflammation via the SIRT1/HMGB1 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4751349 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Yue Li ◽

Taotao Liu ◽

Yitong Li ◽

Dengyang Han ◽

Jingshu Hong ◽

...

Keyword(s):

Cognitive Impairment ◽

Molecular Mechanisms ◽

Cytokine Production ◽

Cognitive Enhancement ◽

Nuclear Translocation ◽

Brain Diseases ◽

Neurocognitive Deficits ◽

Reactive Microglia ◽

Bv2 Cells ◽

Anti Inflammatory

Systemic inflammation often induces neuroinflammation and disrupts neural functions, ultimately causing cognitive impairment. Furthermore, neuronal inflammation is the key cause of many neurological conditions. It is particularly important to develop effective neuroprotectants to prevent and control inflammatory brain diseases. Baicalin (BAI) has a wide variety of potent neuroprotective and cognitive enhancement properties in various models of neuronal injury through antioxidation, anti-inflammation, anti-apoptosis, and stimulating neurogenesis. Nevertheless, it remains unclear whether BAI can resolve neuroinflammation and cognitive decline triggered by systemic or distant inflammatory processes. In the present study, intraperitoneal lipopolysaccharide (LPS) administration was used to establish neuroinflammation to evaluate the potential neuroprotective and anti-inflammatory effects of BAI. Here, we report that BAI activated silent information regulator 1 (SIRT1) to deacetylate high-mobility group box 1 (HMGB1) protein in response to acute LPS-induced neuroinflammation and cognitive deficits. Furthermore, we demonstrated the anti-inflammatory and cognitive enhancement effects and the underlying molecular mechanisms of BAI in modulating microglial activation and systemic cytokine production, including tumor necrosis factor- (TNF-) α and interleukin- (IL-) 1β, after LPS exposure in mice and in the microglial cell line, BV2. In the hippocampus, BAI not only reduced reactive microglia and inflammatory cytokine production but also modulated SIRT1/HMGB1 signaling in microglia. Interestingly, pretreatment with SIRT1 inhibitor EX-527 abolished the beneficial effects of BAI against LPS exposure. Specifically, BAI treatment inhibited HMGB1 release via the SIRT1/HMGB1 pathway and reduced the nuclear translocation of HMGB1 in LPS-induced BV2 cells. These effects were reversed in BV2 cells by silencing endogenous SIRT1. Taken together, these findings indicated that BAI reduced microglia-associated neuroinflammation and improved acute neurocognitive deficits in LPS-induced mice via SIRT1-dependent downregulation of HMGB1, suggesting a possible novel protection against acute neurobehavioral deficits, such as delayed neurocognitive recovery after anesthesia and surgery challenges.

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Sirt1 Protects Against Hippocampal Atrophy and its Induced Cognitive Impairment in Middle-aged Mice

10.21203/rs.3.rs-1126398/v1 ◽

2021 ◽

Author(s):

Zuhao Sun ◽

Shuang Zhao ◽

Xinjun Suo ◽

Yan Dou

Keyword(s):

Cognitive Impairment ◽

Molecular Mechanisms ◽

Hippocampal Volume ◽

Sirtuin 1 ◽

Spatial Learning And Memory ◽

Hippocampal Atrophy ◽

Middle Aged ◽

Adeno Associated Virus ◽

Aged Mice ◽

Magnetic Resonance Imaging Mri

Abstract Background: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. Results: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that p-tau levels were significantly increased while PSD95 levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau pathology and synaptic damage.Conclusions: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

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Associations between prolactin, diabetes and cognitive impairment: a literature review

Neuroendocrinology ◽

10.1159/000521653 ◽

2021 ◽

Author(s):

Hai Duc Nguyen ◽

Hojin Oh ◽

Byung Pal Yu ◽

Ngoc Minh Hong Hoang ◽

Won Hee Jo ◽

...

Keyword(s):

Cognitive Impairment ◽

Literature Review ◽

Cognitive Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Akt Pathway ◽

Molecular Aspects

Background: Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment. Summary: We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment. Key Messages: The PI3K/AKT pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.

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From stress to depression: Development of extracellular matrix-dependent cognitive impairment following social stress

10.1101/806935 ◽

2019 ◽

Author(s):

Maija-Kreetta Koskinen ◽

Yvar van Mourik ◽

August Benjamin Smit ◽

Danai Riga ◽

Sabine Spijker

Keyword(s):

Extracellular Matrix ◽

Cognitive Impairment ◽

Social Stress ◽

Molecular Mechanisms ◽

Recovery Period ◽

Transition Process ◽

Hippocampal Function ◽

Early Stress ◽

Affective Deficits ◽

Depressive Episodes

AbstractStress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. To shed light on this stress-to-depression transition process, we profiled the development of an enduring depressive-like state in rat by assessing affective behavior and hippocampal function during the 2 months following social defeat stress. In addition, we measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during a sustained depressive-like state. We found affective disturbance and cognitive impairment to develop disparately after social stress. While affective deficits emerged gradually, spatial memory impairment was present both early after stress and during the late-emerging chronic depressive-like state. Surprisingly, these phases were separated by a period of normalized hippocampal function. Similarly, the SDPS paradigm induced a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Early after stress, synaptic ECM proteins and the number of perineuronal nets enwrapping parvalbumin-expressing interneurons were decreased. This was followed by a recovery period without ECM dysregulation, before subsequent decreased metalloproteinase activity and ECM build-up, previously shown to impair memory. This suggests that intact hippocampal function requires unaltered ECM levels. Together our data 1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, 2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and 3) support a role of the ECM in mediating long-lasting memory-effects of social stress.

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Sirt1 Mediated High-Glucose-Induced Aβ Deposition and Cognitive Impairment through Activation of the TLR9/p53 Pathway

10.21203/rs.3.rs-34315/v1 ◽

2020 ◽

Author(s):

Yue Sun ◽

Shiyu Zhu ◽

Jinliang Chen ◽

Yuxing Zhao ◽

Jing Zhou ◽

...

Keyword(s):

Cognitive Impairment ◽

High Glucose ◽

Molecular Mechanisms ◽

Short Term Memory ◽

Learning Ability ◽

Central Nervous System Complication ◽

Inflammatory Pathway ◽

Cognitive Improvement ◽

Lentiviral Infection

Abstract Background: Diabetic encephalopathy (DE) is a chronic central nervous system complication caused by diabetes mellitus (DM). β-amyloid (Aβ) deposition has been considered as the main cause of cognitive impairment in DE. Previous researches concerned the effect of canonical TLR9/Myd88 inflammatory pathway. However our study explored the function of non-inflammatory pathway of Toll-like receptor 9 (TLR9), acting on Sirt1 to influence Aβ deposition and cognitive function in DE.Results: We found that, compared with DM mice, TLR9-/-DM mice performed better learning ability and short-term memory, along with lower Aβ in hippocampi, but could be reversed by Sirt1 inhabition. Furthermore, in vitro, after intervention with high glucose and p53 over-expressed lentiviral infection, we observed the positive results of TLR9 inhibition, such as Sirt1 up-regulation, Aβ reduction or cognitive improvement, were altered (all P<0.05).Conclusions: we considered that TLR9/p53/Sirt1 signalling pathway induced by high glucose are one of molecular mechanisms underlying DE. These results not only confirm the importance of blood glucose management but also provide new insights for the diagnosis and treatment of DE.

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The aging venous system: from varicosities to vascular cognitive impairment

GeroScience ◽

10.1007/s11357-021-00475-2 ◽

2021 ◽

Author(s):

Andrea Ágnes Molnár ◽

György László Nádasy ◽

Gabriella Dörnyei ◽

Bernadett Bettina Patai ◽

Jordan Delfavero ◽

...

Keyword(s):

Older Adults ◽

Cognitive Impairment ◽

Molecular Mechanisms ◽

Varicose Veins ◽

Critical Role ◽

Vascular Cognitive Impairment ◽

Venous System ◽

Potential Contribution ◽

Age Related ◽

Venous Diseases

Abstract Aging-induced pathological alterations of the circulatory system play a critical role in morbidity and mortality of older adults. While the importance of cellular and molecular mechanisms of arterial aging for increased cardiovascular risk in older adults is increasingly appreciated, aging processes of veins are much less studied and understood than those of arteries. In this review, age-related cellular and morphological alterations in the venous system are presented. Similarities and dissimilarities between arterial and venous aging are highlighted, and shared molecular mechanisms of arterial and venous aging are considered. The pathogenesis of venous diseases affecting older adults, including varicose veins, chronic venous insufficiency, and deep vein thrombosis, is discussed, and the potential contribution of venous pathologies to the onset of vascular cognitive impairment and neurodegenerative diseases is emphasized. It is our hope that a greater appreciation of the cellular and molecular processes of vascular aging will stimulate further investigation into strategies aimed at preventing or retarding age-related venous pathologies.

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Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link

International Journal of Molecular Sciences ◽

10.3390/ijms20030464 ◽

2019 ◽

Vol 20 (3) ◽

pp. 464 ◽

Cited By ~ 6

Author(s):

Eugene Bok ◽

Myungjin Jo ◽

Shinrye Lee ◽

Bo-Ram Lee ◽

Jaekwang Kim ◽

...

Keyword(s):

Cognitive Impairment ◽

Glial Cells ◽

Dietary Restriction ◽

Molecular Mechanisms ◽

Motor Dysfunction ◽

Current Understanding ◽

Brain Disorders ◽

Chronic Neuroinflammation ◽

Age Related

Chronic neuroinflammation is a common feature of the aged brain, and its association with the major neurodegenerative changes involved in cognitive impairment and motor dysfunction is well established. One of the most potent antiaging interventions tested so far is dietary restriction (DR), which extends the lifespan in various organisms. Microglia and astrocytes are two major types of glial cells involved in the regulation of neuroinflammation. Accumulating evidence suggests that the age-related proinflammatory activation of astrocytes and microglia is attenuated under DR. However, the molecular mechanisms underlying DR-mediated regulation of neuroinflammation are not well understood. Here, we review the current understanding of the effects of DR on neuroinflammation and suggest an underlying mechanistic link between DR and neuroinflammation that may provide novel insights into the role of DR in aging and age-associated brain disorders.

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Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

International Journal of Molecular Sciences ◽

10.3390/ijms20102405 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2405 ◽

Cited By ~ 3

Author(s):

Jakub Hort ◽

Martin Vališ ◽

Kamil Kuča ◽

Francesco Angelucci

Keyword(s):

Cognitive Impairment ◽

Animal Models ◽

Cognitive Deficits ◽

Molecular Mechanisms ◽

Target Population ◽

Vascular Cognitive Impairment ◽

Toxic Waste ◽

Waste Products ◽

Cascade Effects ◽

Vascular Clearance

Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectively represent the complex clinical picture of VCI in humans. Nonetheless, they allow some understanding of the important molecular mechanisms leading to cognitive deficits. VCI may be caused by various mechanisms and metabolic pathways. The pathological mechanisms, in terms of cognitive deficits, may span from oxidative stress to vascular clearance of toxic waste products (such as amyloid beta) and from neuroinflammation to impaired function of microglia, astrocytes, pericytes, and endothelial cells. Impaired production of elements of the immune response, such as cytokines, and vascular factors, such as insulin-like growth factor 1 (IGF-1), may also affect cognitive functions. No single event could be seen as being the unique cause of cognitive deficits in VCI. These events are interconnected, and may produce cascade effects resulting in cognitive impairment.

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