Effects and mechanisms of probucol on aging-related hippocampus-dependent cognitive impairment

Xie, Yunxuan; Song, Anni; Zhu, Yuting; Jiang, Anni; Peng, Wenpeng; Zhang, Chun; Meng, Xianhong

doi:10.1016/j.biopha.2021.112266

Cited by 13 publications

(10 citation statements)

References 63 publications

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“…At the Schaffer collateral‐CA1 synapses (Kim et al, 2020), microtubule‐associated protein 2 is required for the induction of long‐term potentiation (LTP), one major cellular process underlying learning and memory (Nicoll, 2017). Supporting our findings, one recent report with the d ‐galactose‐induced aging model demonstrated that probucol enhanced spine density and dendritic branches in the hippocampal CA1, improved long‐term potentiation at the Schaffer collateral to CA1 synapse and ameliorated aging‐related hippocampus‐dependent cognitive impairment in aging mice (Xie et al, 2021). Taken together, our findings suggest that probucol stimulates post‐injury neuroplastic changes to promote the reorganization of brain networks, thus enhancing functional recovery as well as ameliorating cognitive deficits after TBI.…”

Section: Discussionsupporting

confidence: 89%

“…Therefore, probucol may exert neuroregenerative effects in TBI through increasing expression of BDNF. This mechanism might also play a part in probucol-mediated enhancement of hippocampal synaptic plasticity and improvement of learning/ memory in aging mice (Xie et al, 2021). Notably, in a realistic clinical scenario, direct use of BDNF is limited by its pharmacokinetic profile (Thorne & Frey, 2001), including its short in vivo half-life and low blood-brain barrier permeability, and there are still practical constraints using the stem cell approach, recombinant viruses and intracerebral injection.…”

Section: Probucol Enhances Neurite Outgrowth Via Bdnf/trkb Pathway In...mentioning

confidence: 99%

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Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice

Chen

Gung

et al. 2023

British J Pharmacology

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Background and PurposeTraumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol‐lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI.Experimental ApproachMale mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule‐associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain‐derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol‐mediated effects was examined in primary cultures of cortical neurons.Key ResultsProbucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post‐injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA‐12.Conclusions and ImplicationsProbucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post‐injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.

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Section: Discussionsupporting

confidence: 89%

Section: Probucol Enhances Neurite Outgrowth Via Bdnf/trkb Pathway In...mentioning

confidence: 99%

Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice

Chen

Gung

et al. 2023

British J Pharmacology

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“…The Morris water maze experiment (MWM) was used to investigate the learning and memory abilities of model mice were treated with different groups of drugs. , In the navigation test, we observed several indicators of the mouse’s path length in water, average latency, number of passes through the platform on the sixth day, and percentage of residence time in the target quadrant to determine the efficacy of the drug. The blank group mice showed good learning and memory abilities in water, while the model group mice showed severe learning and memory deficits.…”

Section: Resultsmentioning

confidence: 99%

Borneol-Modified Schisandrin B Micelles Cross the Blood–Brain Barrier To Treat Alzheimer’s Disease in Aged Mice

Li,

Yu,

et al. 2024

ACS Chem. Neurosci.

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Objective: Schisandrin B (Sch B) is a bioactive dibenzocyclooctadiene derizative that is prevalent in the fruit of Schisandra chinensis. Numerous studies have demonstrated that Sch B has a neuroprotective action by reducing oxidative stress and effectively preventing inflammation. It follows that Sch B is a potential treatment for Alzheimer's disease (AD). However, the drug's solubility, bioavailability, and lower permeability of the blood−brain barrier (BBB) can all reduce its efficacy during the therapy process. Therefore, this study constructed borneolmodified schisandrin B micelles (Bor-Sch B-Ms), which increase brain targeting by accurately delivering medications to the brain, effectively improving bioavailability. High therapeutic efficacy has been achieved at the pathological site. Methods: Bor-Sch B-Ms were prepared using the thin film dispersion approach in this article. On the one hand, to observe the targeting effect of borneol, we constructed a blood−brain barrier (BBB) model in vitro and studied the ability of micelles to cross the BBB. On the other hand, the distribution of micelle drugs and their related pharmacological effects on neuroinflammation, oxidative stress, and neuronal damage were studied through in vivo administration in mice. Results: In vitro studies have demonstrated that the drug uptake of bEnd.3 cells was increased by the borneol alteration on the surface of the nano micelles, implying that Bor-Sch B-Ms can promote the therapeutic effect of N 2 a cells. This could result in more medicines entering the BBB. In addition, in vivo studies revealed that the distribution and circulation time of medications in the brain tissue were significantly higher than those in other groups, making it more suitable for the treatment of central nervous system diseases. Conclusion: As a novel nanodrug delivery system, borneol modified schisandrin B micelles have promising research prospects in the treatment of Alzheimer's disease.

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“…Probucol, known for its utilization as a cholesterol-lowering drug, has also demonstrated antioxidant properties by inhibiting the oxidative modification of low-density lipoprotein (LDL) ( Barnhart et al, 1970 ; Parthasarathy et al, 1986 ). The beneficial effects of probucol on cognitive dysfunction have been reported in pathological models, including mice injected with Amyloid beta proteins ( Santos et al, 2012 ), those with D-galactose-induced cognitive deficits ( Huang J. L. et al, 2019 ; Xie et al, 2021 ), and those with drug or high-cholesterol diet-induced diabetes ( Santos et al, 2015 ; Mamo et al, 2019 ). However, clinical trials suggested that the metabolic and antioxidative effects of probucol were relatively mild and primarily found in cases with very high cholesterol levels ( Yamashita et al, 2008 ; Cholesterol Treatment Trialists et al, 2015 ; Yamashita et al, 2016 , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance

Wu,

Yang,

Huang

et al. 2024

Front. Neurosci.

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Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

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Effects and mechanisms of probucol on aging-related hippocampus-dependent cognitive impairment

Cited by 13 publications

References 63 publications

Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice

Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice

Borneol-Modified Schisandrin B Micelles Cross the Blood–Brain Barrier To Treat Alzheimer’s Disease in Aged Mice

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance

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