Microanatomical changes of the cerebral capillary network in aged rats: influence of treatment with a dihydropyridine-type calcium antagonist

A variety of age-dependent changes affect cerebral vasculature. Morphological changes of the brain microvasculature characterized by microvascular fibrosis , vascular convolutions , thickening or membranous changes of the capillary basal membrane and gliofibrillary proliferation have been reported with aging. These changes may be related with age-dependent impairment in behavioral performance. Increasing evidence suggests that Ca+2 antagonists of the dihydropyridine family, which are used primarily in the therapy of cardiovascular disorders may be useful for treating neurologic diseases including cerebral ischemia, age-related neurodegenerative disorders, senile dementia and epilepsy. This in view of the capability of these compounds to decrease Ca+2 overload which can result in increased cell death.Recent studies have shown that the dihydropyridine Ca2+ antagonists delayed the expression of agerelated microvascular changes in the rat forebrain and sciatic nerve without reducing systolic blood pressure. The present study was designed to assess the influence of long term treatment with the dihydropyridine derivative darodipine [diethyl 4-2,1,3- (benzoxadiazal-4-yl)-l,4-dihydro-2,6-dimethylpyridine- 3,5-dicarboxylate, PY 108-068] on age-related microvascular changes occurring in the rat cerebral cortex and hippocampus. The brain capillary network was investigated using alkaline phosphatase histochemistry associated with image analysis.

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Effect of long-term treatment with L-deprenyl on the age-dependent microanatomical changes in the rat hippocampus

Mechanisms of Ageing and Development ◽

10.1016/0047-6374(94)01559-5 ◽

1995 ◽

Vol 79 (2-3) ◽

pp. 169-185 ◽

Cited By ~ 18

Author(s):

Yong-Chun Zeng ◽

Stefano Bongrani ◽

Elena Bronzetti ◽

Sandro Cadel ◽

Alberto Ricci ◽

...

Keyword(s):

Term Treatment ◽

Rat Hippocampus ◽

Long Term Treatment ◽

Age Dependent

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Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

10.21203/rs.3.rs-72160/v1 ◽

2020 ◽

Author(s):

Andrés Fernández ◽

Elena Quintana ◽

Patricia Velasco ◽

Belén de Andrés ◽

Maria Luisa Gaspar ◽

...

Keyword(s):

Choroid Plexus ◽

Inflammatory Cytokines ◽

Hippocampal Formation ◽

Morphological Changes ◽

Interleukin 1 ◽

Brain Parenchyma ◽

Age Related ◽

Inflammatory Changes ◽

Samp8 Mice ◽

The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

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Morphological Changes in Primate Aqueous Humor Formation and Drainage Tissues After Long-Term Treatment with Antiglaucomatous Drugs

Journal of Glaucoma ◽

10.1097/00061198-199300240-00016 ◽

1993 ◽

Vol 2 (4) ◽

pp. 316???328

Author(s):

Elke L??tjen-Drecoll ◽

Paul L. Kaufman

Keyword(s):

Aqueous Humor ◽

Morphological Changes ◽

Term Treatment ◽

Long Term Treatment

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Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

Journal of Alzheimer s Disease ◽

10.3233/jad-215128 ◽

2021 ◽

pp. 1-14

Author(s):

Andrew L. Zhou ◽

Nidhi Sharda ◽

Vidur V. Sarma ◽

Kristen M. Ahlschwede ◽

Geoffry L. Curran ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Single Photon ◽

Photon Emission ◽

Amyloid Β ◽

Emission Computed Tomography ◽

Systemic Injection ◽

Age Related ◽

Age Dependent ◽

Plasma Pharmacokinetics ◽

The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

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Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid β and in mTOR Activity

Antioxidants ◽

10.3390/antiox8060177 ◽

2019 ◽

Vol 8 (6) ◽

pp. 177 ◽

Cited By ~ 9

Author(s):

Natalia A. Muraleva ◽

Oyuna S. Kozhevnikova ◽

Anzhela Z. Fursova ◽

Nataliya G. Kolosova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Developed Countries ◽

Term Treatment ◽

Age Related Macular Degeneration ◽

Eye Health ◽

Age Related ◽

Long Term Treatment

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment and blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. Recent studies strongly indicate that amyloid β (Aβ) accumulation —found in the brain and a defining feature of Alzheimer’s disease—also forms in the retina in both Alzheimer’s disease and AMD. The reason why highly neurotoxic proteins of consistently aggregate in the aging retina, and to what extent they contribute to AMD, remains to be fully addressed. Nonetheless, the hypothesis that Aβ is a therapeutic target in AMD is debated. Here, we showed that long-term treatment with SkQ1 (250 nmol/[kg body weight] daily from the age of 1.5 to 22 months) suppressed the development of AMD-like pathology in senescence-accelerated OXYS rats by reducing the level of Aβ and suppressing the activity of mTOR in the retina. Inhibition of mTOR signaling activity, which plays key roles in aging and age-related diseases, can be considered a new mechanism of the prophylactic effect of SkQ1. It seems probable that dietary supplementation with mitochondria-targeted antioxidant SkQ1 can be a good prevention strategy to maintain eye health and possibly a treatment of AMD.

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Platelet counts in epileptic children receiving valproic acid

Paediatrica Indonesiana ◽

10.14238/pi60.1.2020.13-7 ◽

2020 ◽

Vol 60 (1) ◽

pp. 13-7

Author(s):

Lilik Indrayati ◽

Fadhilah Tia Nur ◽

Bambang Soebagyo

Keyword(s):

Valproic Acid ◽

Epileptic Seizures ◽

Term Treatment ◽

Common Adverse Event ◽

Platelet Counts ◽

Central Java ◽

Long Term Treatment ◽

Epileptic Children ◽

The Brain

Background Epileptic seizures are a transient occurrence resulting from abnormal, excessive, or synchronous neural activity in the brain. Epilepsy requires long-term treatment, increasingly larger doses, and combination therapy. Anti-epileptic drugs (AEDs), especially valproic acid (VPA), are the main treatment of choice. Thrombocytopenia is the most common adverse event from AEDs. Objective To evaluate platelet counts in epileptic children receiving valproic acid monotherapy vs. polytherapy. Methods This analytic, observational, retrospective cohort study was conducted in children with epilepsy below 18 years of age and treated in Dr. Moewardi Hospital, Surakarta, Central Java. Subjects had received VPA treatment for at least 6 months, either as monotherapy or polytherapy. There were 40 subjects in each group (VPA monotherapy vs. VPA polytherapy). The exclusion criteria were patients who had thrombocytopenia and did not take valproic acid regularly. The data was taken from laboratory and the outcome assessed was decreasing of platelet count. Results Administration of VPA as monotherapy vs. polytherapy was not significantly associated with incidence of thrombocytopenia. However, duration of VPA use > 2 years was associated with significantly greater proportion of thrombocytopenia, with OR 33.0 (95%CI 4.157 to 261.962; P=0.001) compared to VPA use < 2 years. Similarly, VPA dose of >30 mg/kg/day was significantly associated with greater proportion of thrombocytopenia, with OR 4.081 (95%CI 1.337 to 12.458; P=0.013) compared to <30 mg/kg/day dosage. Conclusion Incidence of thrombocytopenia is not significantly different between VPA as a monotherapy and polytherapy. However, higher VPA dose and longer VPA duration are associated with higher proportion of thrombocytopenia.

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