Aged Rat Brain Research Articles

Whole-body vibration elicits 40Hz cortical gamma oscillations and ameliorates age-related cognitive impairment through hippocampal astrocyte synapses in male rats.

Age-related cognitive impairment is a prevalent issue in developed societies. Gamma oscil2lations at 40Hz have been identified as a potential therapeutic approach for age-related cognitive decline and can be induced through various modalities, including auditory, visual, electrical, and magnetic stimulation. In this study, we investigated a novel modality of stimulation: whole-body vibration at 40Hz. We examined the effects of 40Hz vibration on cognitive performance and associated neuronal activity in the brains of aged male rats. Our findings revealed that only vibration at 40Hz, rather than 20Hz or 80Hz, elicited cortical gamma oscillations in aged male rats. Additionally, following 8weeks of prolonged treatment, the implementation of 40Hz whole-body vibration significantly augmented the cognitive function of aged male rats as evidenced by behavioral assessments. Mechanistic studies demonstrated that these beneficial effects were attributed to the reduction of neuronal apoptosis in hippocampal CA1 through regulation of synaptic connections between astrocytes and neurons via 40Hz gamma oscillations. Collectively, this suggests a promising intervention for age-related cognitive decline and identifies neuron-astrocyte synapses as potential therapeutic targets.

Does age protect against loss of tonotopy after acute deafness in adulthood?

The mammalian auditory system develops a topographical representation of sound frequencies along its pathways, also called tonotopy. In contrast, sensory deprivation during early development results in no or only rudimentary tonotopic organization. This study addresses two questions: (1) How robust is the central tonotopy when hearing fails in adulthood? (2) What role does age play at time of deafness? To address these questions, we deafened young and old adult rats with previously normal hearing. One month after deafening, both groups were unilaterally supplied with cochlear implants and electrically stimulated for 2 h. The central auditory neurons, which were activated as a result of the local electrical intracochlear stimulation, were visualized using Fos staining. While the auditory system of young rats lost the tonotopic organization throughout the brainstem, the auditory system of the older rats mainly sustained its tonotopy. It can be proposed that plasticity prevails in the central auditory system of young adult rats, while network stability prevails in the brains of aging rats. Consequently, age may be an important factor in protecting a hearing-experienced adult auditory system from a rapid loss of tonotopy when suffering from acute hearing loss. Furthermore, the study provides compelling evidence that acute deafness in young adult patients should be diagnosed as early as possible to prevent maladaptation of the central auditory system and thus achieve the optimal hearing outcome with a hearing prosthesis.

Gestational diabetes mellitus, not obesity, triggers postpartum brain inflammation and premature aging in Sprague-Dawley rats

Previous studies showed that women with gestational diabetes mellitus (GDM) are susceptible to cognitive dysfunction. We investigated the effects of GDM on brain pathologies and premature brain aging in rats. Seven-week-old female Sprague-Dawley rats were fed a normal diet (ND) or a high-fat diet (HFD) after two weeks of acclimatization. On pregnancy day 0, HFD-treated rats received streptozotocin (GDM group) or vehicle (Obese mothers). ND-treated rats received vehicle (ND-control mothers). On postpartum day 21, brains and blood were collected. The GDM group showed increased inflammatory and premature aging markers, mitochondrial changes, and compensatory increases in the blood–brain barrier and synaptic proteins in the prefrontal cortex and hippocampus. GDM triggers maternal brain inflammation and premature aging, suggesting compensatory mechanisms may protect against these effects.

The combined effects of resistance and endurance training with ursolic acid supplementation on some Alzheimer's disease-related biomarkers in a rat model of type 2 diabetes

BackgroundType 2 diabetes is associated with increased inflammation and a risk of Alzheimer's disease (AD). This study aimed to assess the impact of exercise with ursolic acid (UA) on some protein levels in the brains of aged male Wistar rats with diet-induced Type 2. We investigated the effects of exercise with UA on protein levels in rats with type 2 diabetes. The rats were divided into seven groups and underwent different exercise or UA protocols.ResultsThe results showed that type 2 diabetes led to increased levels of tau, IL-1β, TNF-α, and c-Jun, and decreased levels of IRS2 protein. Endurance training improved tau, Jun, and IRS2 levels. UA reduced increased levels of tau, IL-1β, TNF-α, and c-Jun, and increased IRS2 levels. Combining the supplement with training led to further improvements.ConclusionsThese findings suggest that combining training and UA partially reversed the inflammation in the Type 2 diabetes model. However, further research is needed to understand how UA consumption with or without training protocols can reduce the risk of AD in type 2 diabetes.

Morphofunctional changes in brain and peripheral blood in aged Wistar rats due to AlCl3 exposure

The purpose of the study: To examine morphofunctional changes of brain and peripheral blood in aged Wistar rats to observe adaptive reactions as a response on AlCl3 exposure. Methods: The work was performed on male Wistar rats, 24 months of age. Animals consumed a solution of AlCl3 100 mg/kg per day for 60 days. Morphological changes of neurons and microglia, mRNA expression levels of pro- and anti-inflammatory cytokines, microglia activation markers, amyloid-related and hypoxia-related proteins, as well as monocyte and lymphocyte subpopulations in peripheral blood, were examined. Results: AlCl3-treated old rats showed the increasing of hyperchromic neurons in 2 out of 3 examined regions of the hippocampus; morphological features of microglia cells’ dystrophy; the upregulation of pro-inflammatory cytokine Il-18 and the downregulation of anti-inflammatory cytokine Il-10, as well as App, Bace1, and Hif-1a; the decreasing of percentage of B-cells, general CD3+ lymphocyte population, including CD4+ T-helpers and CD8+ cytotoxic cells, but the increasing of CD4+/CD8+ ratio in peripheral blood. Conclusion: AlCl3-treated aged rats demonstrated systemic maladaptation to AlCl3 impact. Unlike adult rodents, aged ones have the background of inflammaging, as well as elderly people. The exposure of AlCl3 could potentially be a replacement of integral cellular and molecular processes accompanying age-related diseases, presenting in most elderly people, as an enhancer of inflammaging and hypoxia. These conditions make this model of neurodegeneration a reliable one to explore the initial mechanisms of such detrimental process, as well as prove aged rats more suitable subjects to perform future researches in this field.

Berberine attenuates brain aging via stabilizing redox homeostasis and inflammation in an accelerated senescence model of Wistar rats.

Aging is a multifaceted and progressive physiological change of the organism categorized by the accumulation of deteriorating processes, which ultimately compromise the biological functions. The objective of this study was to investigate the anti-aging potential of berberine (BBR) in D-galactose (D-Gal) induced aging in rat models. In this study, male Wistar rats were divided into four groups: The control group was given only vehicle, the BBR group was treated with berberine orally, the D-Gal group was treated with D-galactose subcutaneously and the BBR + D-Gal group was treated with D-galactose and berberine simultaneously. D-galactose exposure elevated the pro-oxidants such as malondialdehyde (MDA) level, protein carbonyl and advanced oxidation protein products (AOPP) in the brain. It decreased the anti-oxidants such as reduced glutathione (GSH) and ferric reducing antioxidant potential (FRAP) in the brain. D-galactose treatment also reduced the mitochondrial complexes (I, II, III and IV) activities and elevated the inflammatory markers such as interleukine-6 (IL-6), tumor necrosis factor- α (TNF-α) and C-reactive protein (CRP). The mRNA expressions of IL-6 and TNF-α in the brain were upregulated following D-galactose exposure. Berberine co-treatment in D-galactose induced aging rat model prevented the alteration of pro-oxidant and anti-oxidant in the brain. Berberine treatment restored the mitochondrial complex activities in the brain and also normalized the inflammatory markers. Based on these findings we conclude that berberine treatment has the potential to mitigate brain aging in rats via stabilizing the redox equilibrium and neuroinflammation.

Restoration of norepinephrine release, cognitive performance, and dendritic spines by amphetamine in aged rat brain.

Age-related dysfunctions in specific neurotransmitter systems likely play an important role in cognitive decline even in its most subtle forms. Therefore, preservation or improvement of cognition via augmentation of neurotransmission is a potential therapeutic strategy to prevent further cognitive deficits. Here we identified a particular neuronal vulnerability in the aged Fischer 344 rat brain, an animal model of neurocognitive aging. Specifically, we demonstrated a marked impairment in glutamate-stimulated release of norepinephrine (NE) in the hippocampus and cerebral cortex of aged rats, and established that this release was mediated by N-methyl-D-aspartate (NMDA) receptors. Further, we also demonstrated that this decrease in NE release is fully rescued by the psychostimulant drug amphetamine (AMPH). Moreover, we showed that AMPH increases dendritic spine maturation, and importantly shows preclinical efficacy in restoring memory deficits in the aged rat through its actions to potentiate NE neurotransmission at β-adrenergic receptors. Taken together, our results suggest that deficits in glutamate-stimulated release of NE may contribute to and possibly be a determinant of neuronal vulnerability underlying cognitive decline during aging, and that these deficits can be corrected with currently available drugs. Overall these studies suggest that repurposing of psychostimulants for age-associated cognitive deficits is a potential avenue to delay or prevent cognitive decline and/or frank dementia later in life.

Reduced SV2A and GABAA receptor levels in the brains of type 2 diabetic rats revealed by [18F]SDM-8 and [18F]flumazenil PET

PurposeType 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. MethodsPositron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-β), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. ResultsReduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. ConclusionThese findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.

Ladostigil Reduces the Adenoside Triphosphate/Lipopolysaccharide-Induced Secretion of Pro-Inflammatory Cytokines from Microglia and Modulate-Immune Regulators, TNFAIP3, and EGR1.

Treatment of aging rats for 6 months with ladostigil (1 mg/kg/day) prevented a decline in recognition and spatial memory and suppressed the overexpression of gene-encoding pro-inflammatory cytokines, TNFα, IL1β, and IL6 in the brain and microglial cultures. Primary cultures of mouse microglia stimulated by lipopolysaccharides (LPS, 0.75 µg/mL) and benzoyl ATPs (BzATP) were used to determine the concentration of ladostigil that reduces the secretion of these cytokine proteins. Ladostigil (1 × 10-11 M), a concentration compatible with the blood of aging rats in, prevented memory decline and reduced secretion of IL1β and IL6 by ≈50%. RNA sequencing analysis showed that BzATP/LPS upregulated 25 genes, including early-growth response protein 1, (Egr1) which increased in the brain of subjects with neurodegenerative diseases. Ladostigil significantly decreased Egr1 gene expression and levels of the protein in the nucleus and increased TNF alpha-induced protein 3 (TNFaIP3), which suppresses cytokine release, in the microglial cytoplasm. Restoration of the aberrant signaling of these proteins in ATP/LPS-activated microglia in vivo might explain the prevention by ladostigil of the morphological and inflammatory changes in the brain of aging rats.

Mitochondrial respiratory capacity is not altered in aging rat brains with or without memory impairment.

Mitochondria are essential for supporting the high metabolic demands that are required for brain function. Impairments in mitochondria have been linked to age-related decline in brain functions. Here, we investigate whether the mitochondrial respiratory capacity of brain cells is changed in cognitive aging. We used a rat model of normal cognitive aging and analyzed mitochondrial oxidative phosphorylation in frozen brain samples. Mitochondrial oxygen consumption rate analysis of the frontal cortex did not show any differences between young rats and aged rats with either intact memory or impaired spatial memory. Mitochondrial ATP synthase activity and quantity also did not differ between young and aged rats. These results suggest that the total level of mitochondrial respiratory capacity is preserved in the frontal cortex of aged rats and may not explain aging-associated cognitive impairment.

Inflammatory and metabolic responses in the aging rat brain

AbstractBackgroundThe brain is an energetically demanding organ that mostly relies on glucose oxidation to sustain its sophisticated networks. Transcriptomic studies suggest metabolic‐related genes are downregulated in the aging brain but inflammation‐related genes are highly upregulated. Astrocytes are key mediators of brain inflammation and metabolism. Yet, the relationship between inflammatory signals and energy substrates consumption in the aging brain remains unclear. To address this question, we investigated the response of the young and aged rat brain metabolism to a nonsteroidal anti‐inflammatory (NSAID) drug.MethodFive young adults (4 mo), and five aged (24 mo) male Wistar rats were scanned using positron emission microtomography with 18F‐fluorodeoxyglucose ([18F]FDG‐PET). Scans were done under basal conditions or after three‐day treatment with 5mg/kg ketoprofen (i.p.), an NSAID known to cross the blood‐brain barrier. Standard uptake values ratios (SUVr, pons as reference) were calculated for the main brain regions. Synaptosome and total mitochondria preparations from the cortex had their oxygen consumption rates measured in an Oroboros Instrument, using a SUIT protocol. Results were analyzed by t‐test, with statistical significance P < 0.05.ResultUnder basal conditions, glucose uptake showed no differences between young and aged rats. After ketoprofen treatment, clusters of glucose hypermetabolism appeared in the cortex and hippocampus of the adult but not the aged brain. Synaptosomal and mitochondrial preparations did not present differences in ATP‐linked, maximal, or leak respiration between groups under basal conditions. However, aged synaptosomes (t = 3.417, p = 0.0112) and total mitochondria (t = 3.131, p = 0.0166) presented higher respiratory coupling ratios.ConclusionWe previously showed that [18F]FDG‐PET signal highly depends on astrocyte function. The lack of response to ketoprofen in aged rats may be related to astrocyte dysfunction in aging. As a counter‐response to the aging process, the brain mitochondria are highly coupled, keeping the system as efficient as necessary. Our findings indicate that brain metabolism might not be coupled to inflammation in the aged rat brain. Still, we identified a remarkable plasticity of the mitochondria, which can sustain physiological responses despite the aging process.

Cellular and molecular signatures of motherhood in the adult and ageing rat brain.

Pregnancy is marked by robust changes, including brain changes to volume, structure, connectivity and neuroplasticity. Although some brain changes are restricted to pregnancy and the postpartum, others are long-lasting. Few studies have examined possible mechanisms of these changes or the effects of multiple pregnancies. We characterized various cellular and molecular signatures of parity (nulliparous, primiparous, biparous) in the rat hippocampus. We investigated density of neural stems cells (Sox2), microglia (Iba-1) and levels of a synaptic protein (PSD-95), cell signalling pathways, neuroinflammation, and the tryptophan-kynurenine (TRP-KYN) pathway, one week after weaning their pups from the last pregnancy (age of dam: seven months) and in middle-age (age of dam: 13 months). Parity increased PSD-95 levels in both age groups and prevented the age-related decrease in neural stem cell density observed in nulliparous rats. Biparity increased cell signalling phosphoproteins (pp70S6K, S6RP) and number of microglia in the dentate gyrus, regardless of age. Parity resulted in transient changes to the TRP-KYN system. Thus, previous parity has lasting effects on synaptic plasticity with fewer lasting effects on inflammation and cell signalling phosphoproteins in the whole hippocampus.

The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats

BackgroundLiver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is negatively regulated by the brain serotoninergic system. The present study aimed to investigate changes in the function of the main liver drug-metabolizing CYP enzymes as a result of serotonin depletion in the brain of aging rats, caused by knockout of brain tryptophan hydroxylase gene (TPH2-KO).MethodsThe hepatic CYP mRNA (qRT-PCR), protein level (Western blotting) and activity (HPLC), and serum hormone levels (ELISA) were measured in Dark Agouti wild-type (WT) male rats (mature 3.5-month-old and senescent 21-month-old) and in TPH2-KO senescent animals.ResultsThe expression/activity of the studied CYPs decreased with age in the liver of wild-type rats. The deprivation of serotonin in the brain of aging males decreased the mRNA level of most of the studied CYPs (CYP1A/2A/2B/3A), and lowered the protein level of CYP2C11 and CYP3A. In contrast, the activities of CYP2C11, CYP3A and CYP2C6 were increased. The expression of cytochrome b5 decreased in aging rats, but increased in TPH2-deficient senescent animals. The serum concentration of growth hormone declined in the aged and further dropped down in TPH2-deficient senescent rats.ConclusionsRat liver cytochrome P450 functions deteriorate with age, which may impair drug metabolism. The TPH2 knockout, which deprives brain serotonin, affects cytochrome P450 expression and activity differently in mature and senescent male rats.

Leukotriene signaling as molecular correlate for cognitive heterogeneity in aging: an exploratory study.

Aging is in general associated with a decline in cognitive functions. Looking more closely, there is a huge heterogeneity in the extent of cognitive (dys-)abilities in the aged population. It ranges from the population of resistant, resilient, cognitively unimpaired individuals to patients with severe forms of dementias. Besides the known genetic, environmental and life style factors that shape the cognitive (dys-)abilities in aging, the underlying molecular mechanisms and signals related to cognitive heterogeneity are completely unknown. One putative mechanism underlying cognitive heterogeneity might be neuroinflammation, exerted through microglia, the brain's innate immune cells, as neuroinflammation is central to brain aging and neurodegenerative diseases. Recently, leukotrienes (LTs), i.e., small lipid mediators of inflammation produced by microglia along aging and neurodegeneration, got in the focus of geroscience as they might determine cognitive dysfunctions in aging. Here, we analyzed the brain's expression of key components of the LT synthesis pathway, i.e., the expression of 5-lipoxygenase (5-Lox), the key enzyme in LT production, and 5-lipoxygenase-activating protein (FLAP) in young and aged rats. More specifically, we used a cohort of rats, which, although grown up and housed under identical conditions, developed into aged cognitively unimpaired and aged cognitively impaired traits. Expression of 5-Lox was increased within the brain of aged rats with the highest levels detected in cognitively impaired animals. The number of microglia cells was higher in the aged compared to the young brains with, again, the highest numbers of 5-Lox expressing microglia in the aged cognitively impaired rats. Remarkably, lower cognitive scores in the aged rats associated with higher numbers of 5-Lox positive microglia in the animals. Similar data were obtained for FLAP, at least in the cortex. Our data indicate elevated levels of the LT system in the brain of cognitively impaired animals. We conclude that 5-Lox expressing microglia potentially contribute to the age-related cognitive decline in the brain, while low levels of the LT system might indicate and foster higher cognitive functions and eventually cognitive reserve and resilience in aging.

Crystal-Based X-ray Interferometry and Its Application to Phase-Contrast X-ray Imaging, Zeff Imaging, and X-ray Thermography

Crystal-based X-ray interferometry (CXI) detects X-ray phase shifts by using the superposition of waves, and its sensitivity is the highest among the other X-ray phase-detecting methods. Therefore, phase-contrast X-ray imaging (PCXI) using CXI has the highest density resolution among the PCXI methods and enables fine, non-destructive observation with a density resolution below sub-mg/cm3. It has thus been applied in a wide range of fields, including biology, medicine, geology, and industry, such as visualization of the testis and brains of aged rats with tumors, human embryos at each Carnegie stage, air hydrates in old Antarctic ice, and ion distribution in electrolytes. Novel imaging methods have also been developed to take advantage of its high sensitivity, such as visualization of the effective atomic number (Zeff) and the three-dimensional temperature of samples. This article reviews the principles and history of PCXI and crystal-based X-ray interferometers, as well as a CXI system using synchrotron radiation and its potential applications from biomedical to industrial.

Morphofunctional changes in brain and peripheral blood in aged Wistar rats due to AlCl3 exposure

The purpose of the study: To examine morphofunctional changes of brain and peripheral blood in aged Wistar rats to observe adaptive reactions as a response on AlCl3 exposure. Methods: The work was performed on male Wistar rats, 24 months of age. Animals consumed a solution of AlCl3 100 mg/kg per day for 60 days. Morphological changes of neurons and microglia, mRNA expression levels of pro- and anti-inflammatory cytokines, microglia activation markers, amyloid-related and hypoxia-related proteins, as well as monocyte and lymphocyte subpopulations in peripheral blood, were examined. Results: AlCl3-treated old rats showed the increasing of hyperchromic neurons in 2 out of 3 examined regions of the hippocampus; morphological features of microglia cells’ dystrophy; the upregulation of pro-inflammatory cytokine Il-18 and the downregulation of anti-inflammatory cytokine Il-10, as well as App, Bace1, and Hif-1a; the decreasing of percentage of B-cells, general CD3+ lymphocyte population, including CD4+ T-helpers and CD8+ cytotoxic cells, but the increasing of CD4+/CD8+ ratio in peripheral blood. Conclusion: AlCl3-treated aged rats demonstrated systemic maladaptation to AlCl3 impact. Unlike adult rodents, aged ones have the background of inflammaging, as well as elderly people. The exposure of AlCl3 could potentially be a replacement of integral cellular and molecular processes accompanying age-related diseases, presenting in most elderly people, as an enhancer of inflammaging and hypoxia. These conditions make this model of neurodegeneration a reliable one to explore the initial mechanisms of such detrimental process, as well as prove aged rats more suitable subjects to perform future researches in this field.

Stem Cell Treatments in Preclinical Relevant Stroke Models.

Since stroke has limited treatment options, an active search for new therapeutic approaches is required. Initial excitement of using cell-based therapies to stimulate recovery processes in the ischemic brain turned into a more measured perspective, acknowledging obstacles related to the unfavorable environments associated in part with aging. Given the predominance of stroke in older populations, evaluating the effectiveness of cell therapies in aged brain environments is essential and clinically relevant. Despite a common perception of the aged brain being resistant to regeneration, recent research with neural precursor cells and bone marrow-derived mesenchymal stem cells indicates that cell-based therapy can promote plasticity and remodeling in the aged rat brain. However, significant differences in the aged brain compared to the young brain, such as expedited progression of ischemic injury to brain infarction, decreased rate of endogenous neurogenesis, and delayed onset of neurological recovery, must be noted. The effectiveness of cell-based therapies may further be connected to age-related comorbidities such as diabetes or hyperlipidemia, potentially leading to maladaptive or impaired brain remodeling. These age-related factors need careful consideration in the clinical application of restorative therapies for stroke.

Senescence in brain pericytes attenuates blood-brain barrier function in vitro: A comparison of serially passaged and isolated pericytes from aged rat brains

Aging is associated with the dysfunction of the blood-brain barrier (BBB), which comprises brain microvessel endothelial cells (BMECs), astrocytes, and pericytes. Pericytes are present at intervals along the walls of the brain capillaries and play a key role in maintaining BBB integrity. Accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) in the brain facilitate the development of age-related neurodegenerative diseases with BBB dysfunction. However, the ability of pericytes to support BBB integrity and their correlation with cellular senescence or aging remain unknown. Here, we investigated cellular senescence in pericytes focusing on its impact on BBB function using BBB models comprising intact BMECs co-cultured with senescent pericytes, which were obtained through a serial passage or isolated from 18-month-old rats. To assess BBB function, transendothelial electrical resistance (TEER) and permeability of sodium fluorescein (Na–F) were studied. Both serially passaged pericytes (in passage 4, 7, and 10) and aged pericytes isolated from 18-month-old rats showed decreased TEER and enhanced permeability of BMECs to Na–F compared to that of normal pericytes (passage 2 or young). Furthermore, serially passaged and aged pericytes showed characteristic features of cellular senescence, including increased β-galactosidase activity, cell cycle arrest, enhanced expression of mRNA, and SASP factors. However, the senescence-induced mRNA expression profile of pericyte markers varied between serially passaged and aged pericytes. Hence, in vitro serial passages and isolation from naturally aged rodents differently influenced genetic and biochemical features of senescent brain pericytes. We conclude that senescent brain pericytes can induce BBB dysfunction and those isolated from aged rodents retain the senescence-specific properties. Our findings provide an alternative tool to investigate the senescence in brain pericytes in vitro.

PRUNETIN ATTENUATES D-GALACTOSE-INDUCED BRAIN AGING VIA INHIBITING AMYLOID-Β AND TAU PROTEIN AGGREGATION

The objective of this investigation was to assess the effect of prunetin in D-galactose-induced brain aging in rats and its regulating mechanisms. D-galactose (200 mg kg-1 body wt.) was given orally daily for 45 days to accelerate aging, and prunetin (10, 20,40, and 80 µg kg-1 body wt. respectively) was administered orally. The anti-oxidant and anti-brain aging activities of prunetin in serum were measured by the estimation of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) levels and brain tissues were measured by western blot analysis and histopathological studies. Prunetin therapy decreases elevated levels of glucose, C-reactive protein, cholesterol, and triglyceride levels in the D-galactose-induced rats. D-galactose suppresses the levels of superoxide dismutase, glutathione peroxidase, catalase and total antioxidant capacity in rats; these levels were elevated by treating with prunetin. Malondialdehyde levels were elevated in D-galactose-induced rats. Prunetin significantly decreases the malondialdehyde levels in rat brain tissue. Prunetin decreases mitochondrial dysfunction induced by D-galactose, by improving the activities of Na+K+-ATPase and acetylcholinesterase enzyme activity. Western blot analysis results showed that the degree of brain tissue damage was significantly reduced by prunetin. The results of our study indicated that prunetin treatment reduced oxidative stress by exerting a protective effect against D-galactose-induced aging in rats, by significantly decreasing amyloid - β and tau protein levels in the brain tissue. Prunetin exhibits anti-oxidant activity by increasing anti-oxidant enzymes.

Adropin increases with swimming exercise and exerts a protective effect on the brain of aged rats

Adropin is a protein in the brain that decreases with age. Exercise has a protective effect on the endothelium by increasing the level of adropin in circulation. In this study, whether adropin, whose level in the brain decreases with age, may increase with swimming exercise, and exhibit a protective effect was investigated. Young and aged male Sprague Dawley rats were submitted to 1 h of swimming exercise every day for 8 weeks. Motor activity parameters were recorded at the end of the exercise or waiting periods before the animals were euthanized. Increased motor functions were observed in only the young rats that exercised regularly. Adropin levels in the plasma, and the adropin and VEGFR2 immunoreactivities and p-Akt (Ser473) levels in the frontal cortex were significantly increased in the aged rats that exercised regularly. It was also observed that the BAX/Bcl2 ratio and ROS-RNS levels decreased, while the TAC levels increased in the aged rats that exercised regularly. The results of the study indicated that low-moderate chronic swimming exercise had protective effects by increasing the level of adropin in the frontal cortex tissues of the aged rats. Adropin is thought to achieve this effect by increasing the VEGFR2 expression level and causing Akt (Ser473) phosphorylation. These results indicated that an exercise-mediated increase in endogenous adropin may be effective in preventing the destructive effects of aging on the brain.