Aging exacerbates hypertension‐induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection

Recent studies demonstrate that aging exacerbates hypertension‐induced cognitive decline, but the specific age‐related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension‐induced CMHs young (3 months) and aged (24 months) mice were treated with angiotensin II plus L‐NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension‐induced cerebrovascular oxidative stress and redox‐sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension‐induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension‐induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high‐risk elderly patients.     

Prospective Memory Performance in Non-Psychotic First-Degree Relatives of Patients with Schizophrenia: A Controlled Study

Objective

We aimed at investigating prospective memory and its socio-demographic and neurocognitive correlates in non-psychotic, first-degree relatives (FDRs) of patients with schizophrenia compared to patients with first episode schizophrenia (FES), and healthy controls (HCs).

Methods

Forty-seven FES patients, 50 non-psychotic FDRs (23 offspring and 27 siblings) of patients with chronic schizophrenia (unrelated to the FES group) and 51 HCs were studied. The Chinese version of the Cambridge Prospective Memory Test (C-CAMPROMPT) was used to measure time-based prospective memory (TBPM) and event-based prospective memory (EBPM) performance. Other cognitive functions (involving respective memory and executive functions) were evaluated with standardized tests.

Results

After controlling for basic demographic characteristics including age, gender and educational level, there was a significant difference between FDRs, FES and HCs with respect to both TBPM (F_(2,142) = 10.4, p<0.001) and EBPM (F_(2,142) = 10.8, p<0.001). Multiple linear regression analyses revealed that lower scores of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the STROOP Word-Color Test (SWCT) contributed to TBPM impairment, while lower educational level and higher scores of the Color Trails Test-2 (CTT-2) contributed to EBPM deficit in FDRs.

Conclusions

FDRs share similar but attenuated prospective memory impairments with schizophrenia patients, suggesting that prospective memory deficits may represent an endophenotype of schizophrenia.     

The Relationship between Frontal Lobe Lesions,Course of Post-Stroke Depression,and 1-year Prognosis in Patients with First-Ever Ischemic Stroke

Background and Purpose

Most studies on post-stroke depression (PSD) have focused on a certain time point after stroke instead of the time course of PSD. The aim of this study was to determine the relationship between frontal lobe lesions, course of PSD over a year following the stroke onset, and the 1-year prognosis in patients with first-ever ischemic stroke.

Methods

A total of 1067 patients from the prospective cohort study on the incidence and outcome of patients with post stroke depression in China who were diagnosed with first-ever ischemic stroke and attended 4 follow-up visits at 14±2 days, 3 months, 6 months, and 1 year after stroke onset, were enrolled in the study. PSD was diagnosed according to DSM-IV. The course of PSD was divided into the following two categories: persistent/recurrent depression and no/transient depression. Patients with any ischemic lesion responsible for the indexed stroke event located in the frontal lobe were defined as patients with frontal lobe lesions. Modified Rankin Scale (mRS) ≥2 at 1-year was considered to be poor prognosis.

Results

There were 109 patients with and 958 patients without frontal lobe lesions that formed the frontal lobe (FL) and no-frontal lobe (NFL) groups, respectively. After adjusting for confounding variables, frontal lobe lesion was significantly associated with persistent/recurrent PSD (OR 2.025, 95%CI 1.039–3.949). Overall, 32.7% of patients in the FL group had poor prognosis at 1- year compared with 22.7% in the NFL group (P = 0.021). Compared with no/transient depression, persistent/recurrent depression was found to be an independent predictor of poor prognosis at 1-year both in FL and NFL groups.

Conclusions

Long-term and periodical screening, evaluation and treatment are needed for PSD after the onset of ischemic stroke, particularly for patients with frontal lobe infarction.     

Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets

Recent studies suggest that aggregation of platelets from patients with coronary artery and cerebrovascular disease may be resistant to low-dose aspirin (ASA) treatment, which may promote plaque-associated thrombus formation. However, the underlying mechanisms of platelet ASA resistance are poorly understood. ASA is thought to inhibit platelet aggregation primarily by inactivating the cyclooxygenase (COX), thus decreasing the synthesis of the pro-aggregatory arachidonic acid metabolite thromboxane A(2) (TxA(2)). However, recent studies also identified a non-enzymatic, oxidation-dependent pathway for the synthesis of the arachidonic acid derivative isoprostanes, which exhibit potent vasoconstrictor and pro-aggregatory effects similar to that of TxA(2). Because the pathophysiological conditions that promote arteriosclerotic vascular diseases (e.g. hypercholesterolemia, diabetes, hyperhomocysteinemia) are thought to be associated with an increased formation of reactive oxygen species and increased plasma isoprostane levels, it can be hypothesized that increased COX-independent isoprostane formation in platelets contribute to ASA resistance.     

Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice

Hypopituitary Ames dwarf mice have low circulating growth hormone (GH)/IGF-I levels, and they have extended longevity and exhibit many symptoms of delayed aging. To elucidate the vascular consequences of Ames dwarfism we compared endothelial O2(-) and H2O2 production, mitochondrial reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and nitric oxide (NO) production in aortas of Ames dwarf and wild-type control mice. In Ames dwarf aortas endothelial O2(-) and H2O2 production and ROS generation by mitochondria were enhanced compared with those in vessels of wild-type mice. In Ames dwarf aortas there was a less abundant expression of Mn-SOD, Cu,Zn-SOD, glutathione peroxidase (GPx)-1, and endothelial nitric oxide synthase (eNOS). NO production and acetylcholine-induced relaxation were also decreased in aortas of Ames dwarf mice. In cultured wild-type mouse aortas and in human coronary arterial endothelial cells treatment with GH and IGF significantly reduced cellular O2(-) and H2O2 production and ROS generation by mitochondria and upregulated expression of Mn-SOD, Cu,Zn-SOD, GPx-1, and eNOS. Thus GH and IGF-I promote antioxidant phenotypic changes in the endothelial cells, whereas Ames dwarfism leads to vascular oxidative stress.     

ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia

Anthracyclines are potent cytostatic drugs, the correct dosage being critical to avoid possible cardiac side effects. ABCC1 [ATP-binding cassette, sub-family C, member 1; also denoted as MRP1 (multidrug resistance-associated protein 1)] is expressed in the heart and takes part in the detoxification and protection of cells from the toxic effects of xenobiotics, including anthracyclines. Our objective was to search for associations between LV (left ventricular) function and single-nucleotide polymorphisms of the ABCC1 gene in children receiving anthracycline chemotherapy. Data of 235 paediatric patients with acute lymphoblastic leukaemia was analysed. Patients were followed-up by echocardiography (median follow-up 6.3 years). Nine polymorphisms in the ABCC1 gene were genotyped. The ABCC1 rs3743527TT genotype and rs3743527TT–rs246221TC/TT genotype combination were associated with lower LVFS (left ventricular fractional shortening) after chemotherapy. The results suggest that genetic variants in the ABCC1 gene influence anthracycline-induced LV dysfunction.     

Insulin‐like growth factor 1 deficiency exacerbates hypertension‐induced cerebral microhemorrhages in mice,mimicking the aging phenotype

Clinical and experimental studies show that aging exacerbates hypertension‐induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin‐like growth factor 1 (IGF‐1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF‐1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver‐specific knockdown of IGF‐1 (Igf1^f/f + TBG‐Cre‐AAV8) and control mice by angiotensin II plus l ‐NAME treatment. In IGF‐1‐deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress‐mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension‐induced cerebrovascular oxidative stress and MMP activation were increased in IGF‐1‐deficient mice. We found that IGF‐1 deficiency impaired hypertension‐induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF‐1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF‐1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high‐risk elderly patients.     

Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries

Previous studies have shown that the aging vascular system undergoes pro-atherogenic phenotypic changes, including increased oxidative stress and a pro-inflammatory shift in endothelial gene expression profile. To elucidate the link between increased oxidative stress and vascular inflammation in aging, we compared the carotid arteries and aortas of young and aged (24 mo old) Fisher 344 rats. In aged vessels there was an increased NF-kappaB activity (assessed by luciferase reporter gene assay and NF-kappaB binding assay), which was attenuated by scavenging H(2)O(2). Aging did not alter the vascular mRNA and protein expression of p65 and p50 subunits of NF-kappaB. In endothelial cells of aged vessels there was an increased production of H(2)O(2) (assessed by 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence), which was attenuated by the mitochondrial uncoupler FCCP. In young arteries and cultured endothelial cells, antimycin A plus succinate significantly increased FCCP-sensitive mitochondrial H(2)O(2) generation, which was associated with activation of NF-kappaB. In aged vessels inhibition of NF-kappaB (by pyrrolidenedithiocarbamate, resveratrol) significantly attenuated inflammatory gene expression and inhibited monocyte adhesiveness. Thus increased mitochondrial oxidative stress contributes to endothelial NF-kappaB activation, which contributes to the pro-inflammatory phenotypic alterations in the aged vaculature. Our model predicts that by reducing mitochondrial H(2)O(2) production and/or directly inhibiting NF-kappaB novel anti-aging pharmacological treatments (e.g., calorie restriction mimetics) will exert significant anti-inflammatory and vasoprotective effects.