By Life Extension
Low cerebral blood flow is associated with lower memory function in metabolic syndrome.
BACKGROUND: Metabolic syndrome (MetS)--a cluster of cardiovascular risk factors--is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle-aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed. DESIGN AND METHODS: Late middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention (N = 69, mean age = 60.4 years) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on three or more factors, including abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose. RESULTS: Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF. CONCLUSIONS: The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population.
Obesity (Silver Spring) . 2013 Jul;21(7):1313-20
Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
OBJECTIVE: Cerebral hypoperfusion is common in heart failure (HF) and believed to underlie poor neurocognitive outcomes in this population. Up to 42% of HF patients also exhibit depressive symptomatology that may stem from reduced cerebral blood flow. However, no study has examined this possibility or whether reduced brain perfusion increases risk for future cognitive dysfunction in older adults with HF. METHODS: One hundred HF patients underwent transcranial Doppler ultrasonagraphy to quantify global cerebral blood flow velocity (CBF-V) and were administered a cognitive test battery to assess global cognition, attention/executive function, and memory abilities. All participants then completed the Beck Depression Inventory-II to assess depressive symptomatology. These procedures were performed at baseline and at 12-month follow-up. RESULTS: Repeated measures revealed that CBF-V declined over the 12-month period. Regression analyses showed that reduced baseline CBF-V predicted worse performances in attention/executive function (p < 0.05 for all) and a trend for memory (p = 0.09) in addition to greater depressive symptomatology (p < 0.05) at the 12-month follow-up, even after controlling for baseline factors and medical and demographic variables. CONCLUSIONS: Cerebral perfusion declined over time and was associated with poorer cognitive function and greater depressive symptoms at a 1-year follow-up in HF. Prospective studies with long-term follow-ups that employ neuroimaging are needed to examine whether cognitive dysfunction and depression in HF stem from the adverse effects of cerebral hypoperfusion on the cerebral structure.
Int J Geriatr Psychiatry. 2014 Apr;29(4):428-36
Independent and interactive effects of blood pressure and cardiac function on brain volume and white matter hyperintensities in heart failure.
BACKGROUND: Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated. METHODS: Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging
to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume. RESULTS: Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (P < .01), and higher systolic blood pressure predicted reduced total gray matter volume (P = .03). The combination of higher blood pressure and lower cardiac index exacerbated WMH (P = .048). CONCLUSIONS: Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume, and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations.
J Am Soc Hypertens. 2013 Sep-Oct;7(5):336-43
Inhibitory effects of vinpocetine on the progression of atherosclerosis are mediated by Akt/NF-kB dependent mechanisms in apoE-/- mice.
BACKGROUND: Recent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE(-/-) mice and explore the underlying anti-atherogenic mechanisms in macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Vinpocetine markedly decreased atherosclerotic lesion size in apoE(-/-) mice measured by oil red O. Masson’s trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-a, IL-6, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 expression induced by ox-LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKa/b, IkBa phosphorylation and NF-kB activity induced by ox-LDL, and the inhibition of NF-kB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKa/b and IkBa phosphorylation. CONCLUSIONS: These results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-kB dependent pathway but independent of PDE1 blockade in macrophages.
PLoS One. 2013 Dec 9;8(12):e82509
Vinpocetine attenuates neointimal hyperplasia in diabetic rat carotid arteries after balloon injury.
BACKGROUND: Diabetes exacerbates abnormal vascular smooth muscle cell (VSMC) accumulation in response to arterial wall injury. Vinpocetine has been shown to improve vascular remolding; however, little is known about the direct effects of vinpocetine on vascular complications mediated by diabetes. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism. MATERIALS AND METHODS: Nondiabetic and diabetic rats were subjected to balloon injury of the carotid artery followed by 3-week treatment with either vinpocetine (10 mg/kg/day) or saline. Morphological analysis and proliferating cell nuclear antigen (PCNA) immunostaining were performed on day 21. Rat VSMCs proliferation was determined with 5-ethynyl-20-deoxyuridine cell proliferation assays. Chemokinesis was monitored with scratch assays, and production of reactive oxygen species (ROS) was assessed using a 2’,7’-dichlorodihydrofluorescein diacetate (H2DCFDA) flow cytometric assay. Apoptosis was detected by annexin V-FITC/PI flow cytometric assay. Cell signaling was assessed by immunblotting. RESULTS: Vinpocetine prevented intimal hyperplasia in carotid arteries in both normal (I/M ratio: 93.83 ± 26.45% versus 143.2 ± 38.18%, P<0.05) and diabetic animals (I/M ratio: 120.5 ± 42.55% versus 233.46 ± 33.98%, P<0.05) when compared to saline. The in vitro study demonstrated that vinpocetine significantly inhibited VSMCs proliferation and chemokinesis as well as ROS generation and apoptotic resistance, which was induced by high glucose (HG) treatment. Vinpocetine significantly abolished HG-induced phosphorylation of Akt and JNK1/2 without affecting their total levels. For downstream targets, HG-induced phosphorylation of IkBa was significantly inhibited by vinpocetine. Vinpocetine also attenuated HG-enhanced expression of PCNA, cyclin D1 and Bcl-2. CONCLUSIONS: Vinpocetine attenuated neointimal formation in diabetic rats and inhibited HG-induced VSMCs proliferation, chemokinesis and apoptotic resistance by preventing ROS activation and affecting MAPK, PI3K/Akt, and NF-kB signaling.
PLoS One . 2014 May 12;9(5):e96894
Vinpocetine attenuates lipid accumulation and atherosclerosis formation.
Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partiallythrough suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.
Biochem Biophys Res Commun. 2013 May 10;434(3):439-43
Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats.
OBJECTIVE: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. MATERIALS AND METHODS: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-a (TNF-a) were assayed. Histopathological study of the substantia nigra was also done. RESULTS: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-a increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed inthe rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P<0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-a production was found to be significantly decreased in PIR group (P<0.05). CONCLUSION: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson’s disease.
Indian J Pharmacol. 2012 Nov-Dec;44(6):774-9.
Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE- independent mechanism.
Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9795-800