Sadagopan Thanikachalam

Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats.

Hypertension (HT) is a prevailing risk factor for cognitive impairment, the most common cause of vascular dementia; yet, no possible mechanism underlying the cognitive impairment induced by hypertension has been identified so far. Inhibition of PDE-4 has been shown to increase phosphorylation of cAMP-response element binding protein in the hippocampus and enhance the memory performance. Here, we examined the effects of PDE-4 inhibitors, rolipram and roflumilast, on the impairment of learning and memory observed in hypertensive rats. We used 2k-1c hypertensive model to induce learning and memory defects. In addition, mRNA expression of PDE-4 sub-types A-D was also assessed in the hippocampus tissue. Systolic blood pressure (SBP) was measured by tail-cuff method was significantly increased in 2k-1c rats when compared to sham operated rats; this effect was reversed by clonidine, whereas, PDE-4 inhibitors did not. PDE-4 inhibitors significantly reversed time induced memory deficit in novel object recognition task (NORT). Further, the retention latency on the second day in the elevated plus maze model was significantly shortened after repeated administration of rolipram and roflumilast. Plasma and brain concentrations of rolipram, roflumilast and roflumilast N-oxide were also measured after the NORT and showed linear increase in plasma and brain concentrations. The PDE4B and PDE4D gene expression was significantly enhanced in hypertensive rats compared with sham operated however PDE4A and PDE4C remained unaltered. Repeated treatment with PDE-4 inhibitors caused down regulation of PDE4B and PDE4D in hypertensive rats. These results suggest that inhibition of PDE-4 ameliorates HT-induced impairment of learning and memory functions.

Cuminum cyminum, a Dietary Spice, Attenuates Hypertension via Endothelial Nitric Oxide Synthase and NO Pathway in Renovascular Hypertensive Rats

Cuminum cyminum (CC) is a commonly used spice in South Indian foods. It has been traditionally used for the treatment and management of sleep disorders, indigestion, and hypertension. The present study was carried out to scientifically evaluate the anti-hypertensive potential of standardized aqueous extract of CC seeds and its role in arterial endothelial nitric oxide synthase expression, inflammation, and oxidative stress in renal hypertensive rats. Renal hypertension was induced by the two-kidney one-clip (2K/1C) method in rats. Systolic blood pressure (SBP), plasma nitrate/nitrite, carotid–eNOS, renal–TNF-α, IL-6, Bax, Bcl-2, thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1) mRNA expressions were studied to demonstrate the anti-hypertensive action of CC. Cuminum cyminum was administered orally (200 mg/kg b.wt) for a period of 9 weeks; it improved plasma nitric oxide and decreased the systolic blood pressure in hypertensive rats. It also up-regulated the gene expression of eNOS, Bcl-2, TRX1, and TRXR1; and down-regulated Bax, TNF-α, and IL-6. These data reveal that CC seeds augment endothelial functions and ameliorate inflammatory and oxidative stress in hypertensive rats. The present report is the first of its kind to demonstrate the mechanism of anti-hypertensive action of CC seeds in an animal model of renovascular hypertension.

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

Phosphodiesterase-4 (PDE-4) inhibitors promote memory by blocking the degradation of cAMP. Existing evidence also shows that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response element-binding protein. In this regard, PDE-4 inhibitors have also been shown to reverse pharmacologically and genetically induced memory impairment in animal models. In the present study, the authors examined the effect of both rolipram and roflumilast (PDE-4 inhibitors) on the impairment of learning and memory observed in hypertensive rats. Deoxycorticosterone acetate (DOCA) salt hypertensive model was used to induce learning and memory deficits. The mRNA expression of different PDE-4 subtypes along with the protein levels of pCREB and BDNF in the hippocampus was quantified. Systolic blood pressure was significantly increased in DOCA salt hypertensive rats when compared to sham operated rats. This effect was reversed by clonidine, an α2 receptor agonist, while PDE-4 inhibitors did not. PDE-4 inhibitors significantly improved the time-induced memory deficits in object recognition task (ORT). In DOCA salt hypertensive rats, the gene expression of PDE-4B and PDE-4D was significantly increased. Furthermore, both pCREB and BDNF showed decreased levels of expression in hypertensive rats in comparison to sham operated rats. Repeated administration of PDE-4 inhibitors significantly decreased both PDE-4B and PDE-4D with an increase in the expression of pCREB and BDNF in hypersensitive rats. Also, rolipram, roflumilast and roflumilast N-oxide showed a linear increase in the plasma and brain concentrations after ORT. Our present findings suggested that PDE-4 inhibitors ameliorate hypertension-induced learning impairment via cAMP/CREB signaling that regulates BDNF expression downstream in the rat hippocampus.

Sodium Intake, Blood Pressure, and Dietary Sources of Sodium in an Adult South Indian Population

BACKGROUND The association between prevalence of hypertension and its relationship with dietary sodium intake has never been published from large epidemiological studies in the South Indian population before. OBJECTIVES To assess sodium intake and its association with blood pressure, and major dietary sources of sodium in an adult population in southeastern India. METHODS This study included a representative population-based sample of 8080 individuals (57% women) >20 years of age. Individuals with previous history of hypertension and outliers for sodium intake were excluded, resulting in a sample size of 6876, with 4269 from semi-urban/urban and 2607 from rural areas. Baseline measurements included evaluation of systolic (SBP) and diastolic (DBP) blood pressures, anthropometric, sociodemographic, and psychosocial parameters. Based on 24-hour recall, we calculated total daily sodium intake and the percentage contributed by each food group to the total sodium intake. Participants were assigned based on quintiles of dietary sodium intake. Mixed-effects multivariable linear regression models assessed the association of SBP and DBP with sodium intake. FINDINGS Men had higher mean sodium intake (4.1 ± 2 versus 3.2 ± 1.7 g/day; P < 0.01) with higher mean SBP and DBP (123/77 versus 117/74 mm Hg; P < 0.01), and higher prevalence of hypertension (22.2% versus 12.9%; P < 0.01) compared with women. Mean dietary sodium intake was significantly higher in the hypertensive men (4.2 ± 2 g/day) and women (3.2 ± 1.7 g/day) compared with normotensive men (4 ± 2 g/day), and women (3.2 ± 1.7 g/day; P < 0.05). Significant (P < 0.01) increases in SBP and DBP were evident in men, but not women with increasing quintile of sodium intake. After multivariable adjustments, sodium intake was independently associated with SBP, but not DBP, in both sexes. The predominant source of dietary sodium in both semi-urban/urban and rural populations was from homemade foods where salt is part of the traditional recipe. CONCLUSION In a South Indian population, the dietary intake of sodium was higher than recommendations by major dietary guidelines and was an independent predictor of SBP.

Population Study of Urban, Rural, and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study Rationale, Study Design, and Baseline Characteristics of PURSE-HIS

We designed and implemented the PURSE-HIS (Population Study of Urban, Rural and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study) to understand the prevalence and progression of subclinical and overt endovascular disease (EVD) and its risk factors in urban, semiurban, and rural communities in South India. The study is also designed to generate clinical evidence for effective, affordable, and sustainable community-specific intervention strategies to control risks factors for EVD. As of June 2012, 8,080 (urban: 2,221; semiurban: 2,821; rural: 3,038) participants >20 years of age were recruited using 2-stage cluster sampling. Baseline measurements included standard cardiovascular disease risk factors, sociodemographic factors, lifestyle habits, psychosocial factors, and nutritional assessment. Fasting blood samples were assayed for putative biochemical risk factors and urine samples for microalbuminuria. All nondiabetic participants underwent oral glucose tolerance test with blood and urine samples collected every 30 min for 2 h. Additional baseline measurements included flow-mediated brachial artery endothelial vasodilation, assessment of carotid intimal medial wall thickness using ultrasonography, screening for peripheral vascular disease using ankle and brachial blood pressures, hemodynamic screening using a high-fidelity applanation tonometry to measure central blood pressure parameters, and aortic pulse wave velocity. To assess prevalence of coronary artery disease, all participants underwent surface electrocardiography and documentation of ventricular wall motion abnormality and function using echocardiography imaging. To detect subclinical lesions, all eligible participants completed an exercise treadmill test. Prospectively, the study will assess progression of subclinical and overt EVD, including risk factor-outcome relation differences across communities. The study will also evaluate community-specific EVD prevention using traditional Indian system of medicine versus recognized allopathic (mainstream) systems of medicine.

Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

BackgroundNuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats.MethodsAcute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed.ResultsIn acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment.ConclusionAcute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions.

Polyphenols in madhumega chooranam, a Siddha medicine, ameliorates carbohydrate metabolism and oxidative stress in type II diabetic rats

ETHNOPHARMACOLOGICAL RELEVANCE Present study was undertaken to demonstrate the mode of anti-diabetic action of a polyherbal Siddha Medicine, Madhumega chooranam (MMC). MATERIALS AND METHODS MMC was fractionated into phenolic (PMMC) and non-phenolic (NPMMC) portions in order to identify bioactive fraction. Study was performed in type II diabetic rats. Role of PMMC and NPMMC on liver glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucokinase and glycogen content were determined. Their role on superoxide dismutase, reduced glutathione and lipid peroxidation were investigated. In addition, their effects on GLUT4 and PPARγ gene expression were studied. Pancreas and liver histopathology was studied using hematoxylin and eosin stain. RESULTS PMMC improved carbohydrate metabolism by decreasing glucose-6-phosphatase and fructose-1,6-bisphosphatase and increasing glucokinase and glycogen contents in diabetic rats liver. It alleviated oxidative stress by increasing superoxide dismutase, glutathione and decreasing lipid peroxidation content. PMMC up-regulated liver GLUT4 and PPARγ mRNA expression in comparison to the vehicle or NPMMC rats. CONCLUSION Madhumega chooranam mediates its anti-diabetic action through the inhibition of gluconeogenesis and activation of glycolytic pathways in type II diabetic rats. Increased GLUT4 and PPARγ expressions provide additional information on its glucose uptake/sensitising and hypolipidemic potential. Phenolic components of MMC were found to be the bioactive principles.

Venthamarai chooranam, a polyherbal Siddha medicine, alleviates hypertension via AT1R and eNOS signaling pathway in 2K1C hypertensive rats

The present study was aimed to scientifically demonstrate the anti-hypertensive action of Venthamarai chooranam (VMC) in renal hypertensive rats. Two Kidney One Clip (2K1C) Goldblatt model was adopted to induce hypertension in rats. Male Sprague Dawley rats (270–320 g) were randomized into sham (n = 6), vehicle-treated 2K1C (n = 9) and VMC-treated 2K1C (400 mg/kg, p.o; n = 8) and monitored for nine weeks. Systolic blood pressure (SBP), plasma nitrate/nitrite, carotid endothelial nitric oxide synthetase (eNOS), renal angiotensin type 1 receptor (AT1R), angiotensin type 2 receptor (AT2R), TNFα, IL-6, thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1) mRNA expressions were studied. VMC upregulated eNOS expression which in turn improved plasma nitric oxide and decreased SBP in hypertensive rats. It down-regulated AT1R and simultaneously upregulated AT2R expression in comparison to vehicle-treated 2K1C rats. Further, renal TNFα and IL-6 expressions were down-regulated while TRX1 and TRXR1 were upregulated by VMC. VMC potentially interacts with renin-angiotensin components and endothelial functions, and thereby exerts its antihypertensive action. This is the first study to demonstrate the mechanism of anti-hypertensive action of VMC in an animal model of renovascular hypertension.

Urbanization as a risk factor for aortic stiffness in a cohort in India

Urbanization is associated with higher prevalence of cardiovascular disease worldwide. Aortic stiffness, as measured by carotid-femoral pulse wave velocity is a validated predictor of cardiovascular disease. Our objective was to determine the association between urbanization and carotid-femoral pulse wave velocity. The analysis included 6166 participants enrolled in an ongoing population-based study (mean age 42 years; 58% female) who live in an 80 × 80 km region of southern India. Multiple measures of urbanization were used and compared: 1) census designations, 2) satellite derived land cover (crops, grass, shrubs or trees as rural; built-up areas as urban), and 3) distance categories based on proximity to an urban center. The association between urbanization and carotid-femoral pulse wave velocity was tested in sex-stratified linear regression models. People residing in urban areas had significantly (p < 0.05) elevated mean carotid-femoral pulse wave velocity compared to non-urban populations after adjustment for other risk factors. There was also an inverse association between distance from the urban center and mean carotid-femoral pulse wave velocity: each 10 km increase in distance was associated with a decrease in mean carotid-femoral pulse wave velocity of 0.07 m/s (95% CI: -0.09, -0.06 m/s). The association was stronger among older participants, among smokers, and among those with other cardiovascular risk factors. Further research is needed to determine which components in the urban environment are associated with higher carotid-femoral pulse wave velocity.

Mexican American and South Asian population-based cohorts reveal high prevalence of type 2 diabetes and crucial differences in metabolic phenotypes

Objective Prevalence of type 2 diabetes varies by region and ancestry. However, most guidelines for the prevention of diabetes mellitus (DM) are based on European or non-Hispanic white populations. Two ethnic minority populations—Mexican Americans (MAs) in Texas, USA, and South Indians (SIs) in Tamil Nadu, India—have an increasing prevalence of DM. We aimed to understand the metabolic correlates of DM in these populations to improve risk stratification and DM prevention. Research design and methods The Cameron County Hispanic Cohort (CCHC; n=3023) served as the MA sample, and the Population Study of Urban, Rural, and Semi-Urban Regions for the Detection of Endovascular Disease (PURSE; n=8080) served as the SI sample. Using design-based methods, we calculated the prevalence of DM and metabolic comorbidities in each cohort. We determined the association of DM with metabolic phenotypes to evaluate the relative contributions of obesity and metabolic health to the prevalence of DM. Results In the CCHC (overall DM prevalence 26.2%), good metabolic health was associated with lower prevalence of DM, across age groups, regardless of obesity. In PURSE (overall prevalence 27.6%), probability of DM was not strongly associated with metabolic phenotypes, although DM prevalence was high in older age groups irrespective of metabolic health. Conclusion Our study provides robust, population-based data to estimate the prevalence of DM and its associations with metabolic health. Our results demonstrate differences in metabolic phenotypes in DM, which should inform DM prevention guidelines in non-European populations.