Sekar Sathiya

Total oligomeric flavonoids of Cyperus rotundus ameliorates neurological deficits, excitotoxicity and behavioral alterations induced by cerebral ischemic-reperfusion injury in rats.

Interactions between neurons and astrocytes play a critical role in the central nervous system homeostasis. Cyperus rotundus (family: Cyperaceae), a traditional Indian medicinal herb, used as nervine tonic and nootropic in the Ayurvedic system of medicine. The present study was undertaken to investigate the neuroprotective effect of total oligomeric flavonoids (TOFs), prepared from C. rotundus, in rat model of cerebral ischemia and reperfusion. Male Sprague Dawley rats (290-340g) were subjected to middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 70h. Experimental animals were divided into four groups: Group I - sham operated (n=7); Group II - vehicle treated ischemic-reperfusion (IR) (n=9), and Group III and IV - TOFs treated (100 and 200mg/kg body weight, p.o., respectively; n=7 in each group). Vehicle or TOFs were pretreated for four days before the induction of ischemia and continued for next three days after the ischemia i.e. treatment was scheduled totally for a period of 7 days. MCAO surgery was performed on day 4, 1h after TOFs administration. Neuroprotective effect of TOFs was substantiated in terms of neurological deficits, excitotoxicity (glutamate, glutamine synthetase and Na(+)K(+)ATPase levels), oxidative stress (malondialdehyde, super oxide dismutase, and glutathione) and neurobehavioral functions in the experimental animals. TOFs decreased glutamate, glutamine synthetase (GS) and increased Na(+)K(+)ATPase activity in a dose dependent manner when compared to the IR rats. Treatment with TOFs significantly reduced the neurological deficits and reversed the anxiogenic behavior in rats. Further, it also significantly decreased MDA and increased superoxide dismutase (SOD) and glutathione content in brains of experimental rats. Histopathological examination using cresyl violet staining revealed the attenuation of neuronal loss by TOFs in stroke rats. The present study demonstrates the unswerving involvement of TOFs on ischemia-reperfusion triggered biochemical alterations in MCAO/R rats. Hence, TOFs might be an attractive candidate for further studies in the development of new drugs for cerebral stroke treatment.

Telmisartan attenuates MPTP induced dopaminergic degeneration and motor dysfunction through regulation of α-synuclein and neurotrophic factors (BDNF and GDNF) expression in C57BL/6J mice

Telmisartan (TEL), an angiotensin type 1 receptor (AT1R) antagonist, has been reported to exert neuroprotective effect in animal models of Parkinsons disease (PD). However, its effect on motor functions, mutant protein α-synuclein (SYN) and neurotrophic factors (BDNF and GDNF) expression and their interrelation in PD has not yet been elucidated. In the present study, the effect of TEL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced motor dysfunctions and dopaminergic degeneration was ascertained through investigating the alterations in protein expression of dopamine transporter (DAT), tyrosine hydroxylase (TH) and SYN in C57BL/6J mouse. Further, the role of TEL on the gene expression of neurotrophic factors such as BDNF and GDNF and protein expression of vesicular monoamine transporter 2 (VMAT2) and Glial fibrillary acidic proteins (GFAP) were studied. In TEL treated mouse, strong negative correlation was observed between motor function and SYN, while a strong positive correlation was noted with BDNF and GDNF expression. TEL caused down-regulation of SYN, GFAP and up-regulation of DAT, TH, VAMT2, BDNF and GDNF expressions. Present data suggest that brain renin angiotensin system (RAS) plays a crucial role in motor function and in the regulation of key proteins such as SYN, BDNF and GDNF, DAT, TH, VMAT2 and GFAP in Parkinsonism. In conclusion, the present study shows that angiotensin type 1 receptor antagonists can ameliorate motor dysfunction and act as potential neuroprotective agent in the management of Parkinsonism.

Memantine exerts functional recovery by improving BDNF and GDNF expression in 3-nitropropionic acid intoxicated mice.

Memantine (MN), a NMDA blocker is well known for its protective effect against various neurodegenerative diseases. However, its role in improving motor function and regulation of neurotrophic factors in Huntingtons disease (HD) has not been studied yet. In the present study, we have investigated the effect of MN against 3-nitropropionic acid (3NP), induced motor impairment, and alterations in the expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in mice brain. Further, its role in mitochondrial function was assessed by measuring succinate dehydrogenase (SDH) activity. Glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) immunoreactivity were studied to evaluate the role of MN on glial and neuronal function. Its effect on apoptosis was adjudged by studying the expression of apoptotic markers. MN restored motor functions with an associated up-regulation in neurotrophin expression. MN also enhanced brain SDH activity and decreased glutamate content. MN ameliorated striatal neuronal loss, reduced GFAP immunoreactivity, and exhibited protective effect against neuronal apoptosis. Data from the current study demonstrated that MN exerted neuroprotective effect against 3NP induced neuropathology. Restoration of motor function by MN might be through regulation of neurotrophin expression. MN can therefore be a useful therapeutic choice in the symptomatic management of HD.

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.

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.

Prenatal Exposure to Lamotrigine: Effects on Postnatal Development and Behaviour in Rat Offspring

Use of antiepileptic drugs (AEDs) in pregnancy warrants various side effects and also deleterious effects on fetal development. The present study was carried out to assess the effects of prenatal exposure to lamotrigine (LTG) on postnatal development and behavioural alterations of offspring. Adult male and female Sprague Dawley rats weighing 150–180 g b. wt. were allowed to copulate and pregnancy was confirmed by vaginal cytology. Pregnant rats were treated with LTG (11.5, 23, and 46 mg/kg, p.o) from gestational day 3 (GND 3) and this treatment continued till postnatal day 11 (PND 11). Offspring were separated from their dam on day 21 following parturition. LTG, at 46 mg/kg, p.o, produced severe clinical signs of toxicity leading to death of dam between GND 15 and 17. LTG, at 11.5 and 23 mg/kg, p.o, showed significant alterations in offsprings incisors eruption and vaginal opening when compared to age matched controls. LTG (23 mg/kg, p.o) exposed female offspring expressed hyperactive behaviour and decreased GABA-A receptor expression when compared to control rats. These results reveal that prenatal exposure to LTG may impart differential postnatal behavioural alterations between male and female rats which paves way for further investigations.

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.

Inhibition of PKCβ Mediates Cardioprotective Activity of Ambrex against Isoproterenol-Induced Myocardial Necrosis: in vivo and in silico Studies

Aims and objectives: The current study characterized the morphology of Ambrex formulation by Scanning Electron Microscopy and assessed its cardioprotective activity against Isoproterenol (ISPH)-induced myocardial necrosis in rats by biochemical and histopathological evaluations, and also attempted to predict the prospective protein-targets of Ambrex and the signaling pathway that mediates this activity through molecular docking approach. Materials and methods: Sprague–Dawley male rats (4 groups, 6 rats per group) chosen for the current study were acclimatized to the laboratory conditions for 7 days prior to actual treatment; they were pretreated with Ambrex (40 mg/kg b.wt/day, p.o) everday for 21 days and then intoxicated with ISPH (85 mg/kg b.wt, s.c) on day-20 and 21 to experimentally induce myocardial necrosis. The extent of ISPH-induced myocardial necrosis was quantified in terms of the serum levels of two cardiac biomarkers: creatine kinase-MB and lactate dehydrogenase. The extent of ISPH-induced oxidative stress was quantified in terms of the tissue levels of five oxidative stress biomarkers: superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and lipid peroxidation. Results and discussion: The Scanning Electron Microscopy image of Ambrex formulation showed the formation of nanoparticles with thickness of 65 nm, making Ambrex a unique metal-deficient Siddha-medicine based polyherbal nano-formulation characterized and evaluated in India. Pretreatment with Ambrex attenuated the extent of ISPH-induced oxidative stress, lipid peroxidation and generation of reactive oxygen species as reflected by biochemical evaluations, and also ameliorated the degree of ISPH-induced myocardial necrosis and membrane damage as reflected by histopathological evaluations. The results of molecular docking revealed that Withaferin-A and Methyl Commate-A (the key metabolites of Withania somnifera and Ambrex respectively) inhibit Protein KinaseC Beta, and renders Ambrex its cardioprotective activity by maintaining the intracellular antioxidant homeostasis and myocardial membrane architecture.

Efficacy of Dipeptide-Coated Magnetic Nanoparticles in Lung Cancer Models Under Pulsed Electromagnetic Field

ABSTRACT Lung cancer is the leading cause of cancer deaths and the overall 5-year survival rate is less than 17%. Hyperthermia is an alternative approach for the treatment of lung cancer and is associated with fewer side effects. We employed ironoxide nanoparticles in inducing localized hyperthermia in lung cancer cells using a pulsed electromagnetic field (PEMF). We synthesized, characterized and determined the uptake of dipeptide-coated iron oxide nanoparticles. Further, their ability in inducing localized hyperthermia in PEMF on lung cancer cells was assessed. Results showed nanoparticles are non-cytotoxic and showed enhanced cellular uptake in lung cancer cells. In vivo studies in nude mice lung tumor xenografts confirmed the presence in the tumors. Lung cancer cells pretreated with dipeptide-coated magnetic nanoparticles upon PEMF exposure induced cell death.