Manisha Tiwari

Neuroprotective role of Convolvulus pluricaulis on aluminium induced neurotoxicity in rat brain

AIM OF THE STUDY Convolvulus pluricaulis (Convolvulaceae) has long been used as traditional herbal medicine in India as nerve tonic. We investigated neuroprotective effects of aqueous extract from Convolvulus pluricaulis (CP) against aluminium chloride induced neurotoxicity in rat cerebral cortex. MATERIAL, METHOD AND RESULT Daily administration of CP (150 mg/kg) for 3 months along with aluminium chloride (50 mg/kg) decreased the elevated enzymatic activity of acetylcholine esterase and also inhibited the decline in Na(+)/K(+)ATPase activity which resulted from aluminium intake. Beside, preventing accumulation of lipid and protein damage, changes in the levels of endogenous antioxidant enzymes associated with aluminium administration were also rectified. Oral administration of CP preserved the mRNA levels of muscarinic receptor 1 (M1 receptor), choline acetyl transferase (ChAT) and Nerve Growth Factor-Tyrosine kinase A receptor (NGF-TrkA). It also ameliorated the upregulated protein expression of cyclin dependent kinase5 (Cdk5) induced by aluminium. The potential of CPE to inhibit aluminium induced toxicity was compared with rivastigmine tartrate (1mg/kg), which was taken as standard. The potential of the extract to prevent aluminium-induced neurotoxicity was also reflected at the microscopic level, indicative of its neuroprotective effects. CONCLUSION Convolvulus pluricaulis possesses neuroprotective potential, thus validating its use in alleviating toxic effects of aluminium.

Inhibitory effect of novel diallyldisulfide analogs on HMG-CoA reductase expression in hypercholesterolemic rats: CREB as a potential upstream target.

AIMS Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihyperlipidemic properties. The present study was designed to evaluate the effect of novel synthesized DADS analogs, on the lipid profile of hypercholesterolemic rats and to investigate the molecular correlates of their activity at the cellular level. MAIN METHODS Wistar rats, weighing 100-120 g each, were administered with 5% cholesterol for one week, and subsequently administered with lovastatin, allicin and DADS (20 mg/kg wt) analogs in the second week along with 5% cholesterol. All animals were sacrificed after overnight starvation. KEY FINDINGS Our results show that DADS analogs are effective in reducing the total lipid levels which could be correlated with a significant decrease in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity. DADS analogs strongly inhibit HMGR activity in vivo but not in vitro. These results can be attributed to the significant decrease in the mRNA levels and protein expression of HMGR. Further, we show that DADS analogs significantly inhibited the activation of sterol regulatory element-binding protein-2 (SREBP-2) and interfered with DNA binding activity of cAMP response element-binding protein (CREB) but not nuclear factor-Y (NF-Y), with upstream regulatory sequences of HMGR. Moreover, DADS analogs are also effective in reducing the levels of oxidized low-density lipoprotein (ox-LDL), lipid peroxidation as well as NF-kappaB activity, showing good anti-inflammatory and antioxidant properties. SIGNIFICANCE The unique anti-inflammatory effect and hypolipidemic action of DADS analogs may be beneficial in preventing the vascular complications that are induced by hyperlipidemia and provide a new therapeutic approach for the treatment of cardiovascular and related diseases.

Thiazole: a promising heterocycle for the development of potent CNS active agents.

Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future.

Hyperhomocysteinemia: Impact on Neurodegenerative Diseases

Neurodegenerative diseases are the diseases of the central nervous system with various aetiology and symptoms. Dementia, Alzheimers disease (AD), Parkinsons disease (PD) and autism are some examples of neurodegenerative diseases. Hyperhomocysteinemia (Hhcy) is considered to be an independent risk factor for numerous pathological conditions under neurodegenerative diseases. Along with genetic factors that are the prime cause of homocysteine (Hcy) imbalance, the nutritional and hormonal factors are also contributing to high Hcy levels in the body. Numerous clinical and epidemiological data confirm the direct correlation of Hcy levels in the body and generation of different types of central nervous system disorders, cardiovascular diseases, cancer and others. Till now, it is difficult to say whether homocysteine is the cause of the disease or whether it is one of the impacts of the diseases. However, Hhcy is a surrogate marker of vitamin B deficiency and is a neurotoxic agent. This Mini Review will give an overview of how far research has gone into understanding the homocysteine imbalance with prognostic, causative and preventive measures in treating neurodegenerative diseases.

Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and Amyloid precursor protein (AβPP) expression in rat brain

Aim: Scopolamine is known to produce amnesia due to blockade of the cholinergic neurotransmission. The present study investigated the potential of Convolvulus pluricaulis (CP) to attenuate scopolamine (2 mg/kg, i.p) induced increased protein and mRNA levels of tau, amyloid precursor protein (AβPP), amyloid β (Aβ) levels and histopathological changes in rat cerebral cortex. Materials and Methods: The study was conducted on male Wistar rats (250 ± 20 g) divided into four groups of eight animals each. Groups 1 and 2 served as controls receiving normal saline and scopolamine for 4 weeks, respectively. Group 3 received rivastigmine (standard) and group 4 received aqueous extract of CP simultaneously with scopolamine. Western blot and RT-PCR analysis were used to evaluate the levels of protein and mRNA of amyloid precursor protein (AβPP) and tau in rat cortex and ELISA was used to measure the amyloid β (Aβ) levels. Histopathology was also performed on cortical section of all groups. Result: Oral administration of CP extract (150 mg/kg) to scopolamine treated rats reduced the increased protein and mRNA levels of tau and AβPP levels followed by reduction in Aβ levels compared with scopolamine treated group. The potential of extract to prevent scopolamine neurotoxicity was reflected at the microscopic level as well, indicative of its neuroprotective effects. Conclusion: CP treatment alleviated neurotoxic effect of scopolamine reflects its potential as potent neuroprotective agent.

Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension.

Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20 mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO(x)) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15 mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME-induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3 μM) and high K(+) (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS.

In vivo investigation of the neuroprotective property of Convolvulus pluricaulis in scopolamine-induced cognitive impairments in Wistar rats

Aim: To investigate the neuroprotective effect of Convolvulus pluricaulis aqueous extract (AE) against scopolamine (1 mg/kg body weight (bwt))-induced neurotoxicity in the cerebral cortex of male Wistar rats. Materials and Methods: The study was carried out on male Wistar rats (age matched, weight 250 ± 20 g). The present study investigated cognitive-enhancing property of AE using Elevated plus maze (EPM) (transfer latency [TL]) and Morris water maze (MWM). Besides evaluating the effect of extract on neurochemical enzymes, in vivo antioxidant and free radical scavenging activities were also screened. All the measured parameters were compared with rivastigmine tartrate (1 mg/kg bwt) which was taken as standard. Results: Pretreatment of rats with AE (150 mg/kg bwt) significantly reduced scopolamine-induced increase in the TL in EPM, whereas in MWM, administration of extract improved the impairment of spatial memory induced by scopolamine. The activity of acetylcholinesterase (AChE) was significantly inhibited by extract within the cortex and hippocampus. Reduced activities or contents of glutathione reductase, superoxide dismutase, and reduced glutathione within the cortex and hippocampus induced by scopolamine were elevated by the extract. Taken together, it could be postulated that extract may exert its potent-enhancing activity through both anti-AChE and antioxidant action. Conclusion: AE possesses neuroprotective potential, thus validating its use in alleviating toxic effects of scopolamine.

Design and synthesis of a novel class of carbonic anhydrase-IX inhibitor 1-(3-(phenyl/4-fluorophenyl)-7-imino-3H-[1,2,3]triazolo[4,5d]pyrimidin 6(7H)yl)urea.

Carbonic anhydrase IX (CAIX) is a promising target in cancer therapy especially in the case of hypoxia-induced tumors. The selective inhibition of CA isozymes is a challenging task in drug design and discovery process. Here, we performed fluorescence-binding studies and inhibition assay combined with molecular docking and molecular dynamics (MD) simulation analyses to determine the binding affinity of two synthesized triazolo-pyrimidine urea derived (TPUI and TPUII) compounds with CAIX and CAII. Fluorescence binding results are showing that molecule TPUI has an excellent binding-affinity for CAIX (kD=0.048μM). The TPUII also exhibits an appreciable binding affinity (kD=7.52μM) for CAIX. TPUI selectively inhibits CAIX as compared to TPUII in the 4-NPA assay. Docking studies show that TPUI is spatially well-fitted in the active site cavity of CAIX, and is involve in H-bond interactions with His94, His96, His119, Thr199 and Thr200. MD simulation studies revealed that TPUI efficiently binds to CAIX and essential active site residual interaction is consistent during the entire simulation of 40ns. These studies suggest that TPUI appeared as novel class of CAIX inhibitor, and may be used as a lead molecule for the development of potent and selective CAIX inhibitor for the hypoxia-induced cancer therapy.

Effect of 1-Oxo-5β, 6β-Epoxy-Witha-2-Ene-27-Ethoxy-Olide Isolated from the Roots of Withania somnifera on Stress Indices in Wistar Rats

OBJECTIVE Isolation of biologically active fractions and compounds from the roots of Withania somnifera, a plant used extensively as a constituent of rasayana, in Ayurveda and to test their adaptogenic activity on stress indices using the cold-hypoxia-restraint (C-H-R) model. DESIGN Bioactivity-guided fractionation of an aqueous extract of the roots of Withania somnifera led to the isolation of a new species of withanolide 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide. Structure elucidation, was carried out using proton nuclear magnetic resonance, infrared (IR), ultraviolet (UV), and mass spectroscopic analysis. Stress-related indices were evaluated, namely serum creatine phosphokinase (CPK) activity, serum lactate dehydrogenase (LDH) activity, serum corticosterone levels, and serum lipid peroxidation (LPO) levels. RESULTS There was a significant decrease in a serum CPK, LDH, and LPO levels in animals pretreated with (1) fraction-I (20 mg/kg body weight), (2) 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (2.5 mg/kg body weight) in comparison to control when subjected to C-H-R stress. CONCLUSIONS The results show that the a new species of withanolide, 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (compound-1) could prove to be an effective agent to counteract C-H-R stress.

Synthesis and pharmacological evaluation of new arylpiperazines N-{4-[4-(aryl) piperazine-1-yl]-phenyl}-amine derivatives: Putative role of 5-HT1A receptors

In an attempt to design novel 5-HT(1A) agonists/partial agonists, based on an arylpiperazine nucleus, a series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives were synthesized and biologically tested. The anxiolytic effect of the compounds was investigated employing the Elevated plus Maze (EPM) task. On the basis of in vivo functional test, compound 1c (3mg/kg) and 4c (3mg/kg) induced significant increments in open arm entries and time on EPM as compared to Buspirone. The anxiolytic effects of compounds 1c and 4c were effectively antagonized by WAY-100635, a 5-HT(1A) receptor antagonist (0.5mg/kg). Furthermore, we have also evaluated the concentration of 5-HT in the brain tissue using HPLC with fluorescent detection. Our result showed that serotonin levels were significantly decreased by approximately 38% (p<0.001) and approximately 32% (p<0.001) after acute administration of compounds 1c and 4c, respectively. These findings suggest that the anxiolytic like activity of these new arylpiperazines is mediated via 5-HT(1A) receptors in the brain.