Nandakumar Krishnadas

Impact of caffeic acid on aluminium chloride-induced dementia in rats

Literature favours the in vitro neuroprotective role of caffeic acid, a naturally derived polyphenolic compound. This study was aimed to investigate the role of caffeic acid in experimental model of Alzheimers disease.

Antioxidant and antimutagenic activities of bark extract of Terminalia arjuna

Abstract Objective The alcoholic extract of stem bark of Terminalia arjuna (ALTA) was screened for antioxidant and antimutagenic (anticlastogenic) activity. Methods Antioxidant property was determined by 1, 1, Diphyny l, 2-Picryl hydrazyl (DPPH) assay, super oxide radical scavenging activity, lipid peroxidation assay and total polyphenolic content was determined by Folin-Ciocalteaus reagent. Antimutagenic activity was evaluated using micronucleus test in mice. Results The ALTA has shown potent antioxidant activity with EC 50 of 2.491±0.160, 50.110±0.150 & 71.000±0.250 in DPPH assay, superoxide radical scavenging activity and lipid peroxidation assay, which is comparable with ascorbic acid with EC 50 of 2.471±0.140, 40.500±0.390 and 63.000±0.360 respectively. In micronucleus test, ALTA (100 & 200mg/kg, p.o.) showed significant reduction in percentage of micronucleus in both polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) and also shown significant reduction in P/N ratio. Conclusions These results suggested that ALTA possess significant antioxidant and antimutagenic activity.

Rutin protects against neuronal damage in vitro and ameliorates doxorubicin-induced memory deficits in vivo in Wistar rats

Doxorubicin (DOX) is the most widely used broad-spectrum anticancer agent, either alone or in combination, for most cancers including breast cancer. Long-term use of chemotherapeutic agents to treat breast cancer patients results in cognitive complications with a negative impact on survivors’ quality of life. The study objective was to evaluate rutin (RUT) for its neuroprotective effect against DOX in human neuroblastoma (IMR32) cells in vitro and study its potential to ameliorate DOX-induced cognitive dysfunction in Wistar rats. Cell viability assay (3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neurite growth assay, detection of apoptosis by (acridine orange/ethidium bromide) staining, intracellular reactive oxygen species (ROS) assay, and flowcytometric analysis were carried out to assess neuroprotective potential against DOX. An in vivo study was conducted for assessing protective effect of RUT against memory deficit associated with DOX-induced chemobrain using object recognition task (ORT). Locomotion was assessed using open field test. Serum biochemistry, acetylcholinesterase, oxidative stress markers in hippocampus, and frontal cortex were assessed. Histopathological analysis of major organ systems was also carried out. Prior exposure to RUT at 100 µM protected IMR32 cells from DOX (1 µM) neurotoxicity. DOX exposure resulted in increased cellular death, apoptosis, and intracellular ROS generation with inhibition of neurite growth in differentiated IMR32 cells, which was significantly ameliorated by RUT. Cognitive dysfunction was induced in Wistar rats by administering ten cycles of DOX (2.5 mg/kg, intra-peritoneal, once in 5 days), as we observed significant impairment of episodic memory in ORT. Coadministration with RUT (50 mg/kg, per os) significantly prevented memory deficits in vivo without any confounding influence on locomotor activity. RUT also offered protection against DOX-induced myelosuppression, cardiotoxicity, and nephrotoxicity. In conclusion, RUT may be a possible adjuvant therapeutic intervention to alleviate cognitive and other complications associated with DOX chemotherapy.

Antidiarrheal effect of fractions from stem bark of Thespesia populnea in rodents: Possible antimotility and antisecretory mechanisms.

OBJECTIVE To evaluate antidiarrheal activity of the fractions of aqueous extract from stem barks of Thespesia populnea (Malvaceae). METHODS From the aqueous extract three fractions namely ethyl acetate fraction (EAF), methanolic fraction (MF) and residue fraction (RF) were made and studied for antidiarrheal activity. Antidiarrheal activity of the fractions were evaluated in castor oil induced diarrhea, prostaglandin E(2) (PG-E(2)) induced diarrhea and charcoal meal test as in vivo models and the most potent fraction was further evaluated with in vitro models to determine the possible antimotility effect. RESULTS In castor oil induced diarrhea model, the RF (10, 25, 50 and 100 mg/kg, po.) and MF (100 mg/kg, po.) has significantly reduced the cumulative wet faecal mass, where as the EAF have not shown any significant antidiarrheal activity, RF was found to be more potent than MF. Based on these results and percentage yield, only RF was evaluated in PG-E(2) induced enteropooling and charcoal meal test. RF (10, 25 and 50 mg/kg) had shown significant inhibition of PG-E(2) induced secretions (antisecretory) and decreased the movement of charcoal in charcoal meal test indicating its antimotility activity. Furthermore, RF has showed significant inhibition of acetylcholine, histamine and BaCl(2) induced contractions on rat colon, guinea pig ileum and rabbit jejunum with EC(50) values of 241.7, 303.1 and 286.1 μg/mL, respectively indicating the antimotility effect of RF. The phytochemical analysis of RF showed presence of gums and mucilages and the possible mechanism may be the combination inhibition of elevated prostaglandin biosynthesis and reduced propulsive movement of the intestine. CONCLUSIONS RF possesses good antidiarrheal activity comparing with other two fractions and the possible mechanism thought to be associated with combination of antisecretory and antimolity.

Anti-urolithiatic activity of heart wood extract of Cedrus deodara in rats.

The petroleum ether extract of the heart wood of Cedrus deodara (PECD) was tested for its diuretic and anti-urolithiatic activity. The urolithiasis was experimentally induced by administering sodium oxalate (70 mg/kg, i.p) for 10 days. PECD (100 and 200 mg/kg) was orally gavaged daily 1 h before sodium oxalate (NaOx) administration for 10 days. In NaOx treated rats, crystal was observed in urine under light microscope and elevation of serum parameters indicated the development of nephrolithiasis in the control group. Concomitant administration of PECD for 10 days along with NaOx prevented elevated serum biochemical levels due to the elimination of these in urine. Histology of the kidneys also indicated that PECD treatment had protected against NaOx induced nephroliathiasis. These results obtained, confirmed the beneficiary effect of Cedrus deodara in urolithiasis.

Effect of insulin on spatial memory in aluminum chloride-induced dementia in rats

Latest reports suggest the involvement of insulin in modulating memory. A few published in-vitro studies favor the antidementia effect of insulin. Thus, the present study aimed to evaluate the prophylactic role of insulin and its combination with glucose and its possible mechanism(s) in an aluminum chloride (AlCl3)-induced cognitive dysfunction model in rodents, with a special focus on memory centers namely, the hippocampus and the frontal cortex. Male Wistar rats were exposed to AlCl3 (175 mg/kg orally) for 60 days. Insulin (0.5 IU/kg), Insulin (0.5 IU/kg) in combination with glucose (200 mg/kg), and rivastigmine (1 mg/kg) were administered intraperitoneally 45 min before the administration of AlCl3 for 60 days. Spatial memory was assessed using the Morris water-maze test. After 60 days of treatment, animals were killed, and the hippocampus and frontal cortex were collected and analyzed for acetylcholinesterase activity and antioxidant enzyme level. Blood glucose levels were also analyzed. Treatment with the standard drug, rivastigmine (1 mg/kg), produced a significant reduction in escape latency and increased the time spent in the target quadrant compared with the AlCl3-treated group. Insulin and its combination with glucose could not inhibit the behavioral impairments in aluminum-exposed rats. Treatment with insulin alone and its combination with glucose reversed the increased glucose levels. Insulin alone and its combination with glucose could not inhibit aluminum-induced oxidative stress and impaired cholinergic transmission in the hippocampus and frontal cortex regions. The study suggests the inability of prophylactic insulin administration against cognitive dysfunction induced by environmental toxin (AlCl3) in the hippocampus and the frontal cortex.

Insulin Combined with Glucose Improves Spatial Learning and Memory in Aluminum Chloride−Induced Dementia in Rats

Therapeutic intervention using drugs against Alzheimer disease is curative clinically. At present, there are no reports on the curative role of insulin in chronic models of dementia. We evaluated the curative role of insulin and its combination with glucose in dementia. We also investigated the impact of treatments on blood glucose to correlate with cognitive deficit. Further, we analyzed the interaction of treatments with the cholinergic system and oxidative stress in memory centers (i.e., hippocampus and frontal cortex). The antidementia activity of insulin was assessed against aluminum chloride (AlCl3)-induced dementia in rats. Behavioral parameters (Morris water maze test) along with biochemical parameters (Hippocampus and frontal cortex) such as acetylcholinesterase (AChE), catalase, and glutathione (GSH) levels were assessed to correlate cognitive function with cholinergic transmission and oxidative stress. Rats administered insulin and glucose showed improved cognitive function in the Morris water maze test. The combination corrected the diminished level of antioxidant enzymes such as catalase and GSH in the hippocampus and frontal cortex.Combined administration of insulin and glucose to aluminum-treated rats did not inhibit the aluminum action on the acetylcholinesterase enzyme. No significant changes were observed in blood glucose levels between the treatment groups.

Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders

ABSTRACT Introduction: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists. Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders. Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.

Endothelium Dependent and Independent Mechanisms of Vasorelaxant Activity of Synthesized 2,5-disubstituted-1,3,4-oxadiazole Derivatives in Rat Thoracic Aorta – Ex vivo and Molecular Docking Studies

Background: Vasoconstriction is a major pathological feature of cardiovascular diseases involving endothelium dependent and independent mechanisms. Oxadiazole moiety appeared to be effective in various pathologies.Objective: The aim of the study was to synthesize and evaluate the mechanism of vasorelaxation exhibited by synthesized oxadiazole derivatives.Method: The 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized by an efficient and simple method. The derivatives were investigated for their ex-vivo vasorelaxant action on intact/denuded endothelium rat aortic rings precontracted with norepinephrine/ phenylephrine/KCl.Results: The contractions induced in the aortic rings by the addition of cumulative concentrations of norepinephrine,phenylephrine, KCl and calcium were significantly antagonized by a derivative, OXD-Z2. In another experiment, verapamil pretreatment inhibited phenylephrine and Ca2+-induced aortic contractions and OXD-Z2 did not alter verapamilinduced inhibition. This indicated the role of L-type Ca2+-channels in the OXD-Z2-induced vasorelaxation via inhibition of calcium influx. Further, atropine (muscarinic receptor antagonist), L-NAME (NO synthase inhibitor) and methylene blue (non-selective cGMP inhibitor) inhibited OXD-Z2-induced relaxation in other sets of experiments. These results indicate that OXD-Z2 also mediates vasorelaxation through NO release by muscarinic receptor activation. In addition, the molecular docking studies showed that OXD-Z2 interacts with L-type Ca2+-channel, muscarinic (M2) receptor and eNOS.Conclusion: Thus, it is deduced from the above findings that the vasorelaxant activity of OXD-Z2 involves muscarinic receptor-mediated nitric oxide release in addition to direct inhibition of L-type Ca2+-channels.