Nose-to-brain Drug Delivery System: An Emerging Approach to Chemotherapy-induced Cognitive Impairment.

The rise in global cancer burden, notably breast cancer, emphasizes the need to address chemotherapy-induced cognitive impairment, also known as chemobrain. Although chemotherapy drugs are effective against cancer, they can trigger cognitive deficits. This has triggered the exploration of preventive strategies and novel therapeutic approaches. Nanomedicine is evolving as a promising tool to be used for the mitigation of chemobrain by overcoming the blood-brain barrier (BBB) with innovative drug delivery systems. Polymer and lipid-based nanoparticles enable targeted drug release, enhancing therapeutic effectiveness. Utilizing the intranasal route of administration may facilitate drug delivery to the central nervous system (CNS) by circumventing first-pass metabolism. Therefore, knowledge of nasal anatomy is critical for optimizing drug delivery via various pathways. Despite challenges, nanoformulations exhibit the potential in enhancing brain drug delivery. Continuous research into formulation techniques and chemobrain mechanisms is vital for developing effective treatments. The intranasal administration of nanoformulations holds promise for improving therapeutic outcomes in chemobrain management. This review offers insights into potential future research directions, such as exploring novel drug combinations, investigating alternative delivery routes, or integrating emerging technologies to enhance the efficacy and safety of nanoformulations for chemobrain management.

Enhancing temozolomide antiglioma response by inhibiting O6-methylguanine-DNA methyltransferase with selected phytochemicals: in silico and in vitro approach.

The aim of our study was to investigate the potential of rutin, catechin, dehydrozingerone, naringenin, and quercetin, both alone and in combination with temozolomide, to inhibit the expression of O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. MGMT has been shown to be a major cause of temozolomide resistance in glioma. Our study used both in silico and in vitro methods to assess the inhibitory activity of these phytochemicals on MGMT, with the goal of identifying the most effective combination of compounds for reducing temozolomide resistance. After conducting an initial in silico screening of natural compounds against MGMT protein, five phytochemicals were chosen based on their high docking scores and favorable binding energies. From the molecular docking and simulation studies, we found that quercetin showed a good inhibitory effect of MGMT with its high binding affinity. C6 glioma cells showed increased cytotoxicity when treated with the temozolomide and quercetin combination. It was understood from the isobologram and combination index plot that the drug combination showed a synergistic effect at the lowest dose. Quercetin when combined with temozolomide significantly decreased the MGMT levels in C6 cells in comparison with the other drugs as estimated by ELISA. The percentage of apoptotic cells increased significantly in the temozolomide-quercetin group indicating the potency of quercetin in decreasing the resistance of temozolomide as confirmed by acridine orange/ethidium bromide staining. Our experiment hence suggests that temozolomide resistance can be reduced by combining the drug with quercetin which will serve as an effective therapeutic target for glioblastoma treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03821-7.

Protective effect of ß-glucan on Poly(I:C)-induced acute lung injury/inflammation: Therapeutic implications of viral infections in the respiratory system.

AIMS: Acute lung inflammation, particularly acute respiratory distress syndrome (ARDS), is caused by a variety of pathogens including bacteria and viruses. ß-Glucans have been reported to possess both anti-inflammatory and immunomodulatory properties. The current study evaluated the therapeutic effect of ß-glucans on polyinosinic:polycytidylic acid (Poly(I:C)) induced lung inflammation in both hamster and mice models. MAIN METHODS: Poly(I:C)-induced ALI/inflammation models were developed in hamsters (2.5 mg/kg) and mice (2 mg/kg) by delivering the Poly(I:C) intratracheally, and followed with and without ß-glucan administration. After treatment, lung mechanics were assessed and lung tissues were isolated and analyzed for mRNA/protein expression, and histopathological examinations. KEY FINDINGS: Poly(I:C) administration, caused a significant elevation of inflammatory marker's expression in lung tissues and showed abnormal lung mechanics in mice and hamsters. Interestingly, treatment with ß-glucan significantly (p < 0.001) reversed the Poly(I:C)-induced inflammatory events and inflammatory markers expression in both mRNA (IL-6, IL-1ß, TNF-α, CCL2 and CCL7) and protein levels (TNF-α, CD68, myeloperoxidase, neutrophil elastase, MUC-5Ac and iNOS). Lung functional assays revealed that ß-glucan treatment significantly improved lung mechanics. Histopathological analysis showed that ß-glucan treatment significantly attenuated the Poly(I:C) induced inflammatory cell infiltration, injury and goblet cell population in lung tissues. Consistent with these findings, ß-glucan treatment markedly reduced the number of neutrophils and macrophages in lung tissues. Our findings further demonstrated that ß-glucan could reduce inflammation by suppressing the MAPK pathway. SIGNIFICANCE: These results suggested that ß-glucan may attenuate the pathogenic effects of Poly(I:C)-induced ALI/ARDS via modulating the MAPK pathway, indicating ß-glucan as a possible therapeutic agent for the treatment of viral-pulmonary inflammation/injury.

Box-Behnken Design-Aided Validation and Optimization of a Stability-Indicating Reverse Phase-HPLC Method for the Estimation of Tamoxifen Citrate in Lipidic Nano-Vesicles.

Stability indicating a reverse-phase HPLC analytical method for the quantification of tamoxifen citrate (TMX) in the bulk and lipidic nano-vesicles (LNVs) was developed. The optimized method was validated according to the ICH Q2 (R1) guidelines by following a three-factor interaction Box-Behnken design using Design-Expert® software. The responses measured at 236 nm were retention time (Rt), peak area, tailing factor (TF) and the number of theoretical plates. TMX was eluted best using the Luna® C18 LC Column along with a mobile phase of methanol (MeOH) and ammonium acetate buffer (AAB pH 4.5) 80:20 v/v mixture at 25 ± 2°C temperature. The currently developed method was linear in 100-5,000 ng/mL range with a detection limit of 4.55 ng/mL and a quantification limit of 13.78 ng/mL. The optimized method was utilized to evaluate the stability of TMX in different stress conditions by performing forced degradation studies. The results from the degradation study stipulated that on exposure to various stressors namely acid, alkali, oxidative, thermal and UV light, the TMX did not show considerable degradation except for UV light exposure. Further, the method was successfully used for the quantification of TMX in LNVs.

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase.

BACKGROUND: Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable. OBJECTIVE: The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide. METHODS: The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines. DESCRIPTION: One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy. CONCLUSION: This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.

Prenatal Learning and Memory: Review on the Impact of Exposure.

BACKGROUND: Prenatal Learning is a topic still debated for its existence, although the concept is well known since ancient times. OBJECTIVE: The present review highlights the impact of various stimuli on learning and memory in prenatal and postnatal life. METHODS: For review, various articles from preclinical and clinical studies providing early pieces of evidence of prenatal learning to date were included based on the relevancy of the databases, namely, Scopus, Pubmed, and Google Scholar. RESULTS: Learning is the process of acquiring skills/ preferences/ habits from the experiences of the exposures of the past. These exposures are the stimuli, which help in categorizing learning into associated or nonassociated learning. The stimuli of adults related to auditory, gustatory, olfactory, visual, touch, etc. are also accessible to the prenatal life in utero either directly or indirectly through the mother. The effects of these stimuli are remarkable during prenatal life and can be seen clearly in infants. These stimuli play an important role in prenatal learning and contribute to neuronal development. The present review summarizes the pieces of evidence for each of these types of learning & their impact on the ex utero life, a futuristic view & the scope of understanding prenatal learning. The review also elucidates the factors affecting prenatal learning. CONCLUSION: Studies from clinical and preclinical studies reflected the impacts of several aspects of an infant's life and the memory created during prenatal life was found to be most likely carried on to postnatal life.

Oral Semaglutide in the Management of Type 2 DM: Clinical Status and Comparative Analysis.

BACKGROUND: In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy. OBJECTIVES: This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control, and comparative analysis of semaglutide with the second-line antidiabetic drugs. DESCRIPTION: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide, to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve Glycemic control in obese patients with a reduction in body weight. Still, in clinical practice, in the type 2 DM treatment paradigm, the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control. CONCLUSION: The review highlights the comparative analysis of semaglutide with the existing second- line drugs for the management of type 2 diabetes mellitus by stressing its benefits and adverse events.

Modulation of Gut-Brain Axis by Probiotics: A Promising Anti-depressant Approach.

The human digestive system is embedded with trillions of microbes of various species and genera. These organisms serve several purposes in the human body and exist in symbiosis with the host. Their major role is involved in the digestion and conversion of food materials into many useful substrates for the human body. Apart from this, the gut microbiota also maintains healthy communication with other body parts, including the brain. The connection between gut microbiota and the brain is termed as gut-brain axis (GBA), and these connections are established by neuronal, endocrine and immunological pathways. Thus, they are involved in neurophysiology and neuropathology of several diseases like Parkinson's disease (PD), Alzheimer's disease (AD), depression, and autism. There are several food supplements such as prebiotics and probiotics that modulate the composition of gut microbiota. This article provides a review about the role of gut microbiota in depression and supplements such as probiotics that are useful in the treatment of depression.

Assessment of preclinical effect of (+)-catechin hydrate on sexual function: An in silico and in vivo study.

Considering dopamine-enhancing effect of (+)-catechin, the present study was designed to evaluate dopamine-2 (D2) receptor agonistic and phosphodiesterase-5 (PDE5) enzyme inhibitory effects in in silico and effect on male sexual function of Sprague Dawley rats in vivo. (+)-Catechin and standard (sildenafil and bromocriptine) were docked using Autodock Vina 1.1.2 and visualised by UCSF Chimera 1.14. Significant interactions in terms of binding energies were observed for catechin with both proteins. In in vivo study, the rats were dosed orally for 54 days with (+)-catechin hydrate (50 mg/kg), sildenafil citrate (standard, 4 mg/kg) and carboxymethylcellulose (vehicle, 0.25% w/v). The aphrodisiac effects were evaluated on the day 14, 28, 42 and 54 using the behavioural parameters of mounting and intromission. After the study, animals were sacrificed and testes and spermatozoa were assessed for safety profile. Results showed a significant increase in mount and intromission frequencies and a significant reduction in mount and intromission latencies in the catechin group on all tested days when compared to vehicle control. (+)-Catechin was found to be safe on histology of testes, sperm count, sperm motility and sperm morphology parameters. In conclusion, catechin demonstrated an enhancement in sexual behaviour without eliciting toxicity on the male reproductive system in rats.

Cinnamyl Sulfonamide Hydroxamate Derivatives Inhibited LPS-Stimulated NF-kB Expression in RAW 264.7 Cells In Vitro and Mitigated Experimental Colitis in Wistar Rats In Vivo.

BACKGROUND: Histone deacetylase (HDAC) inhibition has been found to be effective in the treatment of inflammatory bowel disease. Previous studies have reported that Cinnamyl sulfonamide hydroxamate derivatives possess non-selective HDAC inhibition. OBJECTIVE: The present study was designed to screen three selected Cinnamyl sulfonamide hydroxamate derivatives, NMJ-1, NMJ-2, and NMJ3, for in vitro anti-inflammatory response by assessing the expression of pNF-κB in lipopolysaccharide (LPS)-induced inflammatory changes on RAW 264.7 cells, and in vivo anti-inflammatory response in acetic acid (AA) and 2.4-dinitrochlorobenzene (DNCB)-induced colitis models in Wistar rats. METHOD: AA-induced colitis was produced in Wistar rats by intra-colonic administration of 1 ml AA. DNCBinduced colitis was produced by spraying 250 µL DNCB in acetone (20g/L) on the nape of the rats for 14 days, followed by the intracolonic administration on day 15. Drugs were administered for three days after the induction of colitis. RESULTS: In vitro anti-inflammatory effect was observed by NMJ1 and NMJ2 through a significant decrease in pNF-κB overexpression-induced by LPS. Similar effect was observed in anti-colitis response by NMJ2 in both models by reversing the colitis-induced changes in length, weight, anti-oxidant profile and histopathology of the colon. CONCLUSION: NMJ2 was found to be most effective among the tested compounds as an anti-inflammatory agent in both in vitro and in vivo inflammatory studies.

An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review.

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non-toxic chemical that mediates anti-inflammatory effects by down-regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.

Sesamol protects MIN6 pancreatic beta cells against simvastatin-induced toxicity by restoring mitochondrial membrane potentials.

Statins, the drugs for the treatment of dyslipidemia, have been suggested to impact insulin sensitivity, resulting in pancreatic ß-cell dysfunction, and consequently, lead to new onset of diabetes. Taking this as a clue, the present study was designed to evaluate the protective effect of sesamol (a known antioxidant, antidiabetic and antidyslipidemic agent) against the diabetogenic potential of simvastatin. The toxic effects of simvastatin and sesamol on MIN6 insulinoma (Mouse pancreatic ß cells) cells were evaluated separately by MTT assay. The protective effect of sesamol was evaluated at the IC50 value of simvastatin at doses ranging from 7.8 to 62.5 micromolar (µM). Further, the reversal of the impact of simvastatin on cell cycle and mitochondrial membrane potential by sesamol pretreatment was studied. The IC50 for simvastatin and sesamol were found to be 70.05 ± 2.34 µM and 2134 ± 8.41 µM, respectively, after 48 h and 72 h of incubation. Sesamol pretreatment protected the MIN6 cells from simvastatin toxicity (70 µM) in a dose-dependent manner from 7.8 to 31.25 µM. Simvastatin induced cell cycle arrest in G0/G1 phase. However, when cells were preincubated with sesamol for 24 h, a reversal in the cell cycle arrest was observed in simvastatin-treated cells (G0/G1). Pretreatment with sesamol also reduced the mitochondrial membrane potential loss compared to simvastatin treatment alone. These in vitro findings indicate that sesamol has a protective effect against simvastatin-induced toxicity on the pancreatic beta cells.

Catechin ameliorates doxorubicin-induced neuronal cytotoxicity in in vitro and episodic memory deficit in in vivo in Wistar rats.

Cognitive dysfunction by chemotherapy compromises the quality of life in cancer patients. Tea polyphenols are known chemopreventive agents. The present study was designed to evaluate the neuroprotective potential of (+) catechin hydrate (catechin), a tea polyphenol, in IMR-32 neuroblastoma cells in vitro and alleviation of episodic memory deficit in Wistar rats in vivo against a widely used chemotherapeutic agent, Doxorubicin (DOX). In vitro, neuroprotective studies were assessed in undifferentiated IMR-32 cells using percentage viability and in differentiated cells by neurite length. These studies showed catechin increased percentage viability of undifferentiated IMR-32 cells. Catechin pretreatment also showed an increase in neurite length of differentiated cells. In vivo neuroprotection of catechin was evaluated using novel object recognition task in time-induced memory deficit model at 50, 100 and 200 mg/kg dose and DOX-induced memory deficit models at 100 mg/kg dose. The latter model was developed by injection of DOX (2.5 mg/kg, i.p.) in 10 cycles over 50 days in Wistar rats. Catechin showed a significant reversal of time-induced memory deficit in a dose-dependent manner and prevention of DOX-induced memory deficit at 100 mg/kg. In addition, catechin treatment showed a significant decrease in oxidative stress, acetylcholine esterase and neuroinflammation in the hippocampus and cerebral cortex in DOX-induced toxicity model. Hence, catechin may be a potential adjuvant therapy for the amelioration of DOX-induced cognitive impairment which may improve the quality of life of cancer survivors. This improvement might be due to the elevation of antioxidant defense, prevention of neuroinflammation and inhibition of acetylcholine esterase enzyme.

Evaluation of the aphrodisiac potential of a chemically characterized aqueous extract of Tamarindus indica pulp.

ETHNOPHARMACOLOGICAL RELEVANCE: Tamarindus indica is an ingredient in the traditional aphrodisiac formulations in Africa and India. It is also a widely used food ingredient in other tropical countries. AIM OF THE STUDY: The present study was aimed to evaluate the aphrodisiac potential and reproductive safety profile of aqueous extract of Tamarindus indica in male Wistar rats. MATERIALS AND METHODS: The aqueous extract was prepared by maceration of pulp followed by reduction of volume in rotavapor under heat followed by freeze drying. The prepared extract was characterized for contents of total phenol, flavonoid, and saponin. It was also subjected to phytoconstituent analysis using GCMS. Further, the extract was evaluated for acute toxicity study. The aphrodisiac and reproductive toxicity potential were evaluated in animals after grouping them in four with six animals each namely, normal control, standard (Sildenafil citrate, 4mg/kg p.o.) and extract of Tamarindus indica treated groups at two dose levels, 125 and 250mg/kg p.o. The study was conducted for 54 days with daily once dosing of extract and standard. Equal number of females was grouped without treatment for evaluation of parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal (mount latency and intromission latency). These parameters were evaluated on day 14, 28, 42 and 54. Animals were sacrificed on day 54, testes were removed and studied for histopathological changes. RESULTS: The extract showed 6.6mg gallic acid equivalent/g of total phenol, 2.3mg catechin equivalent/g of flavonoid and 11.6% saponin. Forty chemical constituents were identified by GCMS analysis. In acute toxicity study, the extract was found to be safe till 2000mg/kg p.o. Efficacy study showed significant (p<0.05) improvement in parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal on all observed days except mount frequency for 125mg/kg on 42nd day and intromission frequency for both doses of tamarind compared to normal control. Improvements in these parameters were comparable to the standard drug. Histopathology study and sperm count suggested an increase in sperm production without any sign of toxicity in testis. Sperm motility significantly (p<0.05) increased in the treatment groups that received extract at 250mg/kg compared to normal control. CONCLUSION: Aqueous extract of Tamarindus indica possessed aphrodisiac activity together with spermatogenic potential.

Role of the Drug Transporter ABCC3 in Breast Cancer Chemoresistance.

Increased expression of ABC-family of transporters is associated with chemotherapy failure. Although the drug transporters ABCG2, ABCB1 and ABCC1 have been majorly implicated in cancer drug resistance, recent studies have associated ABCC3 with multi drug resistance and poor clinical response. In this study, we have examined the expression of ABCC3 in breast cancers and studied its role in drug resistance and stemness of breast cancer cells in comparison with the more studied ABCC1. We observed that similar to ABCC1, the transcripts levels of ABCC3 was significantly high in breast cancers compared to adjacent normal tissue. Importantly, expression of both transporters was further increased in chemotherapy treated patient samples. Consistent with this, we observed that treatment of breast cancer cell lines with anti-cancer agents increased their mRNA levels of both ABCC1 and ABCC3. Further, similar to knockdown of ABCC1, knockdown of ABCC3 also significantly increased the retention of chemotherapeutic drugs in breast cancer cells and rendered them more chemo-sensitive. Interestingly, ABCC1 and ABCC3 knockdown cells also showed reduction in the expression of stemness genes, while ABCC3 knockdown additionally led to a reduction in the CD44high/CD24low breast cancer stem-like subpopulation. Consistent with this, their ability to form primary tumours was compromised. Importantly, down-modulation of ABCC3 rendered these cells increasingly susceptible to doxorubicin in xenograft mice models in vivo. Thus, our study highlights the importance of ABCC3 transporters in drug resistance to chemotherapy in the context of breast cancer. Further, these results suggest that combinatorial inhibition of these transporters together with standard chemotherapy can reduce therapy-induced resistance in breast cancer.

Sesamol, a lipid lowering agent, ameliorates aluminium chloride induced behavioral and biochemical alterations in rats.

BACKGROUND: Sesame oil from the seeds of Sesamum indicum Linn. (Pedaliaceae) has been used traditionally in Indian medical practice of Ayurveda in the treatment of central nervous system disorders and insomnia. A few published reports favor the anti-dementia effect of sesamol (SML), an active constituent of sesame oil. OBJECTIVE: Thus, the present study was aimed to explore the anti-dementia effect and possible mechanism (s) of SML in aluminium chloride (AlCl3)-induced cognitive dysfunction model in rodents with special emphasis on memory centers viz., hippocampus and frontal cortex. METHODS: Male Wistar rats were exposed to AlCl3 (175 mg/kg p.o.) for 60 days. SML (10 and 20 mg/kg) and rivastigmine (1 mg/kg) were administered orally 45 min before administration of AlCl3 for 60 days. Spatial memory was assessed using Morris water maze test. After 60 days of treatment animals were sacrificed, hippocampus and frontal cortex were collected and analyzed for acetylcholinesterase (AChE) activity, tumor necrosis factor (TNF-α) level, antioxidant enzymes (Glutathione, catalase), lipid peroxidation, and nitrite level. The circulating triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were also analyzed. RESULTS: SML significantly prevented behavioral impairments in aluminium-exposed rats. Treatment with SML reversed the increased cholesterol, triglycerides and LDL while raised the HDL levels. SML significantly corrected the effect of AlCl3 on AChE activity. Further, SML reversed the elevated nitric oxide, TNF-α and reduced antioxidant enzymes in hippocampus and frontal cortex. CONCLUSION: The present study suggests the neuro-protection by SML against cognitive dysfunction induced by environmental toxin (AlCl3) in hippocampus and frontal cortex.

Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats.

OBJECTIVES: Aluminium, a neurotoxic agent in humans, has been implicated in the pathogenesis of neurodegenerative disorders. In this study, we examined the behavioral and biochemical effects of aluminium in rats with special emphasis on memory centres, namely, hippocampus and frontal cortex. Further, the effect of simvastatin treatment on aluminium intoxication was evaluated. METHODS: Rats were exposed to aluminium chloride (AlCl3) for 60 days. Simvastatin (10 mg/kg/p.o.) and rivastigmine (1 mg/kg/p.o.) were administered daily prior to AlCl3. Behavioral parameters were assessed using Morris water maze test and actophotometer followed by biochemical investigations, namely, acetylcholinesterase (AChE) activity, TNF-α level, antioxidant enzymes (GSH, catalase), lipid peroxidation, and nitrite level in hippocampus and frontal cortex. Triglycerides, total cholesterol, LDL, and HDL levels in serum were also determined. KEY FINDINGS: Simvastatin treatment improved cognitive function and locomotor activity in rats. Simvastatin reversed hyperlipidemia and significantly rectified the deleterious effect of AlCl3 on AChE activity. Further, in hippocampus and frontal cortex, aluminium-induced elevation in nitrite and TNF-α and reduction in antioxidant enzymes were inhibited by simvastatin. CONCLUSION: To conclude, the present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin.

Ameliorative effect of caffeic acid against inflammatory pain in rodents.

The present study was designed to evaluate the antinociceptive profile of caffeic acid in mice and rats. Caffeic acid (5-100 mg/kg, p.o.), in a dose dependent manner inhibited acetic acid-induced writhing and late phase of formalin-induced pain in mice, with an ED(50) of 22.38 and 10.92 mg/kg, respectively. However, caffeic acid was ineffective in the hot plate and tail flick tests. Analgesic activity was also examined in carrageenan and lipopolysaccharide (LPS)-induced mechanical hyperalgesia in rats, where locally induced myeloperoxidase (MPO), malondialdehyde (MDA) and nitrite levels in foot pad were estimated by colorimetric assay. Oral administration of caffeic acid (200mg/kg, p.o.) showed analgesic activity similar to nimesulide (4 mg/kg, p.o.) and inhibited MPO, MDA and nitrite generation in the inflamed paw. Histological examination revealed reduction in neutrophil infiltration and protection of tissue damage by caffeic acid. These results suggest that caffeic acid exhibits peripheral analgesic effect in mice and rats and could be further examined for the treatment of chronic painful episodes.

Development and validation of a HPLC method for quantification of rivastigmine in rat urine and identification of a novel metabolite in urine by LC-MS/MS.

A sensitive, specific and accurate HPLC method for the quantification of rivastigmine (RSM) in rat urine was developed and validated. The method involves the simple liquid-liquid extraction of RSM and pyridostigmine as an internal standard (IS) from rat urine with tertiary methyl butyl ether. The chromatographic separation of RSM and IS was achieved with 20 mm ammonium acetate buffer (pH 6.5) and acetonitrile (65:35, v/v) delivered at flow-rate of 1 mL/min on a Kromasil KR-100. The method was in linear range from 50 to 5000 ng/mL. The validation was done as per FDA guidelines and the results met the acceptance criteria. The method was successfully applied for the quantification of RSM in rat urine. Besides method validation, we have identified two metabolites of RSM in urine. Both the metabolites were characterized by HPLC-PDA and LC-MS/MS and it was found that one metabolite is novel.

Anti-osteoporotic activity of the petroleum ether extract of Cissus quadrangularis Linn. in ovariectomized Wistar rats.

BACKGROUND: The plant Cissus quadrangularis (CQ) is used as an osteoprotective agent in Ayurveda, the Indian system of alternative medicine. The present study was done to validate the anti-osteoporotic role of the petroleum ether extract of CQ on ovariectomy-induced osteoporosis in rats. METHODS: Female wistar rats were divided into five groups of six rats each; (1) The Normal control (NC) group (n=6) received no surgery and no treatment, (2). The Sham control (SHAM) group (n=6) received sham surgery but no treatment, (3) the Ovariectomized (OVX) group (n=6) received an ovariectomy and normal saline treatment for 90 days, (4) the Ovariectomized+raloxifene (OVX+RAL) group (n=6) received an ovariectomy and treatment with raloxifene, a known anti-osteoporotic agent for 90 days commencing from 22nd post ovariectomy day and (5) the Ovariectomy+Cissus quadrangularis (OVX+CQ) group (n=6) received an ovariectomy, and treatmentwith the petroleum ether extract of CQ 500 mg/kg body weight daily for 90 days commencing from 22nd post ovariectomy day. At the end of the treatment period, rats in all groups were sacrificed and the right femur was used for biomechanical analysis, and the left femur for histomorphometrical analysis. RESULTS: CQ significantly increased the force required to break the femur (p<0.001) and significantly increased the thickness of both cortical (p<0.001) and trabecular bone (p<0.001). This action of CQ was comparable to the action of raloxifene. CONCLUSIONS: The petroleum ether extract of CQ stem seems to possess anti-osteoporotic activity in rats.