Chronic Daily Administration Research Articles

Structure–Function Correlation in Cobalt-Induced Brain Toxicity

Cobalt toxicity is difficult to detect and therefore often underdiagnosed. The aim of this study was to explore the pathophysiology of cobalt-induced oxidative stress in the brain and its impact on structure and function. Thirty-five wild-type C57B16 mice received intraperitoneal cobalt chloride injections: a single high dose with evaluations at 24, 48, and 72 h (n = 5, each) or daily low doses for 28 (n = 5) or 56 days (n = 15). A part of the 56-day group also received minocycline (n = 5), while 10 mice served as controls. Behavioral changes were evaluated, and cobalt levels in tissues were measured with particle-induced X-ray emission. Brain sections underwent magnetic resonance imaging (MRI), electron microscopy, and histological, immunohistochemical, and molecular analyses. High-dose cobalt caused transient illness, whereas chronic daily low-dose administration led to long-term elevations in cobalt levels accompanied by brain inflammation. Significant neurodegeneration was evidenced by demyelination, increased blood–brain barrier permeability, and mitochondrial dysfunction. Treated mice exhibited extended latency periods in the Morris water maze test and heightened anxiety in the open field test. Minocycline partially mitigated brain injury. The observed signs of neurodegeneration were dose- and time-dependent. The neurotoxicity after acute exposure was reversible, but the neurological and functional changes following chronic cobalt administration were not.

Non-nutritive Sweetener Aspartame Disrupts Circadian Behavior and Causes Memory Impairment in Mice.

As a non-nutritive sweetener, aspartame is widely used in everyday life. However, its safety is highly controversial, especially its effects on neurobehavior. We evaluated the effects of chronic daily oral administration of aspartame-containing drinking water (at doses equivalent to 7-28% of the FDA-recommended human DIV) on memory and rhythm behaviors in mice and further investigated changes at the molecular level in the brains. Our results demonstrated that mice exposed to aspartame exhibited memory impairment. Disorders of hippocampal neurotransmitter metabolism and pathological damage may be responsible for the aspartame-induced memory impairment via inhibition of the BDNF/TrkB pathway. Furthermore, our findings suggested that disturbed clock gene expression in the hypothalamus after aspartame exposure led to altered rest-activity behavior, and this disruption of the circadian rhythm may exacerbate memory impairment. This study highlights the negative neurobehavioral effects of aspartame and provides valuable insights into its rational and safe use.

Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open-Label, Single-Dose, Crossover Study in Healthy Adults.

Omaveloxolone (SKYCLARYS®) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50-mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150-mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (Cmax), AUC0-t, and AUC0-∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median tmax, 10 h) compared with sprinkled capsule contents over applesauce (median tmax, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4-h difference in tmax is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information.

Review on Effect of Medicinal Plants on Female Reproductive System

Vata Gajendra Singha (VGS), an Ayurvedic preparation, is used in traditional medicine to treat rheumatoid arthritis in the rural population. The effect of chronic administration of Vata Gajendra Singha (VGS) on the hematological parameters was studied. The acute test of VGS recorded no death, even at the highest dose of 80 ml/ Kg body weight. During chronic testing, the animals were divided into three groups. The first two groups were given VGS preparation at a low dose of 50 mg/kg and a high dose of 400 mg/kg for 28 days, while the third group that served as the control received water for the same period. After 28 days of chronic administration of the VGS preparation, some hematological parameter changes were noted. There were notable changes in the percentage of neutrophils, lymphocytes, Mean Corpuscular Hemoglobin, and platelets attributed on the high and low dosage of Vata Gajendra Singha. These hematological parameters are some important factors related to a variety of disease conditions. Vata Gajendra Singha negatively affect some hematological parameters abnormally in treated rats and should not be administered chronically at a higher dose.

Hematological Studies of an Ayurvedic Medicine “Vata Gajendra Singha” Used in Rheumatoid Arthritis After Chronic Administration to Male Sprague-Dawley Rats

Vata Gajendra Singha (VGS), an Ayurvedic preparation, is used in traditional medicine to treat rheumatoid arthritis in the rural population. The effect of chronic administration of Vata Gajendra Singha (VGS) on the hematological parameters was studied. The acute test of VGS recorded no death, even at the highest dose of 80 ml/ Kg body weight. During chronic testing, the animals were divided into three groups. The first two groups were given VGS preparation at a low dose of 50 mg/kg and a high dose of 400 mg/kg for 28 days, while the third group that served as the control received water for the same period. After 28 days of chronic administration of the VGS preparation, some hematological parameter changes were noted. There were notable changes in the percentage of neutrophils, lymphocytes, Mean Corpuscular Hemoglobin, and platelets attributed on the high and low dosage of Vata Gajendra Singha. These hematological parameters are some important factors related to a variety of disease conditions. Vata Gajendra Singha negatively affect some hematological parameters abnormally in treated rats and should not be administered chronically at a higher dose.

Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques

To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption. Research animal study. Research institute environment. Adult male rhesus macaques (age, 8-10 years; n = 6). Chronic daily THC edible administration at medically and recreationally relevant contemporary doses followed by cessation of THC use. Testicular volume, serum male hormones, semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing of sperm DNA. Chronic THC use resulted in significant testicular atrophy, increased gonadotropin levels, decreased serum sex steroid levels, changes in seminal fluid proteome, and increased DNA fragmentation with partial recovery after discontinuation of THC use. For every increase of 1 mg/7 kg/day in THC dosing, there was a significant decrease in the total testicular volume bilaterally by 12.6 cm3 (95% confidence interval [CI], 10.6-14.5), resulting in a 59% decrease in volume. With THC abstinence, the total testicular volume increased to 73% of its original volume. Similarly, with THC exposure, there were significant decreases in the mean total testosterone and estradiol levels and a significant increase in the follicle-stimulating hormone level. With increasing THC dose, there was a significant decrease in the liquid semen ejaculate volume and weight of coagulum; however, no other significant changes in the other semen parameters were noted. After discontinuing THC use, there was a significant increase in the total serum testosterone level by 1.3 ng/mL (95% CI, 0.1-2.4) and estradiol level by 2.9 pg/mL (95% CI, 0.4-5.4), and the follicle-stimulating hormone level significantly decreased by 0.06 ng/mL (95% CI, 0.01-0.11). Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. Whole genome bisulfite sequencing identified 23,558 CpGs differentially methylated in heavy-THC vs. pre-THC sperm, with partial restoration of methylation after discontinuation of THC use. Genes associated with altered differentially methylated regions were enriched for those involved in the development and function of the nervous system. This is the first study demonstrating that discontinuation of chronic THC use in rhesus macaques partially restores adverse impacts to male reproductive health, THC-associated sperm differentially methylated regions in genes important for development, and expression of proteins important for male fertility.

Unraveling Molecular and Metabolic Gut‐Brain Signalling Disruptions and Potential Therapy in New Bardet‐Biedl Syndrome Mouse

Obesity is a cardinal feature of Bardet‐Biedl syndrome (BBS), a syndromic ciliopathy caused by mutations in genes for BBS 1‐21. BBS proteins control the function of primary cilia that act as a sensory antenna on virtually all mammalian cells. The mechanisms of BBS‐induced obesity remain poorly understood, resulting in a lack of therapeutic options for these patients. The overarching goal of the study was to define underlying mechanisms involved in the pathogenesis of BBS‐induced obesity and use this knowledge to identify novel therapeutic targets. Given the importance of cilia in interoceptive and homeostatic sensing, we hypothesized that disruption of cilia function by BBS mutation would impair negative feedback resulting in a proinflammatory microenvironment in adipose tissue and disruption of neuroendocrine control of feeding in hypothalamus.In this study, we first characterized the metabolic phenotype of a novel BBS5 knockout mouse (BBS5‐/‐; n=6‐12/strain/gender). Next, we performed immunophenotyping of adipocytes and unbiased RNA sequencing of the hypothalamus of BBS5‐/‐ and WT mice. To validate the predictions from transcriptomic data, we performed pharmacological‐based feeding experiments and tested a putative therapeutic for BBS‐induced obesity.We found that BBS5‐/‐ mice exhibits all the classic symptoms observed in human patients with BBS, including hyperphagia, cognitive impairments, glucose, and insulin intolerance, and 3 to 4‐fold increased fat mass on chow diet compared to wildtype mice (p<0.001). BBS5‐/‐ mice had increased proinflammatory M1 macrophages and decreased functional regulatory T‐cells in adipocytes suggesting that extrinsic factors promote fat mass gain. Pathway analysis of the transcriptomics data revealed altered endocrine receptor signaling in the hypothalamus of BBS5‐/‐ mice. Feeding experiments confirmed the development of both leptin and cholecystokinin resistance independent of body weight (p>0.05). The receptor for glucagon‐like‐peptide‐1 (GLP1) was found to be upregulated in the hypothalamus of BBS5‐/‐ mice (p<0.001). Chronic daily pharmacological administration of GLP1 receptor agonist (Semaglutide) for two weeks significantly reduced food intake, body weight, elevated glucose levels, and fat mass (p<0.001).In conclusion, BBS5‐/‐ mice are a valuable new translational tool to elucidate interoceptive and homeostatic gut‐brain axis alterations in BBS‐induced obesity. We identify adipose inflammation, and impaired hypothalamic leptin, insulin, and cholecystokinin signalling as underlying mechanisms for the metabolic pathogenesis of ciliopathy. Our results support using GLP1 receptor agonist as a novel therapeutic strategy for treating obesity in patients with BBS.

Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response.

Background:There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC.Method:Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC).Results:As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC–mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC–mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake.Conclusions:The synergism between VEN and vHPC–mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC–mPFC pathway.

A Serotonin 2A-Receptor Decoy Peptide Potently Lowers Blood Pressure in Male Zucker Diabetic, Fatty, Hypertensive Rats.

To test whether a novel 5-hydroxytryptamine 2A decoy receptor peptide, SN..8 (Sertuercept), administered via intraperitoneal injection, acutely lowers arterial blood pressure in obese, hypertensive male Zucker diabetic rats (ZDF). To examine the safety, tolerability and possible reno-protective effects following chronic alternate daily administration of Sertuercept (for 10 weeks) in the male ZDF rat. Systolic and diastolic blood pressure were determined at baseline and regular intervals for up to 48 hours after a single IP administration of either Sertuercept (2 mg/kg), vehicle (saline) or an identical concentration of a scrambled sequence of the decoy receptor peptide, LN…8, in male ZDF and Zucker lean rats using tail cuff plethysmography. Plasma autoantibodies were obtained in thirteen male ZDF rats for determination of 5-hydroxytryptamine 2A receptor-mediated neurotoxicity using an acute neurite retraction assay in mouse neuroblastoma cells. Rats were sacrificed at 25-weeks of age, the kidneys were perfused, fixed and sections were stained using Masson's trichrome for semi-quantitative determination of glomerular and interstitial fibrosis. Sertuercept (2 mg/kg IP) potently lowered systolic and diastolic blood pressure in both 11-week-old and 25-week-old male ZDF rats and in a subset of hypertensive Zucker lean rats. There was no significant blood pressure-lowering effect of vehicle (saline) or scrambled peptide sequence (LN.8). Blood pressure-lowering was rapid in onset (15-30 minutes following IP injection) and sustained for at least 24 hours. Alternate daily IP administration of 2 mg/kg dose of Sertuercept vs. scrambled peptide (for 10 weeks) was safe, well-tolerated and associated with a significant decrease in glomerulosclerosis in 25-week-old male ZDF rats. Plasma autoantibody-induced neurotoxicity correlated significantly with the global index of renal fibrosis severity in 25-week-old male ZDF rats. These data indicate potent arterial blood pressure-lowering efficacy from a decoy receptor peptide comprised of a second extracellular loop region of the human 5-hydroxytryptamine receptor. Chronic administration of the decoy receptor peptide (10 weeks) was safe, well-tolerated and protected against renal glomerulosclerosis in the male ZDF rat.

Treatment adherence to pegvisomant in patients with acromegaly in Spain: PEGASO study.

The burden of chronic daily subcutaneous administration of pegvisomant on adherence has not been previously studied. This study was aimed to determine the adherence to pegvisomant treatment in acromegaly patients in the real-world clinical practice setting in Spain. Multicenter, observational, descriptive, cross-sectional study in patients with acromegaly treated with pegvisomant for at least 12 months. Patient adherence was indirectly determined by Batalla and Haynes-Sackett questionnaires and directly by prescription record review. Additionally, treatment satisfaction was assessed by the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) and treatment convenience by an ad-hoc Pegvisomant questionnaire. Errors in reconstitution and administration process were determined by direct observation. 108 patients were included in the analysis. Rates of adherence varied from 60.7 to 92.1% and did not correlate with disease control. Older patient age and alternative schedules other than daily pegvisomant dosing were associated with lower adherence. Treatment satisfaction and convenience was high, with a mean (SD) total SATMED-Q score of 74.6 ± 15.4 over 100 and a total ad-hoc Pegvisomant questionnaire score of 71.2 ± 15.2 over 100. 34.3% of patients made mistakes during the reconstitution /administration process. Patient adherence to pegvisomant was high (60.7-92.1%), but more than a third of the patients in the study made mistakes during the administration process, with a potential impact on disease control. Besides dosing compliance, correct administration of medication should be carefully assessed in these patients.

Effect of Chandraprabha Batika on Thyroid Hormone Profile in Male Sprague-Dawley Rats

Chandraprabha Batika (CPB) is an Ayurvedic preparation that is used in the rural population for different purposes as traditional medicine. In this study, the effect of CPB on thyroid hormone profile was evaluated after chronic administration of this drug to male Sprague-Dawley rats. The acute pharmacological test of CPB recorded no death or any signs of toxicity even at the highest dose of 4,000 mg/kg body weight. For chronic pharmacological evaluation, the animals were divided into two groups. The first group was given CPB preparation at a dose of 40 mg/kg body weight for 28 days while the second group that served as the control received water for the same period. After 28 days of chronic administration of the CPB preparation, the following effects on the thyroid hormone panel were noted: a statistically insignificant decrease in the serum circulating total thyroxine (tT4) and total triiodothyronine (tT3) levels of the male rats; a decrease in the serum circulating free thyroxine (fT4) level of the male rats, the increase though not significant yet it was prominent; a statistically insignificant increase in the serum circulating free triiodothyronine (fT3) level of the male rats; an increase in the serum circulating thyroid-stimulating hormone level of the male rats, the increase though not significant yet it was prominent.

Preclinical HbA1c level studies of Brihat Khadir Batika and Chandraprabha Batika after chronic administration to male Sprague-Dawley rats

Background: Brihat Khadir Batika (BKD) and Chandraprabha Batika (CPB) are Ayurvedic preparations used as traditional medicines for different clinical indications in the rural population. BKD is used in diseases of throat and CPB is used in glandular enlargement. In this study we evaluate the influence of these preparations on HbA1c (%) level.Methods: To find out the average plasma glucose concentration over prolonged period of time, Ayurvedic medicinal preparations BKD and CPB were administered chronically to the male Sprague-Dawley rats at a dose of 400 mg/kg. After 28 days of chronic administration of BKD and CPB the following changes were noted. In this experiment Glycated Hemoglobin A1C level was determined.Results: The results of the study of in vitro quantitative determination of rat Glycated hemoglobin A1c concentrations in serum studies are thus: BKD caused a statistically insignificant (p=0.066) increase in the HbA1c level of the male rat (16.87% increase). CPB demonstrated a statistically insignificant (p=0.079) (17.47%) increase in the HbA1C level of the blood of the male rat.Conclusions: Both preparation BKD and CPB found in increasing HbA1c level of the blood of the male rat.

Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo.

There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629-42. ©2018 AACR.

Oral curcumin supplementation improves fine motor function in the middle-aged rhesus monkey

Aged individuals experience decreased fine motor function of the hand and digits, which could result, in part, from the chronic, systemic state of inflammation that occurs with aging. Recent research for treating age-related inflammation has focused on the effects of nutraceuticals that have anti-inflammatory properties. One particular dietary polyphenol, curcumin, the principal curcuminoid of the spice turmeric, has been shown to have significant anti-inflammatory effects and there is mounting evidence that curcumin may serve to reduce systemic inflammation. Therefore, it could be useful for alleviating age-related impairments in fine motor function. To test this hypothesis we assessed the efficacy of a dietary intervention with a commercially available optimized curcumin to ameliorate or delay the effects of aging on fine motor function of the hand of rhesus monkeys. We administered oral daily doses of curcumin or a control vehicle to 11 monkeys over a 14- to 18-month period in which they completed two rounds of fine motor function testing. The monkeys receiving curcumin were significantly faster at retrieving a food reward by round 2 of testing than monkeys receiving a control vehicle. Further, the monkeys receiving curcumin demonstrated a greater degree of improvement in performance on our fine motor task by round 2 of testing than monkeys receiving a control vehicle. These findings reveal that fine motor function of the hand and digits is improved in middle-aged monkeys receiving chronic daily administration of curcumin.

Palmitoylethanolamide Dampens Reactive Astrogliosis and Improves Neuronal Trophic Support in a Triple Transgenic Model of Alzheimer's Disease: In Vitro and In Vivo Evidence.

Alzheimer's disease (AD) is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. It is widely accepted that the main hallmarks of AD are not only senile plaques and neurofibrillary tangles but also reactive astrogliosis, which often precedes detrimental deposits and neuronal atrophy. Such phenomenon facilitates the regeneration of neural networks; however, under some circumstances, like in AD, reactive astrogliosis is detrimental, depriving neurons of the homeostatic support, thus contributing to neuronal loss. We investigated the presence of reactive astrogliosis in 3×Tg-AD mice and the effects of palmitoylethanolamide (PEA), a well-documented anti-inflammatory molecule, by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3×Tg-AD-derived astrocytes and the ability of PEA to counteract such phenomenon and improve viability of 3×Tg-AD-derived neurons. In vivo observations, performed using ultramicronized- (um-) PEA, a formulation endowed with best bioavailability, confirmed the efficacy of this compound. Moreover, the schedule of treatment, mimicking the clinic use (chronic daily administration), revealed its beneficial pharmacological properties in dampening reactive astrogliosis and promoting the glial neurosupportive function. Collectively, our results encourage further investigation on PEA effects, suggesting it as an alternative or adjunct treatment approach for innovative AD therapy.

Effect of conjugated linoleic acids and omega-3 fatty acids with or without resistance training on muscle mass in high-fat diet-fed middle-aged mice.

What is the central question of this study? This study examined the effects of 20weeks of administration of conjugated linoleic acids/omega-3 fatty acids with or without programed resistance exercise training on body composition, skeletal muscle properties and functional capacity in middle-aged mice fed a high-fat diet. What is the main finding and its importance? Chronic daily administration of conjugated linoleic acids/omega-3 fatty acids with resistance exercise training can help to blunt fat gain, alleviate loss of myogenic capacity and sensorimotor function and lower tissue inflammation in middle-aged mice during chronic high-fat diet-induced catabolism. This study investigated the effects of 20weeks of combined conjugated linoleic acid (CLA)/omega-3 fatty acid (n-3) administration independently or combined with resistance exercise training (RET) on skeletal muscle in middle-aged mice consuming a high-fat diet (HFD). Nine-month-old C57BL/6 mice were randomly assigned into four experimental groups (H, high-fat diet; HE, H+RET; HCN, H+CLA/n-3; and HECN, H+CLA/n3+RET). Body composition and functional capacity were assessed pre- and post-intervention. Muscle tissues were collected at 14months of age. ANOVA was used, with significance set at P≤0.05. Fat mass significantly increased in H (+74%), HE (+142%) and HECN (+43%) but not in HCN. Muscle wet weights were significantly lower in H and HCN than in HE and HECN. Grip strength substantially declined in H (-15%) and HCN (-17%), whereas sensorimotor function significantly declined only in H (-11%). HECN exhibited improvement in strength (+22%) and sensorimotor coordination (+17%). In comparison to H, muscle tumour necrosis factor-α mRNA expression was significantly lower in HE (-39%), HCN (-24%) and HECN (-21%), respectively. Mean myofibre cross-sectional areas were markedly lower in H and HCN than in HE and HECN. H showed significantly lower satellite cell abundance and numbers of myonuclei than all other groups. Our findings suggest that long-term daily CLA/n-3 intake with resistance training improved sensorimotor function, ameliorated fat gain and prevented loss of myogenic capacity while lowering tumour necrosis factor-α expression during chronic HFD.

Preclinical HbA1c level studies of makaradhwaja and siddha makaradhwaja after chronic administration to male Sprague-Dawley rats

Background: Makaradhwaja (MD) and Siddha Makaradhwaja (SMD) are Ayurvedic preparations used as traditional medicines for different clinical indications in the rural population. Principle purpose of using MD is controlling hypotension and while SMD is useful in peripheral circulatory failure treatment. In this study we evaluate the influence of these preparations on HbA1c (%) level.Methods: To find out the average plasma glucose concentration over prolonged period of time, MD and SMD were administered chronically to the male Sprague-Dawley rats at a dose of 40 mg/kg. After 28 days of chronic administration of MD and SMD the following changes were noted and Glycated Hemoglobin (HbA1c) level was determined.Results: The results of the study of in vitro quantitative determination of rat HbA1c concentrations in serum studies, MD demonstrated a negligible (0.61%) decrease in the HbA1c level of the blood of the male rat (p=0.902). Whereas SMD demonstrated a negligible (1.83%) increase in the HbA1c level of the blood of the male rat (p=0.782).Conclusions: Between these preparation MD slightly decreases HbA1c level of the blood of the male rat, whereas SMD found in increasing HbA1c level of the blood of the male rat.

Preclinical Anemia Panel Studies of “Makardhvaja” after Chronic Administration to Male Sprague-Dawley Rats

Makardhvaja (MD) is an Ayurvedic preparation used as a traditional medicine in the treatment of sexual dysfunction in the rural population. The effect of chronic administration of Makardhvaja on the hematological parameters and serum iron profi le was studied in this experiment. The acute toxicity test of MD recorded no death, even at the highest dose of 80 ml/kg body weight. During the chronic toxicity test, animals were divided into two groups. The fi rst group was given MD preparation at a dose of 40 mg/kg body weight for 28 days while the second group that served as the control received water for the same period. After 28 days of chronic administration of the MD preparation to the male Sprague-Dawley rats, the following hematological changes were noted. Erythrocytic indices such as red blood count (RBC), hemoglobin, Hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell volume distribution width (RDW) did not change signifi cantly. In the male rats, a statistically highly signifi cant (p=0.003) decrease (27.35%) in the serum iron level, an increase (26.42%) in the serum ferritin level, which, though not signifi cant, was prominent (p=0.120), and a statistically very highly signifi cant (p=0.001) decrease (47.05%) in the serum total iron binding capacity (TIBC) were noted.

Steroidal and Gonadotropin Hormone Profile Studies of a Classical Ayurvedic Preparation of “Makardhvaja” after Chronic Administration to Male Sprague-Dawley Rats

In this study, the effect of the classical Ayurvedic formulation of Makardhvaja (MD) on steroidal and gonadotropin hormone was evaluated after chronic administration. MD is used as a traditional medicine in the treatment of Rasayan in the rural population. The acute pharmacological test of MD recorded no death or any signs of effectivity even at the highest dose of 80 ml/Kg body weight. For chronic pharmacological evaluation, animals were divided into two groups. The first group was given MD preparation at a dose of 40 mg/kg body weight for 28 days while the second group that served as the control received water for the same period. After 28 days of chronic administration of the MD preparation, the following effects on the steroidal hormone panel were noted: There is a statistically significant (p 5 0.040) increase in the serum circulating progesterone level of the male rat. [20.38% increase]. The steroidal hormone indices such as serum circulating dehydroepiandrosterone sulfate (DHEA-S), serum circulating total testosterone, serum circulating 17-beta-Estradiol (E2) does not change significantly. The significant effects on the gonadotropin hormone profile after chronic administration were thus: There is a statistically significant (p 5 0.047) increase in the serum circulating luteinizing hormone (LH) level of the male rat [76.07% increase]. Serum circulating follicle stimulating hormone (FSH) level does not change significantly.

Neuronal maturation in the hippocampal dentate gyrus via chronic oral administration of Artemisa annua extract is independent of cyclooxygenase 2 signaling pathway in diet-induced obesity mouse model.

Recently, we reported that Artemisia annua (AA) has anti-adipogenic properties in vitro and in vivo. Reduction of adipogenesis by AA treatment may dampen systemic inflammation and protect neurons from cytokine-induced damage. Therefore, the present study was undertaken to assess whether AA increases neuronal maturation by reducing inflammatory responses, such as those mediated by cyclooxygenase 2 (COX-2). Mice were fed normal chow or a high-fat diet with or without chronic daily oral administration of AA extract (0.2 g/10 mL/kg) for 4 weeks; then, changes in their hippocampal dentate gyri were measured via immunohistochemistry/immunofluorescence staining for bromodexoxyuridine, doublecortin, and neuronal nuclei, markers of neuronal maturation, and quantitative western blotting for COX-2 and Iba-1, in order to assess correlations between systemic inflammation (interleukin-6) and food type. Additionally, we tested the effect of AA in an Alzheimer's disease model of Caenorhabditis elegans and uncovered a potential benefit. The results show that chronic AA dosing significantly increases neuronal maturation, particularly in the high-fat diet group. This effect was seen in the absence of any changes in COX-2 levels in mice given the same type of food, pointing to the possibility of alternate anti-inflammatory pathways in the stimulation of neurogenesis and neuro-maturation in a background of obesity.