Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP⁺)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP⁺-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.     

Delivery of Brain-Derived Neurotrophic Factor via Nose-to-Brain Pathway

Purpose  

To investigate the plausibility of delivering brain-derived neurotrophic factor (BDNF) to brain via nose-to-brain pathway using chitosan as barrier-modulating agent.     

Protective effect of Sargassum polycystum (brown alga) against acetaminophen-induced lipid peroxidation in rats

Lipid peroxidation is believed to play an important role in the pathogenesis of several diseases, such as cancer, diabetic mellitus and liver injury. Aqueous and ethanol extracts of Sargassum polycystum C. Agardh (Phaeophyta) were screened for their protective effects against acetaminophen (ACP; Paracetamol)-induced lipid peroxidation in rats. A single dose of acetaminophen significantly elevated the levels of lipid peroxides (LPO) with decreased levels of free radical scavenger enzymes (SOD, CAT, GSH, GPx, GST) in liver homogenate. The oral pretreatment of rats with ethanol and aqueous extracts of Sargassum polycystum C. Agardh (100 mg, 200 mg[sol ]kg body wt[sol ]day respectively, for a period of 15 days) significantly reduced the acetaminophen-induced oxidative stress in rats. The animals treated with the ethanol and aqueous extracts alone did not show any toxicity on liver tissue. This observation shows that the seaweed crude extracts probably acted to protect against acetaminophen-induced lipid peroxidation through their free radical scavenging property.     

Anti-inflammatory effect of Spirulina fusiformis on adjuvant-induced arthritis in mice

The present study was carried out to evaluate the anti-inflammatory effect of Spirulina fusiformis on adjuvant-induced arthritis in mice. Arthritis was induced by intra dermal injection of complete freund's adjuvant (0.1 ml) into the right hind paw of Swiss albino mice. Spirulina fusiformis (800 mg/kg/b.wt) was orally administered for 8 d (from 11th to 18th day) to arthritic animals after adjuvant injection. The anti-inflammatory activity of Spirulina fusiformis was assessed by measuring paw volume, body weight, levels of lysosomal enzymes, tissue marker enzymes and glycoproteins in control and experimental animals. In adjuvant-induced arthritic animals, the levels of lysosomal enzymes, tissue marker enzymes, glycoproteins and the paw volume were increased significantly. However the body weight was found to be reduced when compared to control animals. Oral administration of Spirulina fusiformis (800 mg/kg/b.wt) significantly altered these above physical and biochemical changes observed in arthritic animals to near normal conditions. Hence results of this study clearly indicate that Spirulina fusiformis has promising anti-inflammatory activity against adjuvant-induced arthritic animals.     

Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy

Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (s.c.) doses of 2.25 microg/kg every week and s.c. doses of 6.75 microg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after s.c. doses of 0.5 microg/kg every week to 15 microg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important.     

A preliminary study on plasma concentration achieved following intrapterygomandibular space injection of dexamethasone as a route of drug delivery with lignocaine inferior alveolar nerve block–correlation of clinical effects

Purpose

To determine the quantity of dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone when co-administered with inferior alveolar nerve block correlating with the clinical effects in the postoperative phase.

Objective

A preliminary prospective study to evaluate the dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone with 2% lignocaine inferior alveolar nerve block to achieve hemi-mandibular anesthesia for minor oral surgical procedures and derive clinical correlations.

Background

Dexamethasone is a glucocorticoid, chiefly used for the management of postsurgical sequelae like trismus and swelling in maxillofacial surgical practice. Conventionally, parenteral dexamethasone is administered via intravenous or intramuscular route. Intrapterygomandibular space injection is a novel route of steroid delivery described in literature. For minor oral surgical procedures in maxillofacial surgical practice requiring inferior alveolar nerve block, dexamethasone can be administered along with local anesthetic through a single injection as a mixture (twin mix).

Methods

Prospective double-blind randomized clinical trial was designed to evaluative plasma concentration of dexamethasone achieved following injection of a freshly prepared mixture of 1.8 ml of 2% lignocaine with adrenaline (1:200000) and 1 ml (4 mg) dexamethasone [2.8 ml solution of twin mix] in the pterygomandibular space. The 30 candidates included for the trial were randomly split into three study groups (ten each)—(1) control group (C); (2) intramuscular group (IM); (3) intraspace group (IS).

Results

The mean plasma dexamethasone concentration at 30 min postinjection in group IM was 226.41?±?48.67 ng/ml and for IS group it was 209.67?±?88.13 ng/ml. Post hoc (Bonferroni-Holm test) intergroup comparison for plasma dexamethasone concentration (IM and IS) was found statistically insignificant (P?=?0.605).

Conclusion

Intraspace route of drug administration can be utilized to deliver dexamethasonized local anesthetics safely with predictable clinical effects in the patients requiring mandibular minor oral surgery under local anesthesia.

     

The prevalence of Vibrio spp. in drinking water and environmental samples in Vellore South India.

The prevalence of Vibrio cholerae in drinking water, lakes and sewage outfalls during July and August 1996 in Vellore, India was determined. Drinking water samples were collected on single occasions from 12 sites in different geographic areas of the town where cholera had been reported. Samples of water, plankton and sediment were collected from fixed sites at three lakes on three occasions separated by at least 3 days during the course of the study. Samples from open sewers were taken from two representative sites in four areas of the town. Bacteria isolated from samples were identified by standard biochemical tests and isolated strains of V. cholerae tested for their ability to agglutinate O1 and O139 antisera. Water samples from lakes were also tested for the presence of V. cholerae O1 and O139 by fluorescent antibody staining. Non-O1, non-O139 strains of V. cholerae were detected in 41% of drinking water samples and 100% of water, sediment and plankton samples from the test lakes. Eighty-seven per cent of open sewers sampled contained viable non-O1, non-O139 V. cholerae. Fluorescent antibody staining gave positive results for V. cholerae O1 and O139 for all water samples from the three lake sites. Strains of Aeromonas spp. were isolated from 58% of drinking water samples and from 66% of sediment, 77% of plankton and 55% of water samples from lakes. All open sewers sampled contained Aeromonas spp. PCR amplification employing specific primers demonstrated that none of the non-agglutinating V. cholerae isolates contained the ctx operon. The non-O1, non-O139 V. cholerae isolates showed different patterns of antibiotic resistance to ampicillin, ciprofloxacin, chloramphenicol, tetracycline and trimethoprim.     

Antihepatotoxic nature of Ulva reticulata (Chlorophyceae) on acetaminophen-induced hepatoxicity in experimental rats

Ulva reticulata, a marine edible green alga, is a known source of proteins, vitamins, and sulfated polysaccharides. Though there are many reports in the literature regarding the composition and antiviral property of Ulva sp., studies of the antihepatotoxic property of green seaweeds in animal model are scarce. We have studied the antihepatotoxic nature of this marine green edible alga, U. reticulata, in a hot water extract (150 mg/kg of body weight for a period of 15 days) against acetaminophen- induced hepatotoxicity in experimental albino rats. The acetaminophen-induced rats showed significant elevation in levels of the serum marker enzymes aspartate transaminase and alanine transaminase and of lipid peroxides in liver tissue with decreased levels of antioxidant enzymes such as superoxide dismutase and catalase. The levels of reduced glutathione and vitamins (E and C) were also decreased in the liver tissue of acetaminophen-intoxicated rats. The oral pretreatment with a hot water extract of U. reticulata reduced the hepatotoxicity triggered by acetaminophen considerably by improving the antioxidant status in experimental animals with depleted levels of lipid peroxides. These results indicate that the oral pretreatment with a hot water extract of U. reticulata in rats is effective in reducing the hepatic oxidative stress via free radical scavenging properties, suggesting an antihepatotoxic activity.