TSPO imaging in animal models of brain diseases

Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

Chronic Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta) with Cisterna Magna Ports: Update on Refinements

More than 20 y ago, we developed an animal model for chronic and continuous collection of cerebrospinal fluid (CSF) from conscious rhesus macaques. Since our previous publication in 2003, we have successfully implanted 168 rhesus macaquesusing this approach. Our experience enables us to provide up-to-date information regarding the model, including refinementsto our implant design, reductions in maintenance, and new procedures for dealing with contamination. The results of our experiences have reduced the number of surgeries required and helped to increase the longevity of the implant, with some functioning for more than 18 y. Building on our success in rhesus macaques, we attempted to develop similar animal models in the African green monkeys and dogs but have been unable to develop reliable chronic models for CSF collection in these species.

ANTI-ARTHRITIC ACTIVITY OF AMARANTHUS ROXBURGHIANUS NEVSKI HYDROALCOHOLIC AREAL PLANT EXTRACT IN ACUTE AND CHRONIC MODELS IN ALBINO WISTAR RATS

Objective: Evaluation of anti-arthritic activity of hydroalcoholic extract of Amaranthus roxburghianus Nevski aerial parts in albino Wistar rats. Materials and Methods: A. roxburghianus dried aerial parts were extracted with ethyl alcohol: water (70:30) ratio, respectively, by the hot Soxhlet method. Hydroalcoholic A. roxburghianus extract (HARE) was further concentrated to obtain a semisolid residue. Two doses 200 and 400 mg/kg of HARE were tested against formaldehyde-induced acute non-immunological and Freund’s complete adjuvant (FCA)-induced chronic immunological arthritis in albino Wistar rats. Arthritis assessment was done by morphological studies (paw volume, paw diameter, and body wt.) and hematological parameters radiological, histopathological, and organ wt. studies were also done on the 28th day after animals were sacrificed. Results: Dose-dependent and significant inhibition of edema were observed in both acute as well as chronic models. The extract at dose 400 mg/kg showed most potent and significant (p<0.05) paw edema inhibition which is supported by the results of paw volume and diameter, hematological parameters, in FCA-induced arthritis model. Treatment with HARE also decreased the histopathological alterations induced by FCA model. Conclusion: HARE protects synovial membrane by improving the health status exhibits promising anti-arthritic activity. This finding thus supports the traditional use of A. roxburghianus for arthritis. However, further studies are needed to carry out the isolation of active constituents of the fraction responsible for the activity.

Synergistic Anxiolytic Effect of Curcumin and Zinc on Acute and Chronic Models of Anxiety in Mice

Introduction: Anxiety disorders being ranked at sixth position in the global burden of diseases is affecting over 250 million people. Curcumin, an active phytochemical flavonoid, has shown to induce the monoamine neurotransmitter serotonin, a prominent neurotransmitter in modulating the brain state in anxiety. Also, evidences reveal that zinc plays a key role in human neurodevelopment and supplementation of zinc enhanced the efficacy of antidepressant drugs through synergistic action. Aim: To evaluate the synergistic antianxiety effect of curcumin and zinc on acute and chronic models of anxiety in male swiss albino mice. Materials and Methods: A total of 36 male Swiss Albino mice, weighing 20-30 g, were randomly grouped to six groups, such that each group consisted of six mice. Group 1 served as control. Group 2 received standard drug diazepam 3 mg/kg Intra Peritoneal (IP). Group 3 and 4 received curcumin at doses of 5 and 10 mg/kg, respectively. Group 5 and 6 received curcumin at doses 5 and 10 mg/kg per oral (p.o) along with zinc chloride 10 mg/kg IP, respectively. The anxiolytic effect was studied in two validated models of anxiety such as Elevated Plus Maze (EPM) test and light/dark box test. Each animal was tested initially in the EPM followed by light/dark box test after administration of drug/vehicle one hour prior to the experiment in acute study. Following a washout period of one week, the animals were utilised for the study of chronic anxiolytic effect wherein the drugs were administered once daily for 14 days. Results: Curcumin at doses of 5 mg/kg and 10 mg/kg with zinc chloride 10 mg/kg showed a significant increase in the number of entries and time spent in open arm in EPM both on acute and chronic administration (p<0.001). In the light/dark box test, curcumin at doses of 5 mg/kg and 10 mg/kg when given along with zinc chloride 10 mg/kg significantly increased the number of entries and time spent in the light compartment both in acute and chronic models (p<0.001). Conclusion: The anxiolytic effect of synergistic action of curcumin and zinc was efficacious in both acute and chronic models of anxiety in mice.

Long-Lasting, Antinociceptive Effects of pH-Sensitive Niosomes Loaded with Ibuprofen in Acute and Chronic Models of Pain

Ibuprofen is one of the non-steroidal anti-inflammatory drugs (NSAIDs) widely used to treat pain conditions. NSAIDs encounter several obstacles to passing across biological membranes. To overcome these constraints, we decided to study the effects of a new pH-sensitive formulation of niosomes containing Polysorbate 20 derivatized by Glycine and loaded with ibuprofen (NioIbu) in several animal models of pain in mice. We performed two tests commonly used to study acute antinociceptive activity, namely the writhing test and the capsaicin test. Our results demonstrated that NioIbu, administered 2 h before testing, reduced nociception, whereas the free form of ibuprofen was ineffective. In a model of inflammatory pain, hyperalgesia induced by zymosan, NioIbu induced a long-lasting reduction in hyperalgesia in treated mice. In a model of neuropathic pain induced by sciatic nerve chronic constriction, NioIbu reduced both neuropathy-induced allodynia and hyperalgesia. The results obtained in our experiments suggest that pH-sensitive niosomes containing Polysorbate 20 derivatized by Glycine is an effective model for NSAIDs delivery, providing durable antinociceptive effects and reducing the incidence of side effects.

DOSE DEPENDENT ANTIHYPERLIPIDEMIC ACTIVITY OF ETHANOLIC EXTRACT OF MENTHA ARVENSIS LEAVES IN TRITON AND HIGH CHOLESTEROL DIET INDUCED RATS

A study was undertaken to evaluate antihyperlipidemic activity of ethanolic extract of leaves of Mentha arvensis in Triton and high cholesterol diet induced hyperlipidemic male albino Wstar rats. Acute hyperlipidemia was induced by administration of Triton WR-1339 (100 mg / kg i.v.) to the male albino Wstar rats. In chronic models; the animals were fed with high cholesterol diet for a period of 10 days. EEMA leaves at a dose of 200 and 400 mg/kg of body weight were administered at a single dose per day to the hyperlipidemic induced rats for a period of 14 days. In hyperlipidemic rats there is significant increase in TC, TG, LDL, VLDL level and significant decrease in HDL level, but after post treatment with EEMA, there was a significant decrease in TC, TG, LDL, VLDL and increase in HDL level. Post treatment with EEMA leaves lowered levels of total protein and triglycerides.