Unexpected Neuronal Protection of SU5416 Against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthase.
Unexpected Neuronal Protection of SU5416 against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthase.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(9): e46253
Cui W, Zhang Z, Li W, Mak S, Hu S, Zhang H, Yuan S, Rong J, Choi TC, Lee SM, Han Y
SU5416 was originally designed as a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) for cancer therapy. In this study, we have found for the first time that SU5416 unexpectedly prevented 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neuronal apoptosis in cerebellar granule neurons, and decreased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons and impairment of swimming behavior in zebrafish in a concentration-dependent manner. However, VEGFR-2 kinase inhibitor II, another specific VEGFR-2 inhibitor, failed to reverse neurotoxicity at the concentration exhibiting anti-angiogenic activity, strongly suggesting that the neuroprotective effect of SU5416 is independent from its anti-angiogenic action. SU5416 potently reversed MPP(+)-increased intracellular nitric oxide level with an efficacy similar to 7-nitroindazole, a specific neuronal nitric oxide synthase (nNOS) inhibitor. Western blotting analysis showed that SU5416 reduced the elevation of nNOS protein expression induced by MPP(+). Furthermore, SU5416 directly inhibited the enzyme activity of rat cerebellum nNOS with an IC(50) value of 22.7 µM. In addition, knock-down of nNOS expression using short hairpin RNA (shRNA) abolished the neuroprotective effects of SU5416 against MPP(+)-induced neuronal loss. Our results strongly demonstrate that SU5416 might exert its unexpected neuroprotective effects by concurrently reducing nNOS protein expression and directly inhibiting nNOS enzyme activity. In view of the capability of SU5416 to cross the blood-brain barrier and the safety for human use, our findings further indicate that SU5416 might be a novel drug candidate for neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.
HubMed – drug
Individual and county-level factors associated with use of multiple prescribers and multiple pharmacies to obtain opioid prescriptions in california.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(9): e46246
Han H, Kass PH, Wilsey BL, Li CS
Use of multiple prescribers and pharmacies is a means by which some individuals misuse opioids. Community characteristics may be important determinants of the likelihood of this phenomenon independent of individual-level factors. This was a retrospective cohort study with individual-level data derived from California’s statewide prescription drug monitoring program (PDMP) and county-level socioeconomic status (SES) data derived from the United States Census. Zero-truncated negative binomial (ZTNB) regression was used to model the association of individual factors (age, gender, drug schedule and drug dose type) and county SES factors (ethnicity, adult educational attainment, median household income, and physician availability) with the number of prescribers and the number of pharmacies that an individual used during a single year (2006). The incidence rates of new prescriber use and new pharmacy use for opioid prescriptions declined across increasing age groups. Males had a lower incidence rate of new prescriber use and new pharmacy use than females. The total number of licensed physicians and surgeons in a county was positively, linearly, and independently associated with the number of prescribers and pharmacies that individuals used for prescription opioids. In summary, younger age, female gender, and living in counties with more licensed physicians and surgeons were associated with use of more prescribers and/or more pharmacies for obtaining prescription opioids.
HubMed – drug
Quantification of ligand binding to g-protein coupled receptors on cell membranes by ellipsometry.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(9): e46221
Kriechbaumer V, Nabok A, Widdowson R, Smith DP, Abell BM
G-protein-coupled receptors (GPCRs) are prime drug targets and targeted by approximately 60% of current therapeutic drugs such as ?-blockers, antipsychotics and analgesics. However, no biophysical methods are available to quantify their interactions with ligand binding in a native environment. Here, we use ellipsometry to quantify specific interactions of receptors within native cell membranes. As a model system, the GPCR-ligand CXCL12? and its receptor CXCR4 are used. Human-derived Ishikawa cells were deposited onto gold coated slides via Langmuir-Schaefer film deposition and interactions between the receptor CXCR4 on these cells and its ligand CXCL12? were detected via total internal reflection ellipsometry (TIRE). This interaction could be inhibited by application of the CXCR4-binding drug AMD3100. Advantages of this approach are that it allows measurement of interactions in a lipid environment without the need for labelling, protein purification or reconstitution of membrane proteins. This technique is potentially applicable to a wide variety of cell types and their membrane receptors, providing a novel method to determine ligand or drug interactions targeting GPCRs and other membrane proteins.
HubMed – drug
In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(9): e46196
Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, Jan C, Chaigneau M, Hantraye P, Lestage P, Dhenain M
Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimer’s disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.
HubMed – drug
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