ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.     

Über die Wirkung verschiedener Faktoren,insbesondere narkotisierender Substanzen auf die vitale Methylenblaufärbung bei in vitro gezüchteten Fibrocyten

Ohne Zusammenfassung     

Highly potent side chain–main chain cyclized dermorphin–deltorphin analogues: An integrated approach including synthesis,bioassays, NMR spectroscopy and molecular modelling

Our continuing efforts to study structure–activity relationships of peptide opioids have resulted in the synthesis of a series of cyclic opioids related to dermorphins and deltorphins. The biological activities of the compounds have been determined and the conformational analyses carried out using ¹H-NMR spectroscopy and molecular modelling. The three compounds in the series Tyr-c[D -Orn-Phe-Ala], Tyr-c[D -Lys-Phe-Ala], and Tyr-c[A₂Bu-Phe-Ala-Leu] are cyclized via a lactam bridge from the side-chain of the residue at the second position with the carboxyl terminus of each compound. The molecules incorporate 12-, 13- and 14-membered rings, respectively. They include a phenylalanine at the third position which is a distinguishing characteristic of dermorphins and deltorphins. The guinea pig ileum and mouse vas deferens assays show that the compounds are highly active at both μ- and δ-opioid receptors. The compounds are all highly effective antinociceptive agents as measured by the intrathecal rat hot plate test. Conformational analyses of the molecules indicate that they can adopt topochemical arrays required for bioactivity at both μ- and δ-receptors which explains their high activity in both guinea pig ileum and mouse vas deferens in vitro assays. The results support our models for μ- and δ-receptor activity for constrained peptide opioids.     

Verging on Extra-Vagance: Anthropology, History, Religion, Literature, Arts… Showbiz.

Verging on Extra-Vagance: Anthropology, History, Religion, Literature, Arts… Showbiz. James A. Boon. Princeton, NJ: Princeton University Press, 1999. 361 pp.