1.CNS safety pharmacology: A focus on cognitive functions.
Hernier AM1, Froger-Colléaux C2, Castagné V1. J Pharmacol Toxicol Methods. 2016 Apr 9. pii: S1056-8719(16)30029-6. doi: 10.1016/j.vascn.2016.04.002. [Epub ahead of print]
INTRODUCTION: The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint.
2.Learning and memory in the forced swimming test: effects of antidepressants having varying degrees of anticholinergic activity.
Enginar N1, Yamantürk-Çelik P2, Nurten A3, Güney DB3. Naunyn Schmiedebergs Arch Pharmacol. 2016 Apr 1. [Epub ahead of print]
The antidepressant-induced reduction in immobility time in the forced swimming test may depend on memory impairment due to the drug's anticholinergic efficacy. Therefore, the present study evaluated learning and memory of the immobility response in rats after the pretest and test administrations of antidepressants having potent, comparatively lower, and no anticholinergic activities. Immobility was measured in the test session performed 24 h after the pretest session. Scopolamine and MK-801, which are agents that have memory impairing effects, were used as reference drugs for a better evaluation of the memory processes in the test. The pretest administrations of imipramine (15 and 30 mg/kg), amitriptyline (7.5 and 15 mg/kg), trazodone (10 mg/kg), fluoxetine (10 and 20 mg/kg), and moclobemide (10 and 20 mg/kg) were ineffective, whereas the pretest administrations of scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) decreased immobility time suggesting impaired "learning to be immobile" in the animals.
3.Glucose deprivation stimulates Cu2+ toxicity in cultured cerebellar granule neurons and Cu2+-dependent zinc release.
Isaev NK1, Genrikhs EE2, Aleksandrova OP2, Zelenova EA2, Stelmashook EV2. Toxicol Lett. 2016 Apr 5;250-251:29-34. doi: 10.1016/j.toxlet.2016.04.002. [Epub ahead of print]
Copper chloride (0.01mM, 2h) did not have significant influence on the survival of cerebellar granule neurons (CGNs) incubated in balanced salt solution. However, CuCl2 caused severe neuronal damage by glucose deprivation (GD). The glutamate NMDA-receptors blocker MK-801 partially and antioxidant N-acetyl-l-cysteine (NAC) or Zn2+ chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) almost entirely protected CGNs from this toxic effect. Measurements of intracellular calcium ions using Fluo-4 AM, or zinc ions with FluoZin-3 AM demonstrated that 1 h-exposure to GD induced intensive increase of Fluo-4 but not FluoZin-3 fluorescence in neurons. The supplementation of solution with CuCl2 caused an increase of FluoZin-3, Fluo-4 and CellROX Green (reactive oxygen species probe) fluorescence by GD. The stimulation of Fluo-4 but not FluoZin-3 fluorescence by copper could be prevented partially by MK-801 and as well as CellROX Green fluorescence by NAC at GD.
4.Glutathione-Induced Calcium Shifts in Chick Retinal Glial Cells.
Freitas HR1, Ferraz G2, Ferreira GC1,3, Ribeiro-Resende VT1, Chiarini LB4, do Nascimento JL5, Matos Oliveira KR5, Pereira Tde L5, Ferreira LG6, Kubrusly RC7, Faria RX8, Herculano AM5, Reis RA1. PLoS One. 2016 Apr 14;11(4):e0153677. doi: 10.1371/journal.pone.0153677. eCollection 2016.
Neuroglia interactions are essential for the nervous system and in the retina Müller cells interact with most of the neurons in a symbiotic manner. Glutathione (GSH) is a low-molecular weight compound that undertakes major antioxidant roles in neurons and glia, however, whether this compound could act as a signaling molecule in neurons and/or glia is currently unknown. Here we used embryonic avian retina to obtain mixed retinal cells or purified Müller glia cells in culture to evaluate calcium shifts induced by GSH. A dose response curve (0.1-10mM) showed that 5-10mM GSH, induced calcium shifts exclusively in glial cells (later labeled and identified as 2M6 positive cells), while neurons responded to 50mM KCl (labeled as βIII tubulin positive cells). BBG 100nM, a P2X7 blocker, inhibited the effects of GSH on Müller glia. However, addition of DNQX 70μM and MK-801 20μM, non-NMDA and NMDA blockers, had no effect on GSH calcium induced shift.