Plenary lectures

Neuroprotective action of tianeptine against staurosporine- anddoxorubicin-induced apoptosis: caspase-3-independent effectDanuta Jantas, W³adys³aw Lasoñ

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12,PL 31-343 Kraków, Poland

Tianeptine has been reported to possess anti-apoptoticproperties against stress- and proinflammatorycytokines-induced cell damage in rodent brain as wellin in vitro models of neuronal and glia cell degenera-tion. However, the molecular and cellular mechanismof neuroprotection mediated by this drug has beenonly partially unraveled. The aim of the present studywas comparison of effectiveness of tianeptine andother antidepressants (imipramine, fluoxetine, citalo-pram, reboxetine, mirtazapine) in models of cell dam-age induced by activation of intracellular (staurospor-ine, St) and extracellular (doxorubicin, Dox) apop-totic pathways in primary cortical neurons and inretinoic acid-differentiated human neuroblastomaSH-SY5Y cell line. Tianeptine (0.01 and 0.1 μM) butnot other antidepressants showed neuroprotective ef-fects on St- and Dox-evoked cell death in primaryneurons and in SH-SY5Y cells as confirmed by bio-

chemical analysis (LDH release and MTT reductionassays) and microscopic evaluation. The neuroprotec-tion mediated by tianeptine was connected with at-tenuation of St- and Dox-induced DNA fragmentationbut not with influence on St- and Dox-inducedcaspase-3 activity. The neuroprotective action of tia-neptine was prevented by PI3-K (LY 294002) andMAPK/ERK1/2 (U0126) inhibitors. In the next partof the study on primary glia cells we demonstrated theprotective effects of all tested antidepressants(0.1–10 μM) against the cell damage induced by Doxas was confirmed by MTT reduction assay. The pres-ent study showed that tianeptine but not other antide-pressants clearly exerts neuroprotective effects.Moreover, the anti-apoptotic action of tianeptine inneuronal cells appears to engage PI3-K/Akt andMAPK/ERK1/2 survival pathways but is not con-nected with inhibition of caspase-3 activity.

The changing face of neurotoxinsRichard M. Kostrzewa1, John P. Kostrzewa1, Ryszard Brus2

�Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA;�Department of Nursing, High School of Strategic Planning, Koœcielna 6, PL 41-303 D¹browa Górnicza, Poland

Chemical neurotoxins, historically, have been re-garded as agents able to produce nerve damage orovert neurodegeneration. Starting with the era of “se-lective neurotoxins” in the 1950s, neurotoxins havetaken multiple forms, acting by a variety of mecha-

nisms: a) suppression of neurotrophins (anti-NerveGrowth Factor); b) production of intracellular reactiveoxygen species (6-OHDA); c) formation of a toxicmetabolite with specificity for mitochondrial com-plexes (MPTP � MPP+); d) impairment of neuro-

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transmitter synthetic enzymes (DSP-4); e) inactiva-tion of exocytosis (botulinum toxin); f) excitotoxinaction at unique receptor types (kainate); g) evolutionto a toxic species during continuous administration(cocaine); h) suicide inhibition of an intraneuronal en-zyme (3-nitropropionate); inactivation of ribosomalprotein (IgG-saporin); i) alkylation of the neuronaltransporter site (ethylcholine aziridinium); j) desensi-tization of membranous receptors (capsaicin). The listis not exclusive, and it has the caveat that many neu-rotoxins act by multiple means. Surely, many otherneurotoxins are yet to be discovered, and actions aredestined to be at sites not yet known. Also, the term“selective neurotoxin” is entering a grey zone. Rote-

none, a mitochondrial poison in any cell, is now givenlong-term to specifically model Parkinson’s disease –an outcome marked by dopaminergic neuronal dam-age accompanied by alpha-synuclein deposits. N-methyl-D-aspartate receptor (NMDA-R) antagonists,known neuroprotectants, become neurotoxic when ad-ministered during ontogeny. And the dopamine D2-Ragonist quinpirole, when administered repeatedly,produces life-long D2-R supersensitivity – a neuro-toxic outcome unaccompanied by any sign of overtneuronal damage. The character and definition ofa selective neurotoxin is amorphous, and is likely tobecome more uncertain in the future.

Neuroprotective effects of statins during ischemic strokeJacek Kurzepa

Department of Biochemistry and Molecular Biology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland

Ischemic stroke is the third leading cause of death andpatients’ disability in industrialized countries. Thestroke prevention, as well as a successful neuroprotec-tion during acute brain ischemia, is one of the urgentproblems of the current pharmacology. Inhibitors ofHMG-CoA reductse (statins) are widely appliedas a cholesterol-lowering drug. Numerous studiesstrongly suggest that the therapy with statins playsa role in stroke prevention mostly due to the protec-tion against carotid atherosclerosis. Statins, besidesthe antilipemic properties, posses numerous pleio-tropic activities that can bring the benefits during theacute phase of ischemic stroke. Among several pro-posed mechanisms of statins neuroprotective activity,the most important are: an increase in nitric oxidebioavailability (regulation of cerebral perfusion and

improvement of endothelial function), antioxidantproperties and anti-inflammatory effects. In animalmodels of stroke the administration of statins, beforethe onset of cerebrovascular event, significantly de-creases the ischemic focus volume. The early statinstreatment from the first day of stroke results in the de-crease of serum level of proinflammatory compoundsas TNF�, IL-6. The serum levels of CRP, MMP-9/TIMP-1 ratio and tau protein (the biomarker of neu-rons damage) are also decreased in comparison withnon-statins patients. Despite the clear effect on bio-chemical parameters during the acute phase ofischemic stroke, statins effect on patients clinical out-come met the same fate as other potential neuropro-tective compounds – is uncertain.

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