Mechanisms of penitrem-induced cerebellar granule neuron death in vitro:
Possible involvement of GABAA receptors and oxidative processes
https://doi.org/10.1016/j.neuro.2013.01.004
NeuroToxicology 2013 vol. 35, 129-136
Berntsen, H. F.
Wigestrand, M. B.
Bogen, I. L.
Fonnum, F.
Walaas, S. I.
Moldes-Anaya, A.
The fungal neurotoxin penitrem A has previously been found to cause
neurological disorders in animals and humans after ingestion of
contaminated food and/or feed. It penetrates the blood–brain-barrier and
causes cerebellar pathology in rats, including mild effects on granule
neurons. The aim of the current study was to investigate the potential
toxicity of penitrem A in rat cerebellar granule neurons in vitro, and
to examine the involvement of the GABAA, AMPA and NMDA receptors,
intracellular signalling pathways as well as the role of oxidative
stress in penitrem A-induced neuronal death. Cerebellar granule cells
were exposed to penitrem A, alone or together with different
pharmacological agents, before cell survival was assessed with the MTT
assay or formation of reactive oxygen species (ROS) was investigated
with the DCF assay. Penitrem A caused a time- and
concentration-dependent reduction in cell survival, as well as a
concentration-dependent increase in ROS production. Co-incubation with
diazepam, GABA, BAPTA-AM, vitamin E, SP600125 and cyclosporine A
significantly reduced cell death. Our results show that penitrem A is
toxic to cerebellar granule neurons in vitro. Further, ROS production
and the GABAA receptor are likely to be involved in the induction of
neuronal death following penitrem A exposure. A disruption of calcium
homeostasis and activation of the JNK pathway may also play a role in
penitrem A neurotoxicity.
Keywords: Penitrem A, Neurological disorders, Cerebellar granule neurons, Oxidative stress, GABA receptors
Avainsanat: Penitrem A, neurologiset sairaudet, hermoston sairaudet, oksidatiivinen stressi, GABA-reseptorit
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