+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Small interfering RNA-mediated knockdown of protein kinase C zeta attenuates domoic acid-induced cognitive deficits in mice

, : Small interfering RNA-mediated knockdown of protein kinase C zeta attenuates domoic acid-induced cognitive deficits in mice. Toxicological Sciences 128(1): 209-222

Accumulated evidence indicates that domoic acid (DA)–induced excitatory neuronal injury is associated with excessive reactive oxygen species (ROS) production. Protein kinase C zeta (PKC-)/nicotinamide adenine dinucleotide phosphate (NOX) signaling regulates ROS levels and is involved in various neurodegenerative disorders including excitoneurotoxicity. Our previous studies have demonstrated that ROS-induced activation of the stress-activated protein kinase/c-jun-N-terminal kinase (SAPK/JNK) pathway plays a key role in the pathogenesis of cognitive deficits induced by DA. However, the precise biological mechanisms underlying these effects are not well understood. In this study, we investigate whether the PKC- mediates DA-induced cognitive deficits and further explored the potential molecular processes. DA treatment significantly increased the expression of PI3K p85α, and PKC- in the hippocampus of mice, which promoted the p47phox phosphorylation and expression, enhanced NOX activity, and increased the levels of ROS and protein carbonyls. In turn, the abnormal ROS levels in the hippocampus of DA-treated mice activated SAPK/JNK pathway, decreased FoxO1 phosphorylation, stimulated the nuclear translocation of FoxO1, activated FasL/Fas signaling, and promoted the activation of caspase-8 and caspase-3, which resulted in neuron apoptosis and cognitive deficits in mice. However, PKC- knockdown reversed these changes in mice. It was further demonstrated that FoxO1 was a downstream target of SAPK/JNK signaling by FoxO1 small interfering RNA and SP6125 (an inhibitor of SAPK/JNK pathway) treatment. Additionally, SP6125 treatment or FoxO1 knockdown also blocked FasL/Fas signaling–dependent apoptosis and improved DA-induced cognitive deficits in the hippocampus of mice. These results suggest that PKC- could be a possible target for the prevention or treatment of cognitive deficits in excitotoxic and other brain disorders.


PMID: 22474074

DOI: 10.1093/toxsci/kfs124

Other references

Cardona, F.; Bonanni, M.; Soldaini, G.; Goti, A., 2008: One-pot synthesis of nitrones from primary amines and aldehydes catalyzed by methyltrioxorhenium. One-pot condensation/oxidation of primary amines and aldehydes using urea-hydrogen peroxide (UHP) as the stoichiometric oxidant in the presence of methyltrioxorhenium (MTO) as catalyst affords nitrones in a simple and regioselective manner. UHP is...

Tedesco Steven, 2003: Use of iodine surface geochemistry for exploration of Silurian reefs in the Illinois and Michigan Basins with other examples. Annual Conference - Ontario Petroleum Institute 42: (Paper No

Scheps, R., 1989: Efficient laser diode pumped Nd lasers. Results are presented for laser diode axially pumped Nd:YAG and Nd:BEL lasers. For Nd:YAG, in excess of 870 mW was obtained with a differential slope efficiency of 56%, and for Nd:BEL in excess of 635 mW was obtained with a slope efficiency of 46%...

Sadava, D.; Kane, S., 2001: Liposomal daunorubicin overcomes drug resistance in human breast, ovarian and lung cancer cells. International Journal of Antimicrobial Agents 17(Supplement 1): S13, June

Ma, D.; Zerangue, N.; Raab Graham, K.; Jan,; Jan, L.Y.h, 2002: Potassium channel trafficking. Journal of General Physiology 120(1): 1a, July

Cheung, N.W.; Chipps, D.; Hendon, S.; McLean, M., 2005: Letter regarding "Comparison of blood glucose meters in Australia" [Diab. Res. Clin. Pract., doi:10.1016/j.diabres.2005.05.13. Diabetes Research and Clinical Practice 72(2): 216-7; Author Reply 218

An, H.K., 1978: Trigger finger, a report on a series of cases. Medical Journal of Malaysia 33(1): 7-9

Kalinin, A.P.; Fekson, E.G.; Nurmanbetov, D.N.; Agafonov, B.V., 1986: Arterial hypertension in patients with primary hyperparathyroidism. Terapevticheskii Arkhiv 58(10): 104-107

Jiang, Y.C.; Markind, J.E., 1997: Losartan versus ACE inhibitors in the treatment of hypertension. Annals of PharmacoTherapy 31(11): 1388-1391

Anonymous, 1999: News that isn't ready to use. Harvard Women's Health Watch 6(9): 1-1