Subscribe to RSS
DOI: 10.1055/s-0035-1545937
Upregulatory Effects of Nobiletin, a Citrus Flavonoid with Anti-dementia Activity, on the Gene Expression of mAChR, ChAT, and CBP
Publication History
received 22 October 2014
revised 17 March 2015
accepted 20 March 2015
Publication Date:
23 April 2015 (online)
Abstract
We previously showed that nobiletin, a polymethoxylated flavone from the peels of Citrus depressa Hayata, improves impaired memory in dementia model animals. It was also reported that nobiletin stimulates cAMP response element-dependent transcription through activation of the cAMP response element-binding protein signaling pathway. To determine whether nobiletin alters the expression of genes involved in learning and memory, we performed real-time polymerase chain reaction after treating PC12 cells with nobiletin. Nobiletin upregulated the expression of muscarinic acetylcholine receptor subtype M1, choline acetyltransferase, and cAMP response element-binding protein genes in the cells. The muscarinic acetylcholine receptor M1 and choline acetyltransferase mRNA levels reached maximum values at 6 h after nobiletin treatment, whereas the cAMP response element-binding protein mRNA levels peaked at 12 h. These results suggest that nobiletin enhanced the expression of genes involved in learning and memory by stimulating the cAMP response element-dependent transcription.
Key words
Nobiletin - Citrus depressa - Rutaceae - gene expression - muscarinic acetylcholine receptor - choline acetyltransferase-
References
- 1 Nagase H, Omae N, Omori A, Nakagawasai O, Tadano T, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochem Biophys Res Commun 2005; 337: 1330-1336
- 2 Matsuzaki K, Yamakuni T, Hashimoto M, Haque AM, Shido O, Mimaki Y, Sashida Y, Ohizumi Y. Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimerʼs disease model rats. Neurosci Lett 2006; 400: 230-234
- 3 Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C, Nakagawasai O, Tadano T, Yokosuka A, Mimaki Y, Sashida Y, Ohizumi Y. Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci 2007; 105: 122-126
- 4 Nakajima A, Yamakuni T, Matsuzaki K, Nakata N, Onozuka H, Yokosuka A, Sashida Y, Mimaki Y, Ohizumi Y. Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther 2007; 321: 784-790
- 5 Onozuka H, Nakajima A, Matsuzaki K, Shin R, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin, a citrus flavonoid, improves memory impairment and Aβ pathology in a transgenic mouse model of Alzheimerʼs disease. J Pharmacol Exp Ther 2008; 326: 739-744
- 6 Yamamoto Y, Shioda N, Han F, Moriguchi S, Nakajima A, Yokosuka A, Mimaki Y, Sashida Y, Yamakuni T, Ohizumi Y, Fukunaga K. Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation. Brain Res 2009; 1295: 218-229
- 7 Nagase H, Yamakuni T, Matsuzaki K, Maruyama Y, Kasahara J, Hinohara Y, Kondo S, Mimaki Y, Sashida Y, Tank AW, Fukunaga K, Ohizumi Y. Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry 2005; 44: 13683-13691
- 8 Lalli E, Lee JS, Lamas M, Tamai K, Zazopoulos E, Nantel F, Penna L, Foulkes NS, Sassone-Corsi P. The nuclear response to cAMP: role of transcription factor CREM. Philos Trans R Soc Lond B Biol Sci 1996; 351: 201-209
- 9 Chang JH, Vuppalanchi D, van Niekerk E, Trepel JB, Schanen NC, Twiss JL. PC12 cells regulate inducible cyclic AMP (cAMP) element repressor expression to differentially control cAMP response element-dependent transcription in response to nerve growth factor and cAMP. J Neurochem 2006; 99: 1517-1530
- 10 Levey AI. Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci U S A 1996; 93: 13541-13546
- 11 Benito E, Barco A. CREBʼs control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci 2010; 33: 230-240
- 12 Chen G, Zou X, Watanabe H, van Deursen JM, Shen J. CREB binding protein is required for both short-term and long-term memory formation. J Neurosci 2010; 30: 13066-13077