Abstract
We previously demonstrated that auraptene (AUR), a natural coumarin derived from citrus plants, exerts anti-inflammatory effects in the brain, resulting in neuroprotection in some mouse models of brain disorders. The present study showed that treatment with AUR significantly increased the release of glial cell line-derived neurotrophic factor (GDNF), in a dose- and time-dependent manner, by rat C6 glioma cells, which release was associated with increased expression of GDNF mRNA. These results suggest that AUR acted as a neuroprotective agent in the brain via not only its anti-inflammatory action but also its induction of neurotrophic factor. We also showed that (1) the AUR-induced GDNF production was inhibited by U0126, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2, and by H89, a specific inhibitor of protein kinase A (PKA); and (2) AUR induced the phosphorylation of cAMP response element-binding protein (CREB), a transcription factor located within the nucleus. These results suggest that AUR-stimulated gdnf gene expression was up-regulated through the PKA/ERK/CREB pathway in C6 cells.
Highlights
Auraptene (7-geranyloxycoumarin, AUR) is a coumarin derivative isolated from the peel of certain citrus fruits, and it is the most abundant form of naturally occurring geranyloxycoumarins
The present study revealed that AUR had the ability to induce glial cell line-derived neurotrophic factor (GDNF) release in C6 cells (Figure 2), and that the AUR-induced GDNF release was associated with increased expression of GDNF mRNA (Figure 4)
Considering these results and our findings suggests the possibility that AUR exerts reversible effects on U87 cells, devastating type of astrocytic tumor, and C6 cells, astrocytoma cells that resemble normal astrocytes
Summary
Auraptene (7-geranyloxycoumarin, AUR) is a coumarin derivative isolated from the peel of certain citrus fruits, and it is the most abundant form of naturally occurring geranyloxycoumarins. We used rat C6 glioma cells (rat glial tumor cell line), which have been frequently and extensively used as an alternative to astrocytes in primary culture [9,10,11,12,13], because these cells have similarities with primary astrocytes in culture [14,15] and have ability to synthesize/secrete high levels of GDNF [9,10,11]. Ianltt.eJr. nMaotl.ivSeci.t2o02a0s,t2r1o, c2y53tes in primary culture [9,10,11,12,13], because these cells have similarities with pri2mofa1r0y astrocytes in culture [14,15] and have ability to synthesize/secrete high levels of GDNF [9,10,11]. Lbartaeirn, itabnedcatmhaetcilteaarlsthoaht aGsDaNnFeius reoxpprroestescetdivaebuenffdeacnt tolynthnrooruagdhreonuetrtghiec bnreauinroannsdinththateiltoaclussochearsulaeunesuorforpordoetnectsti[v2e0–e2ff2e]c.t on noradrenergic neurons in the locus ceruleus of rodenItnst[h2i0s–s2t2u]d. y we successfully found that AUR had the ability to induce GDNF synthesis/secretion in C6Inctehlliss satnuddythwene sinuvcceesstisgfuatlleydfothuendsigthnaatl AtrUanRsdhaudcttihoen ambiolilteycutolei(nsd) uatcewGoDrkNtFhastynatllhoewsiesd/seAcrUetRiotno iinndCu6cceeglldsnaf ngdenteheenxpirnevsessioting.ated the signal transduction molecule(s) at work that allowed AUR to induce gdnf gene expression
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