4′-Demethylnobiletin

4′-Demethylnobiletin is a bioactive metabolite that activates the PKA/ERK/CREB signaling pathway, enhances CRE-mediated transcription in hippocampal neurons, and reverses memory impairment associated with NMDA receptor antagonism by stimulating ERK signaling.

4′-Demethylnobiletin (1-100 μM, 0-60 min) can activate the phosphorylation of ERK and CREB in rat hippocampal neurons in a time- and concentration-dependent manner, and in a PKA/MEK/ERK pathway-dependent manner, It can also stimulate CRE-mediated transcription by activating PKA/MEK/ERK-dependent signaling pathways^[1].

4′-Demethylnobiletin (10 or 50 mg/kg, ip, once daily for seven consecutive days) dose-dependently reverses MK-801-induced learning impairment in male ddY mice without affecting the mice's mobility . Mice treated with MK-801 shows less freezing than control mice and induced inhibition of ERK learning activation in the hippocampus of mice, which is also reversed by 4′-Demethylnobiletin^[1].
4′-Demethylnobiletin (10 or 50 mg/kg, ip, once daily for seven consecutive days) reverses the inhibition of MK-801 on NMDA-stimulated phosphorylation of ERK and PKA substrates in hippocampal neurons^[1].

References:
[1]. Md Al Rahim, et al. 4'-Demethylnobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade. Biochemistry. 2009 Aug 18;48(32):7713-21.