Nobiletin has a trifecta of procognitive effects: it boosts excitatory signaling and long-term potentiation (LTP) by concomitantly increasing AMPA receptor open probability and upregulating NMDA receptor subunit transcription, promotes neurite growth in a manner analogous to Nerve Growth Factor (NGF), and rescues cognitive impairments in animal models of Alzheimer’s disease.
Nobiletin is a small molecule flavanoid derived from citrus peels that was first identified by Nagase’s group in Japan when they conducted a screen for substances exhibiting neurotrophic activity. In their 2005 paper, they found that Nobiletin rescued bulbectomy-induced memory impairment and elicited neurite outgrowth in PC12D cells (a rat pheochromocytoma cell line) in a manner analogous to Nerve Growth Factor (NGF). Since Nobiletin-induced neurite outgrowth was inhibited by PD98059 and U0126 but not K252a, they concluded that Nobiletin induced a dose-dependent enhancement of Erk/MAP kinase phosphorylation, resulting in the stimulation of CREB phosphorylation and CRE-mediated transcription.
(CREB or cAMP response element-binding protein is a cellular transcription factor with well-documented roles in neuronal plasticity, learning and memory, and is indispensable to spatial memory consolidation.) Finally, Nagase’s group reported that Nobiletin inhibited calcium/cAM-dependent phosphodiesterases in vitro. (Cyclic nucleotide Phosphodiesteases terminate the action of the second messenger cAMP, and therefore phosphodiesterase inhibition augments intracellular signal transduction.)
Nobiletin potentiates excitatory AMPA signaling by augmenting PKA-mediated phosphorylation of the GluR1 subunit
In 2007, Kentaro Matsuzaki et al reported that the citrus flavonoid Nobiletin potentiates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents by augmenting protein kinase A (PKA)-mediated phosphorylation of the GluR1 AMPA receptor subunit and enhances the postsynaptic response to glutamate in murine hippocampus. Moreover, their electrophysiological data suggest that nobiletin enhanced synaptic transmission at CA1 pyramidcal cell synapses in hippocampal slices by a postsynaptic mechanism.
Three phosphorylation sites have been identified at the GluR1 AMPA receptor at the C-terminal intracellular domain: (1) Ser 818 (the PKC site), (2) Ser 831 (the calcium/calmodulin-dependent protein kinase II (CaMK II) or protein kinase C (PKC) site) and Ser 845 (the PKA site). The phosphorylation of the GluR1 subunit at Ser 845 is the best characterized, and has been demonstrated to increase peak open probability of AMPA channels which enhances the strength of synpatic transmission. The nootropic activity of many racetams (e.g., piracetam) is hypothesized to be related to their ability to positively allosterically modulate the AMPA receptor and thereby promote neuronal excitability.
(The notation Ser # indicates the amino acid in a polypeptide or protein-in this case Serine- and the relative position of the residue. So Ser 845 is the 845th amino acid residue, counting from left to right, i.e., N-terminus to C-terminus.)
Nobiletin upregulates mRNA expression of NMDA receptor subunits
In 2014, Kimura J et al reported that nobiletin (1) activates cAMP response element-binding protein (CREB) signaling, (2) rescues NMDA receptor antagonist-induced cognitive impairment, and (3) upregulates mRNA expression of the NMDA receptor subunits NR1, NR2A, and NR2B in PC12D cells. The N-methyl-D-Aspartate (NMDA) receptor is one of the three receptors whose endogenous ligand is glutamate (the other two are AMPA and the Kainic acid receptor). NMDARs play an extensively characterized role in learning and memory and underly long-term potentiation (LTP).
(The discovery that Nobiletin increases mRNA transcription of NMDA receptor subunits suggests that Nobiletin may potentially increase the density of NMDA receptors in the postsynaptic membrane which would make excitatory neurotransmission more robust.)
Finally, Nakajima A et al found that Nobiletin treatment rescues cognitive impairment and reduces soluble amyloid-beta burden in a triple transgenic model of Alzheimer’s disease (3XTg-AD). Specifically, 3 month treatment with Nobiletin (30mg/kg) reversed short-term and recognition memory deficits, ameliorated hippocampal reactive oxygen species (ROS), and ELISA analysis revealed a reduction in soluble amyloid-beta load *in vivo. *Taken together, these results suggest that Nobiletin is a natural flavanoid that exhibits nootropic potential and is a promising candidate for the treatment of Alzheimer’s disease.
Summary of Publications
2005, Nagase H et al. Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry. 2005;44(42):13683-91.
2008, Matsuzaki K et al. A citrus flavonoid with neurotrophic action; augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit; GluR1; and the postsynaptic receptor response to glutamate in murine hippocampus. Eur J Pharmacol. 2008;578(2-3):194-200.
2014, Kimura J et al. Upregulation of N-methyl-D-aspartate receptor subunits and c-Fos expressing genes in PC12D cells by nobiletin. Biol Pharm Bull. 2014;37(9):1555-8.
2015, Nakajima A et al. A citrus flavonoid improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer’s disease (3XTg-AD). Behav Brain Res. 2015.