ANA-12 explained

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF).^[1] ANA-12 was originally discovered and developed by Cazorla M. and colleagues at Université Paris and Inserm in 2011. The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes (~400 nM) and as long as 6 hours (~10 nM) following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.

Research

ANA-12 has two binding sites on TrkB, a high- and low-affinity site (K_d = 10 nM and 12 μM, respectively).

ANA-12 produces rapid antidepressant- and anxiolytic-like effects in animal models, the former of which have been elucidated to be mediated by blockade of BDNF signaling in the nucleus accumbens.^{[2] [3]} It has also been found to alleviate methamphetamine-induced depression-like behavior (including anhedonia), behavioral sensitization, and nucleus accumbens neuroplasticity changes with subchronic (14-day) administration in mice, whereas the TrkB agonist 7,8-dihydroxyflavone was ineffective in doing so.^[4]

ANA-12 blocks the cognitive-enhancing effects of environmental enrichment and calorie restriction in rodents, which are mediated by BDNF signaling through TrkB in the hippocampus.^{[5] [6]} It also blocks hippocampal neurogenesis induced by physical exercise in rodents, and may block the cognitive-enhancing effects of exercise as well.^[7]

See also

• Tropomyosin receptor kinase B § Antagonists

Notes and References

1. Cazorla M, Prémont J, Mann A, Girard N, Kellendonk C, Rognan D . Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice . The Journal of Clinical Investigation . 121 . 5 . 1846–1857 . May 2011 . 21505263 . 3083767 . 10.1172/JCI43992 .
2. Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, Li SX, Shirayama Y, Hashimoto K . 6 . Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation . The International Journal of Neuropsychopharmacology . 18 . 4 . pyu077 . October 2014 . 25628381 . 4360225 . 10.1093/ijnp/pyu077 .
3. Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K . Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist . European Neuropsychopharmacology . 25 . 12 . 2449–2458 . December 2015 . 26419294 . 10.1016/j.euroneuro.2015.09.002 . 851 .
4. Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K . BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms . Translational Psychiatry . 5 . 10 . e666 . October 2015 . 26506052 . 4930133 . 10.1038/tp.2015.157 .
5. Fan D, Li J, Zheng B, Hua L, Zuo Z . Enriched Environment Attenuates Surgery-Induced Impairment of Learning, Memory, and Neurogenesis Possibly by Preserving BDNF Expression . Molecular Neurobiology . 53 . 1 . 344–354 . January 2016 . 25432890 . 10.1007/s12035-014-9013-1 . 15795328 .
6. Kishi T, Hirooka Y, Nagayama T, Isegawa K, Katsuki M, Takesue K, Sunagawa K . Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats . International Heart Journal . 56 . 1 . 110–115 . 2015 . 25503654 . 10.1536/ihj.14-168 . free .
7. Ambrogini P, Lattanzi D, Ciuffoli S, Betti M, Fanelli M, Cuppini R . Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF . Brain Research . 1534 . 1–12 . October 2013 . 23973748 . 10.1016/j.brainres.2013.08.023 . 35405574 . 11576/2575580 .