Cyclotraxin B, A Selective Antagonist of TrkB Receptors



Cyclotraxin B , a potent antagonist of TrkB receptors, inhibits BDNF-induced TrkB activity (IC50 = 0.30 nM). Research shows it prevents BDNF-induced cold allodynia and exhibits putative anxiolytic properties in mice. Cyclotraxin B may represent a potential powerful tool for the novel therapeutic strategies aimed to treat or prevent some forms of chronic pain.

Pharmacologic action

Brain-derived neurotrophic factor (BDNF) can play a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors. And the activation of TrkB receptors triggers intracellular signaling cascades which leads to central sensitization. Cyclotraxin B allosterically alters TrkB receptor conformation, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities, but does not alter brain-derived neurotrophic factor (BDNF) binding. The strong effectiveness of cyclotraxin B was possibly due to its ability to block any indirect or direct processes which activate TrkB receptors.


The systemic administration of cyclotraxin-B to mice leads to the TrkB inhibition in the brain with specific anxiolytic-like behavioral effects but without antidepressant-like activity. Cyclotraxin B can either reverse or prevent the effects of intracisternal BDNF on cold nociception. Besides, the blockade of TrkB receptor by Cyclotraxin B inhibited the mechanisms that either maintain or initiate cold allodynia in the ipsilateral vibrissal pad skin after unilateral constriction of the infraorbital nerve. It is possible that the sustained inhibition of trigeminal cold allodynia by systemic Cyclotraxin B was mediated by its high-affinity, slowly reversible blockade of the TrkB receptor in central nervous system tissues.

Pharmacokinetics and metabolism

Research showed that the i.p. administration of Cyclotraxin B did not evidently modify on its own rubbing/scratching behavior of mice. Nevertheless, the pretreatment of Cyclotraxin B prevented the allodynia induced by 100 ng of BDNF (i.c.). In addition, the respective AUC values during the 28-day observation period (AUC, 0–28 days) clearly suggested that Cyclotraxin B prevented BDNF-induced cold allodynia, completely (BDNF: 515.58 ± 10.95 seconds; Cyclotraxin B + BDNF: 313.08 ± 41.92 seconds; n = 6 in each group; P < .001). On the contrary, the AUC values of the rubbing/scratching behavior of mice for this same period indicated that Cyclotraxin B was inactive on its own (Cyclotraxin B: 371.08 ± 39.10 seconds; saline: 278.33 ± 16.20 seconds; n = 6 in each group).


L. Constandil, M. Goich, A. Hernández, L. Bourgeais, M. Cazorla, M. Hamon and T. Pelissier. Cyclotraxin-B, a new TrkB antagonist, and glial blockade by propentofylline, equally prevent and reverse cold allodynia induced by BDNF or partial infraorbital nerve constriction in mice. J. Pain, 2012, 13(6), 579-589.

M. Cazorla, A. Jouvenceau, C. Rose, J. P. Guilloux, C. Pilon, A. Dranovsky and J. Prémont. Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice. PloS one, 2010, 5(3), e9777.

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