PgmNr Z6265: Hair cell regeneration in the zebrafish lateral line is impared by crude root extracts of Valeriana officinalis.

Authors:
R. E. Rodriguez Morales; A. Santana; M. Behra


Institutes
University of Puerto Rico, MSC, PR.


Abstract:

Hair cells (HCs) are sophisticated mechanoreceptors found in sensory tissues of all vertebrate inner ears that transduce sound waves into electrical signals. Mammals, unlike birds and fish cannot regenerate them, making HCs loss the leading cause for hearing impairment in humans. We are interested in finding new agents that can trigger or hamper HC regeneration, but sensory tissues are deeply buried in the skull and therefore hard to reach and manipulate. We took advantage of the fact that HCs are also found in a fish/amphibian mechanosensory organ which is called the lateral line (LL). It is composed of stereotypically and superficially distributed sensory patches, the neuromasts (NMs), which contain HCs surrounded by supporting cells (SCs). Cilia of HCs are directly exposed to and deflected by currents of surrounding waters. HCs of the LL are sensitive to a range of ototoxic drugs (antibiotics, metals…) which are present in the water and can be easily and quite specifically destroyed this way. It was shown that HC destruction will trigger proliferation and differentiation of SCs into new functional HCs in all NMs over the course of 3 days. To ablate HCs, we treated 5 day post fertilization (dpf) larvae with copper and observed HC regeneration during the following 3 day post treatment (dpt) in the presence of crude plant extracts. One of them, Valeriana officinalis (Val) crude root extracts did significantly delay HC regeneration. Moreover, several regenerating NMs seemed unstable and starting at 2 dpt they presented apoptotic-like features. This was never observed in animals which had not been copper treated, suggesting that the presence of the extract had no effect on LL development but was specifically affecting its regeneration. Val contains more than 150 active components. One of them is Valeric acid which led to the synthesis of an FDA approved drug, valproic acid (VPA).  One of the postulated roles of VPA is to be a potent inhibitor of histone deacetylase (HDAC). VPA and Trichostatin A, another HDAC, were both shown to affect HC regeneration possibly by affecting SCs division and survival. We are currently exploring this tantalizing lead to understand the mode of action by which Val is hampering HC regeneration. Our work shows for the first time that a crude root extract of Valeriana officinalis is interfering with HC regeneration.