428
sistent with hair cell death research in the inner ears of amniotic vertebrates, particularly
chickens and rodents, demonstrating conservation of hair cell death mechanisms
across mechanosensory systems and taxa (Matsui et al. 2002 , 2004 ; Cunningham
et al. 2004 ). Even the lack of consensus on caspase activation parallels mammalianbased research, as some studies in the rodent inner ear suggest a requirement for
caspases in aminoglycoside ototoxicity, while others demonstrate activation of
caspase- independent mechanisms (Cunningham et al. 2002 ; Cheng et al. 2005 ;
Jiang et al. 2006 ).
Larval zebrafi sh are particularly amenable for large-scale drug screening, an
unbiased drug discovery process that probes a collection of chemical compounds
for a phenotypic effect or behavioral response of interest (Peterson et al. 2000 ;
reviewed in Kaufman et al. 2009 ). The lateral line also provides a tractable model
system for identifying novel compounds that may protect hair cells from ototoxininduced damage. Ton and Parng ( 2005 ) fi rst took advantage of this system in a
small-scale drug screen, demonstrating that several antioxidants, including glutathione and D-methionine, attenuated hair cell death from the chemotherapy agent cisplatin. Screens of libraries of FDA-approved drugs and similar bioactive compounds
have yielded several otoprotective molecules for potential translational development, including antidepressants such as paroxetine (Paxil) and anticholinergics
(Tacrine) (Ou et al. 2009 ; Vlasits et al. 2012 ). Other otoprotection screens have cast
a wider net, including a screen of 10,000+ small molecules with diverse chemical
structures that discovered a novel benzothiophene carboxamide, now called
PROTO-1, which robustly protects zebrafi sh hair cells from aminoglycoside toxicity (Owens et al. 2008 ). Together, these studies have identifi ed new potential uses
for several approved drugs and uncovered new drug candidates for future development. The majority of drug discovery studies have relied on morphological criteria
for hair cell protection, but recent advances in physiology and behavior set the stage
for functional studies of newly identifi ed protective compounds (Zeddies and Fay
2005 ; Trapani and Nicolson 2010 ; Brack and Ramcharitar 2012 ; Buck et al. 2012 ;
Suli et al. 2012 ; Bhandiwad et al. 2013 ).
4.2 Regeneration
All fi shes examined to date robustly regenerate hair cells, although the time course
of recovery depends on the sensory system in question (inner ear vs. lateral line),
developmental stage of the test organism, and ototoxin administered (Lombarte
et al. 1993 ; Ma et al. 2008 ; reviewed in Brignull et al. 2009 ; Lush and Piotrowski
2014 ). In the ear of adult oscars, structural regeneration post-gentamicin treatment
is complete 10 days after observation of maximum damage (20 days from fi rst
gentamicin injection; Lombarte et al. 1993 ). A similar recovery time course is seen
in Atlantic cod that received an intrasaccular gentamicin injection (Faucher et al.
2009 ), suggesting that ~20 days post-trauma is a typical regeneration period for
adult fi shes. In contrast, larval zebrafi sh manifest complete lateral line
A.B. Coffi n and J. Ramcharitar
sistent with hair cell death research in the inner ears of amniotic vertebrates, particularly
chickens and rodents, demonstrating conservation of hair cell death mechanisms
across mechanosensory systems and taxa (Matsui et al. 2002 , 2004 ; Cunningham
et al. 2004 ). Even the lack of consensus on caspase activation parallels mammalianbased research, as some studies in the rodent inner ear suggest a requirement for
caspases in aminoglycoside ototoxicity, while others demonstrate activation of
caspase- independent mechanisms (Cunningham et al. 2002 ; Cheng et al. 2005 ;
Jiang et al. 2006 ).
Larval zebrafi sh are particularly amenable for large-scale drug screening, an
unbiased drug discovery process that probes a collection of chemical compounds
for a phenotypic effect or behavioral response of interest (Peterson et al. 2000 ;
reviewed in Kaufman et al. 2009 ). The lateral line also provides a tractable model
system for identifying novel compounds that may protect hair cells from ototoxininduced damage. Ton and Parng ( 2005 ) fi rst took advantage of this system in a
small-scale drug screen, demonstrating that several antioxidants, including glutathione and D-methionine, attenuated hair cell death from the chemotherapy agent cisplatin. Screens of libraries of FDA-approved drugs and similar bioactive compounds
have yielded several otoprotective molecules for potential translational development, including antidepressants such as paroxetine (Paxil) and anticholinergics
(Tacrine) (Ou et al. 2009 ; Vlasits et al. 2012 ). Other otoprotection screens have cast
a wider net, including a screen of 10,000+ small molecules with diverse chemical
structures that discovered a novel benzothiophene carboxamide, now called
PROTO-1, which robustly protects zebrafi sh hair cells from aminoglycoside toxicity (Owens et al. 2008 ). Together, these studies have identifi ed new potential uses
for several approved drugs and uncovered new drug candidates for future development. The majority of drug discovery studies have relied on morphological criteria
for hair cell protection, but recent advances in physiology and behavior set the stage
for functional studies of newly identifi ed protective compounds (Zeddies and Fay
2005 ; Trapani and Nicolson 2010 ; Brack and Ramcharitar 2012 ; Buck et al. 2012 ;
Suli et al. 2012 ; Bhandiwad et al. 2013 ).
4.2 Regeneration
All fi shes examined to date robustly regenerate hair cells, although the time course
of recovery depends on the sensory system in question (inner ear vs. lateral line),
developmental stage of the test organism, and ototoxin administered (Lombarte
et al. 1993 ; Ma et al. 2008 ; reviewed in Brignull et al. 2009 ; Lush and Piotrowski
2014 ). In the ear of adult oscars, structural regeneration post-gentamicin treatment
is complete 10 days after observation of maximum damage (20 days from fi rst
gentamicin injection; Lombarte et al. 1993 ). A similar recovery time course is seen
in Atlantic cod that received an intrasaccular gentamicin injection (Faucher et al.
2009 ), suggesting that ~20 days post-trauma is a typical regeneration period for
adult fi shes. In contrast, larval zebrafi sh manifest complete lateral line
A.B. Coffi n and J. Ramcharitar