Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.

Uribe PM, Kawas LH, Harding JW, Coffin AB

Frontiers in cellular neuroscience28 Jan 2015Cited by 10 (Europe PMC)

PMID25674052PMCIDPMC4309183DOI10.3389/fncel.2015.00003PepBankPUB-25674052

Summary

Loss of sensory hair cells from exposure to certain licit drugs (e.g., aminoglycoside antibiotics, platinum-based chemotherapy agents) can result in permanent hearing loss. Here we ask if allosteric activation of the hepatocyte growth factor (HGF) cascade via Dihexa, a small molecule drug candidate, can protect hair cells from aminoglycoside toxicity. Unlike native HGF, Dihexa is chemically stable and blood-brain barrier permeable. As a synthetic HGF mimetic, it forms a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades. To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins. A dose-response relationship for Dihexa protection was established using two ototoxins, neomycin and gentamicin. We found that a Dihexa concentration of 1 μM confers optimal protection from acute treatment with either ototoxin. Pretreatment with Dihexa does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating that Dihexa's protection is likely mediated by intracellular events and not by inhibiting aminoglycoside entry. Dihexa-mediated protection is attenuated by co-treatment with the HGF antagonist 6-AH, further evidence that HGF activation is a component of the observed protection. Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK. Addition of an amino group to the N-terminal of Dihexa also attenuates the protective response, suggesting that even small substitutions greatly alter the specificity of Dihexa for its target. Our data suggest that Dihexa confers protection of hair cells through an HGF-mediated mechanism and that Dihexa holds clinical potential for mitigating chemical ototoxicity.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

3 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In larval zebrafish, Dihexa at 1 μM provided optimal hair cell protection from acute neomycin treatment.
In plain wordsIn zebrafish, Dihexa provided optimal hair cell protection from acute neomycin exposure at the reported concentration.
Peptide
Dihexa
Outcome
IncreaseHair cell protection against neomycin
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
1 μMAs given in this study (Zebrafish).
Measurements
Optimal protective concentration
1 μM
acute neomycin treatment
Source sentences
Summary
We found that a Dihexa concentration of 1 μM confers optimal protection from acute treatment with either ototoxin.
2 context sentences(design, population, supporting numbers)
Summary · context
A dose-response relationship for Dihexa protection was established using two ototoxins, neomycin and gentamicin.
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
Show in the study text Report a problemFND-2567405201
02AnimalAnimal study (in vivo)Efficacy outcome
In larval zebrafish, Dihexa at 1 μM provided optimal hair cell protection from acute gentamicin treatment.
In plain wordsIn zebrafish, Dihexa provided optimal hair cell protection from acute gentamicin exposure at the reported concentration.
Peptide
Dihexa
Outcome
IncreaseHair cell protection against gentamicin
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
1 μMAs given in this study (Zebrafish).
Measurements
Optimal protective concentration
1 μM
acute gentamicin treatment
Source sentences
Summary
We found that a Dihexa concentration of 1 μM confers optimal protection from acute treatment with either ototoxin.
2 context sentences(design, population, supporting numbers)
Summary · context
A dose-response relationship for Dihexa protection was established using two ototoxins, neomycin and gentamicin.
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
Show in the study text Report a problemFND-2567405202
03AnimalAnimal study (in vivo)Mechanism
In larval zebrafish, Dihexa pretreatment did not affect fluorescent gentamicin entry into hair cells.
In plain wordsIn zebrafish, Dihexa pretreatment did not change fluorescent gentamicin entry into hair cells.
Peptide
Dihexa
Outcome
No significant changeGentamicin hair cell entry
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Pretreatment with Dihexa does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating that Dihexa's protection is likely mediated by intracellular events and not by inhibiting aminoglycoside entry.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
Show in the study text Report a problemFND-2567405203

Studies that did not test the peptide alone5

In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Dihexa.

04AnimalNot a test of Dihexa aloneAnimal study (in vivo)Mechanism
In larval zebrafish, co-treatment with HGF antagonist 6-AH attenuated Dihexa-mediated hair cell protection.
In plain wordsIn zebrafish, the HGF antagonist 6-AH reduced hair cell protection associated with Dihexa.
Peptide
Dihexa
Outcome
DecreaseProtection attenuation by HGF antagonist
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Dihexa-mediated protection is attenuated by co-treatment with the HGF antagonist 6-AH, further evidence that HGF activation is a component of the observed protection.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dihexa.
Show in the study text Report a problemFND-2567405204
05AnimalNot a test of Dihexa aloneAnimal study (in vivo)Mechanism
In larval zebrafish, co-treatment with Akt inhibitors partially attenuated Dihexa-mediated hair cell protection.
In plain wordsIn zebrafish, Akt inhibitors partly reduced hair cell protection associated with Dihexa.
Peptide
Dihexa
Outcome
DecreaseProtection attenuation by Akt inhibition
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dihexa.
Show in the study text Report a problemFND-2567405205
06AnimalNot a test of Dihexa aloneAnimal study (in vivo)Mechanism
In larval zebrafish, co-treatment with TOR inhibitors partially attenuated Dihexa-mediated hair cell protection.
In plain wordsIn zebrafish, TOR inhibitors partly reduced hair cell protection associated with Dihexa.
Peptide
Dihexa
Outcome
DecreaseProtection attenuation by TOR inhibition
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dihexa.
Show in the study text Report a problemFND-2567405206
07AnimalNot a test of Dihexa aloneAnimal study (in vivo)Mechanism
In larval zebrafish, co-treatment with MEK inhibitors partially attenuated Dihexa-mediated hair cell protection.
In plain wordsIn zebrafish, MEK inhibitors partly reduced hair cell protection associated with Dihexa.
Peptide
Dihexa
Outcome
DecreaseProtection attenuation by MEK inhibition
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dihexa.
Show in the study text Report a problemFND-2567405207
08AnimalNot a test of Dihexa aloneAnimal study (in vivo)Activity measurement
In larval zebrafish, addition of an N-terminal amino group to Dihexa attenuated the protective response.
In plain wordsIn zebrafish, adding an amino group to the start of Dihexa reduced its protective response.
Peptide
Dihexa
Outcome
DecreaseProtection after N-terminal amino substitution
Study
Zebrafishn: not reported in source
Larval zebrafish lateral line hair cells
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Addition of an amino group to the N-terminal of Dihexa also attenuates the protective response, suggesting that even small substitutions greatly alter the specificity of Dihexa for its target.
1 context sentence(design, population, supporting numbers)
Summary · context
To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins.
In this study, Dihexa was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dihexa.
Show in the study text Report a problemFND-2567405208

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
14 Oct 2026, 05:02 UTC
Study results updated
Version 1
14 Oct 2026, 01:45 UTC
First added · source update from Europe PMC

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