Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration

Wakizono, Takahiro; Nakashima, Hideyuki; Yasui, Tetsuro; Noda, Teppei; Aoyagi, Kei; Okada, Kazuko; Yamada, Yasuhiro; Nakagawa, Takashi; Nakashima, Kinichi

doi:10.1172/jci.insight.139171

Cited by 12 publications

(11 citation statements)

References 39 publications

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“…An established model of auditory neuropathy in mammals is the application of ouabain to the round-window membrane of the cochlea. In the Mongolian gerbil, mice, and rats, this lesion paradigm induces a rapid loss of spiral ganglion neurons while leaving the function of sensory hair cells intact ( Schmiedt et al, 2002 ; Lang et al, 2005 ; Fu et al, 2012 ; Wakizono et al, 2021 ). Therefore, we decided to establish a lesion paradigm based on the application of ouabain to the sensory neurons in the adult SAG.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, application of aminoglycosides, commonly prescribed antibiotics to treat bacterial infections, results in hair cell ablation in rats, mice, guinea pigs and Mongolian gerbils with no indication of subsequent regeneration ( Astbury and Read, 1982 ; Forge, 1985 ; Taylor et al, 2008 ; Abbas and Rivolta, 2015 ). Similarly, application of the neurotoxin ouabain, an Na+/K+-ATPase inhibitor, results in the induction of cell death in most neurons of the eighth cranial nerve in mice, rats, and Mongolian gerbils with no signs of regeneration ( Schmiedt et al, 2002 ; Lang et al, 2005 ; Fu et al, 2012 ; Wakizono et al, 2021 ). In contrast to mammals, all other vertebrates, such as birds, reptiles, amphibians, and fish have the remarkable intrinsic capacity to regenerate lost hair cells ( Corwin and Cotanche, 1988 ; Ryals and Rubel, 1988 ; Stone and Rubel, 2000 ; Schuck and Smith, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

Schwarzer

Rekhade

Machate

et al. 2022

Front. Cell Dev. Biol.

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Sensorineural hearing loss is caused by the loss of sensory hair cells and/or their innervating neurons within the inner ear and affects millions of people worldwide. In mammals, including humans, the underlying cell types are only produced during fetal stages making loss of these cells and the resulting consequences irreversible. In contrast, zebrafish produce sensory hair cells throughout life and additionally possess the remarkable capacity to regenerate them upon lesion. Recently, we showed that also inner ear neurogenesis continues to take place in the zebrafish statoacoustic ganglion (SAG) well into adulthood. The neurogenic niche displays presumptive stem cells, proliferating Neurod-positive progenitors and a high level of neurogenesis at juvenile stages. It turns dormant at adult stages with only a few proliferating presumptive stem cells, no proliferating Neurod-positive progenitors, and very low levels of newborn neurons. Whether the neurogenic niche can be reactivated and whether SAG neurons can regenerate upon damage is unknown. To study the regenerative capacity of the SAG, we established a lesion paradigm using injections into the otic capsule of the right ear. Upon lesion, the number of apoptotic cells increased, and immune cells infiltrated the SAG of the lesioned side. Importantly, the Neurod-positive progenitor cells re-entered the cell cycle displaying a peak in proliferation at 8 days post lesion before they returned to homeostatic levels at 57 days post lesion. In parallel to reactive proliferation, we observed increased neurogenesis from the Neurod-positive progenitor pool. Reactive neurogenesis started at around 4 days post lesion peaking at 8 days post lesion before the neurogenesis rate decreased again to low homeostatic levels at 57 days post lesion. Additionally, administration of the thymidine analog BrdU and, thereby, labeling proliferating cells and their progeny revealed the generation of new sensory neurons within 19 days post lesion. Taken together, we show that the neurogenic niche of the adult zebrafish SAG can indeed be reactivated to re-enter the cell cycle and to increase neurogenesis upon lesion. Studying the underlying genes and pathways in zebrafish will allow comparative studies with mammalian species and might provide valuable insights into developing cures for auditory and vestibular neuropathies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

Schwarzer

Rekhade

Machate

et al. 2022

Front. Cell Dev. Biol.

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show abstract

“…In addition to the work described above, hiPSCs have been differentiated to other cell types that are associated but that are not necessarily restricted to the inner ear, such as NC cells [ 69 ] and Schwann cell precursors [ 70 ]. Of note, Wakizono et al (2021) have reported that Schwann cell precursors proliferate following ouabain-induced damage to the SGNs of adult mice; they have also shown that administration of EGF and bFGF leads to increased proliferation of these precursors [ 71 ]. Co-injection of these GFs with the histone deacetylase inhibitor valproic acid results in a significant increase in PROX1+ type 1 SGNs that appear to originate from the proliferating Schwann cell pool and in a partial recovery of the hearing function in ouabain-treated animals.…”

Section: Hipsc-based Cultures To Model Inner Ear Developmentmentioning

confidence: 99%

Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss

Alonso

Petković

2022

Cells

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Hearing loss is the most prevalent sensorineural impairment in humans. Yet despite very active research, no effective therapy other than the cochlear implant has reached the clinic. Main reasons for this failure are the multifactorial nature of the disorder, its heterogeneity, and a late onset that hinders the identification of etiological factors. Another problem is the lack of human samples such that practically all the work has been conducted on animals. Although highly valuable data have been obtained from such models, there is the risk that inter-species differences exist that may compromise the relevance of the gathered data. Human-based models are therefore direly needed. The irruption of human induced pluripotent stem cell technologies in the field of hearing research offers the possibility to generate an array of otic cell models of human origin; these may enable the identification of guiding signalling cues during inner ear development and of the mechanisms that lead from genetic alterations to pathology. These models will also be extremely valuable when conducting ototoxicity analyses and when exploring new avenues towards regeneration in the inner ear. This review summarises some of the work that has already been conducted with these cells and contemplates future possibilities.

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“…71 Valproate combined with growth factors restored hearing loss in a rodent model of sensorineural hearing loss. 72 HDAC2 inhibition is thought to result in "juvenile-like induced plasticity" in the brain, given that the deletion of HDAC2 prolongs the critical period in the visual cortex of mice. 69 Notably, if either of these two factors-critical period reopening and appropriate environmental stimuli-are missing, no restoration of function can be expected.…”

Section: Valproate As An Histone Deacetylase 2 Inhibitor and Critical...mentioning

confidence: 99%

Valproate Adjuvant Cognitive Behavioral Therapy in Panic Disorder Patients With Comorbid Bipolar Disorder: Case Series and Review of the Literature

Choi

2022

Psychiatry Investig

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Anxiety disorders are the most common comorbid psychiatric disorders in patients with bipolar disorder. Managing anxiety symptoms in comorbid conditions is challenging and has received little research interest. The findings from preclinical research on fear conditioning, an animal model of anxiety disorder, have suggested that memory reconsolidation updating (exposure-based therapy) combined with valproate might facilitate the amelioration of fear memories. Here, three cases of successful amelioration of agoraphobia and panic symptoms through valproate adjuvant therapy for cognitive behavioral therapy in patients who failed to respond to two to three consecutive standard pharmacotherapy trials over several years are described. To the best of the author’s knowledge, this is the first attempt to combine CBT with valproate in patients with panic disorder, agoraphobia, and comorbid bipolar disorder. Additionally, the background preclinical research on this combination therapy based on the reconsolidation-updating mechanism, the inhibition of histone deacetylase 2, and critical period reopening, off-label use of valproate in panic disorder, plasticity-augmented psychotherapy, and how to combine valproate with CBT is discussed.

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Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration

Cited by 12 publications

References 39 publications

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss

Valproate Adjuvant Cognitive Behavioral Therapy in Panic Disorder Patients With Comorbid Bipolar Disorder: Case Series and Review of the Literature

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