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

ABSTRACT: Spiral ganglion neurons (SGNs) are primary auditory neurons in the spiral ganglion that transmit sound information from the inner ear to the brain and play an important role in hearing. Impairment of SGNs causes sensorineural hearing loss (SNHL), and it has been thought until now that SGNs cannot be regenerated once lost. Furthermore, no fundamental therapeutic strategy for SNHL has been established other than inserting devices such as hearing aids and cochlear implants. Here we show that the mouse spiral ganglion contains cells that are able to proliferate and indeed differentiate into neurons in response to injury. We suggest that SRY-box transcription factor 2/SRY-box transcription factor 10-double-positive (Sox2/Sox10-double-positive) Schwann cells sequentially started to proliferate, lost Sox10 expression, and became neurons, although the number of new neurons generated spontaneously was very small. To increase the abundance of new neurons, we treated mice with 2 growth factors in combination with valproic acid, which is known to promote neuronal differentiation and survival. This treatment resulted in a dramatic increase in the number of SGNs, accompanied by a partial recovery of the hearing loss induced by injury. Taken together, our findings offer a step toward developing strategies for treatment of SNHL.

SUBMITTER: Wakizono T

PROVIDER: S-EPMC8663787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNo agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways.MethodsYorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis.ResultsBrain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery.ConclusionValproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

Project description:IntroductionPersistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive.MethodsThe cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection.ResultsIn this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes.ConclusionHDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

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

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