The role of selective serotonin reuptake inhibitors and tricyclic antidepressants in addressing reduction of Meniere's disease burden: A scoping review.

Objective: To assess the effect of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in reducing vertigo, tinnitus, and hearing loss among patients with Meniere's disease (MD). Data Sources: The following databases were utilized in this scoping review: Ovid Medline, PubMed-NCBI, CINAHL, Cochrane Library, Web of Science, and Clinicaltrials.gov. Method: Studies were identified through the following search phrases: "serotonin specific reuptake inhibitors" OR "tricyclic antidepressants" AND "Meniere's disease." References from included manuscripts were examined for possible inclusion of additional studies. Results: The literature search yielded 23 results, which were screened by three independent reviewers. Seventeen studies and three duplicates were excluded. An examination of references from the included studies yielded two additional publications. A total of four published studies assessing SSRIs and TCAs among 147 patients with MD were ultimately included. Four studies described significant reductions in vertigo attack frequency among patients treated with either SSRIs or TCAs compared to their pretreatment baseline. Three studies assessed the drugs' effects on hearing, of which none found a significant difference among patients treated with SSRIs or TCAs. One study found a significant decrease in patient-reported tinnitus following treatment with TCAs or SSRIs compared to their pretreatment baseline. Conclusions: Data exploring SSRIs and TCAs among patients with MD suggests that these medications may reduce the frequency of tinnitus and vertigo, although there was significant heterogeneity in outcome reporting. There remains a need for larger-scale prospective studies that emphasize objective data to evaluate their effectiveness in reducing common MD symptoms.

Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease.

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere's disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.

Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.

Multikinase Abl/DDR/Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration.

BACKGROUND AND OBJECTIVES: Inhibition of Abelson (Abl) tyrosine kinase as a therapeutic target has been gaining attention in neurodegeneration. Post-mortem Alzheimer's and Parkinson's disease brains show that the levels of several other tyrosine kinases, including Discoidin Domain Receptors (DDR1/2) are elevated. Knockdown of these tyrosine kinases with shRNA reduces neurotoxic proteins, including alpha-synuclein, beta-amyloid and tau. METHODS: Direct profiling of the pharmacokinetics of multi-kinase inhibitors Nilotinib, Bosutinib, Bafetinib, Radotinib and LCB-03-0110 shows differential levels of brain penetration but the ability of these agents to reduce toxic proteins is independent of brain concentration and selectivity to Abl. RESULTS: Our results indicate that the effective dose of Nilotinib has the lowest plasma:brain ratio (1%) followed by Bosutinib and Radotinib (5%), Bafetinib (12%) and LCB-03-0110 (12%). However, similar doses of multi-kinase Abl/DDR inhibitor Nilotinib, DDR/Src inhibitor LCB-03-0110 and Abl/Src inhibitor Bosutinib were much more effective than the more selective Abl inhibitors Radotinib and Bafetinib. Taken together, these data suggest that a multi-kinase target that includes Abl and other tyrosine kinases (DDRs, and Src) may offer more advantages alleviating neurodegenerative pathologies than the absolute CNS drug concentration and selectivity to Abl. CONCLUSION: DDRs and Src are other potential co-targets with Abl in neurodegeneration.