Cochlear implant surgery facilitates intracochlear distribution of perioperative systemic steroids.

BACKGROUND: Systemically administered steroids are widely utilised for hearing preservation therapies. More recently, steroids have been administered to achieve hearing protection after cochlear implant surgery. Currently there is a lack of understanding as to which administration route offers most therapeutic efficacy, local or systemic administration. Paramount to this are observations in animal studies that systemic administration following implantation offers hearing protection and reduced cochlear fibrosis, despite observations that perilymphatic levels are up to 10-fold higher after local administration in non-implanted cochleae. AIMS/OBJECTIVES: This paper explores the impact that cochlear implantation and associated acute inflammation has on steroid distribution and uptake following systemic administration of dexamethasone. MATERIAL AND METHODS: Eight guinea pigs received systemic dexamethasone 60 min prior to cochlear implantation. Implanted and contralateral non-implanted cochlea were harvested for tissue immunohistochemistry and detection of dexamethasone. RESULTS: Cochleostomy with scala tympani implantation resulted in a significant increase in cochlear dexamethasone signal. This was most notable at the organ of Corti, stria vascularis, and blood product in the scala tympani. CONCLUSIONS AND SIGNIFICANCE: This study demonstrates that the inner ear distribution of systemically administered steroids is enhanced following surgery for cochlear implantation and provides rationale for systemic perioperative steroids in hearing preservation surgery.

Spironolactone Ameliorates Cochlear Implant Induced Endolymphatic Hydrops.

BACKGROUND: Endolymphatic hydrops (EH) has been observed in both animal and human cochleae following cochlear implant (CI) surgery. We tested whether EH could be eliminated by administration of mineralocorticoid steroid antagonist spironolactone and explored the electrophysiological consequences of this. METHODS: Sixty-four adult guinea pigs underwent cochlear implantation with a dummy electrode. Animals then survived either 2, 7, or 28 days. Auditory function was monitored by recording electrocochleography from the round window membrane preimplantation, and on the last day of the experiment. Spironolactone or control solution was added to animals' feed for 7 days (if they survived that long) beginning immediately prior to surgery. The presence of EH was determined using thin-sheet laser imaging microscopy. RESULTS: Treatment with spironolactone resulted in significant reduction in EH in the second cochlear turn 7 days postimplantation. In all animals, the compound action potential (CAP) threshold was elevated 2 days postimplantation, but for most frequencies had recovered substantially by 28 days. There was no treatment effect on CAP thresholds. SP/AP ratios were elevated at day 2. The amplitude growth of the CAP did not differ between test and control groups at any time after implantation. CONCLUSIONS: EH can be suppressed by antagonism of mineralocorticoid receptors in the week after cochlear implantation. Reduction in EH did not lead to any change in hearing, and there was no indication of synaptopathy signalled by reduced CAP amplitude at high sound intensities. We found no electrophysiological evidence that EH early after implantation impacts negatively upon preservation of residual hearing.

Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients.

Glucocorticoids have direct anti-inflammatory, anti-oxidant and anti-apoptotic effects on cochlear hair cells. Cochlear glucocorticoid therapy has gained particular attention for its ability to enhance the protection of residual hearing following hearing preservation cochlear implantation. Local drug delivery methods achieve high drug concentrations within the inner ear fluids but are reliant upon diffusion across the round window membrane. Diffusion has been shown to demonstrate large individual variability. This study explores the role of "adjuvant agents", which when administered with glucocorticoids, enhance inner ear absorption and distribution. Guinea pig cochleae were administered either dexamethasone alone or in combination with hyaluronic acid, histamine, or combination histamine and hyaluronic acid, targeted at the round window membrane. Control subjects received saline. Perilymph was sampled from the cochlear apex, and basal to apical dexamethasone concentrations recorded with mass spectroscopy. Cochleae were harvested, and immunohistochemistry employed to explore dexamethasone tissue penetration and distribution. Basal to apical gradients were observed along the scala tympani, with higher dexamethasone concentrations observed at the cochlear base. Gradients were more pronounced and uniform when administered on a hyaluronic acid sponge, while histamine increased absolute concentrations reaching the inner ear. Tissue penetration correlated with perilymph concentration. Our results demonstrate that adjuvant agents can be employed to enhance dexamethasone absorption and distribution in the inner ear, thus proposing therapeutic strategies that may enhance steroid facilitated hearing protection.

A comparison of cochlear distribution and glucocorticoid receptor activation in local and systemic dexamethasone drug delivery regimes.

Local and systemically delivered glucocorticoids are commonly administered to protect the cochlea against damage associated with a variety of insults. There is reason to believe that dexamethasone administered by these routes may arrive at cochlear target sites via different pathways. Clinically, there is a lack of clarity as to which route is more effective in any specific circumstance. This study explores dexamethasone distribution within the guinea pig cochlea following local and systemic delivery methods. A combination of mass spectroscopy and immunohistochemistry were employed to compare both perilymph distribution, tissue uptake and receptor activation. Local administration of dexamethasone to the round window membrane resulted in greater perilymph concentrations, with a basal to apical gradient that favours the cochlear base. Tissue immunofluorescence was intimately related to perilymph concentration following local administration. Systemic administration resulted in much lower perilymph concentrations, with an inverse basal to apical gradient favouring the cochlear apex. Lower perilymph concentrations following systemic administration were associated with minimal tissue immunofluorescence. Despite this, GR activation of the SGNs was equivalent in both administration regimes. These results bring into question the efficacy of measuring perilymph concentrations alone as a surrogacy for dexamethasone distribution and activity in the cochlea, suggesting that the steroid ligand may arrive at its target receptor via alternative pathways. Our results suggest an equivalence in efficacy between local and systemic administration routes early after drug delivery, when the ultimate outcome of GR activation is the goal.

Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection.

Much recent work is investigating the role of oxidative stress and inflammatory mechanisms in the aetiology of neurodegeneration in Parkinson's disease. The present study evaluated whether the green tea constituent epigallocatechin gallate (EGCG) which has both anti-oxidant and anti-inflammatory properties, exerts neuroprotection and symptomatic effects when administered orally as a pre-treatment prior to 6-hydroxydopamine (6-OHDA) lesions. Groups of rats were given either 1mg/kg, 2mg/kg EGCG or vehicle solution for 14 days. Sham or 6-OHDA surgery was performed on day 11 of the drug administration protocol. Behavioural analysis was conducted before drugs/vehicle solution, again during the treatment period and then repeated at fortnightly intervals for 2 months post-operatively. Whilst some subtle behavioural improvements in postural abnormalities and ability to cross a narrow beam were observed in lesioned rats after EGCG (vs. vehicle) there was no evidence of neuroprotection on post-mortem quantification of degree of nigral dopaminergic neuronal loss when comparing the lesioned groups given the various treatments.