Glial cell line-derived neurotrophic factor has a dose dependent influence on noise-induced hearing loss in the guinea pig cochlea

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

“…Surprisingly, when increasing the dose of pVAX2 --rGDNF plasmid to 60 mg, a significant reduction of scotopic b-wave amplitude, ONL and PR IS thickness was observed as compared with the same dose of control plasmid ET demonstrating an inverse dose-response effect. Such potential deleterious effect of GDNF dose has not been previously reported in the eye but was described in other parts of the central nervous system such as in the inner ear 64 and in the brain 65,66 using continuous GDNF-releasing systems. GDNF induced a dosedependent protective effect on sensory cell preservation and hearing function when applied directly into the guinea pig cochlea in a noise-induced hearing loss model.…”

“…GDNF induced a dosedependent protective effect on sensory cell preservation and hearing function when applied directly into the guinea pig cochlea in a noise-induced hearing loss model. 64 However, at the highest dose of 1 mg ml --1 (12 ng day --1 ), GDNF exacerbated hair cell and hearing loss along the cochlea in noise-exposed ears but not in healthy ears, indicating that GDNF could increase hair cells sensitivity to noise damage in the cochlea. 64 In the brain, a 6-month toxicologic study conducted in healthy rhesus monkeys demonstrated that chronic intraputamenal infusion of GDNF at the highest dose of 100 mg day --1 for 3 months followed by a 3-month treatment-free recovery period induced cerebellar Purkinje cell loss.…”

“…64 However, at the highest dose of 1 mg ml --1 (12 ng day --1 ), GDNF exacerbated hair cell and hearing loss along the cochlea in noise-exposed ears but not in healthy ears, indicating that GDNF could increase hair cells sensitivity to noise damage in the cochlea. 64 In the brain, a 6-month toxicologic study conducted in healthy rhesus monkeys demonstrated that chronic intraputamenal infusion of GDNF at the highest dose of 100 mg day --1 for 3 months followed by a 3-month treatment-free recovery period induced cerebellar Purkinje cell loss. 65 This toxicity was neither observed in brain treated by lower doses of GDNF and submitted to the same recovery period nor in tissues continuously exposed to the highest dose of GDNF for 6 months, without any recovery period, suggesting that lesions could result from withdrawal of high GDNF dose.…”

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

“…However, tracer studies â which use visuallydetectable markers â have revealed that much of the introduced substances bound nonspecifically to non-neural tissues such as the basilar membrane, osseous spiral lamina, spiral ligament and organ of Corti, with only minor quantities of tracer detected in the cell bodies of SGNs [59,60]. Additionally, neurotrophins, as well as gene transfer vectors and transplanted cells, have been shown to spread beyond the cochlea to the vestibular apparatus, the central nervous system (CNS) and the contralateral cochlea [61][62][63][64][65]. The cerebrospinal fluid (CSF) provides a direct link to these organs via the cochlear aqueduct â a bony channel which connects the perilymphatic space of the basal turn of the cochlea with the subarachnoid space of the posterior cranial cavity.…”

Inner Ear Therapy for Neural Preservation

“…Aside from visual identification of contralateral spread, there is also evidence that contralateral diffusion can be great enough to produce measurable outcomes. The unilateral infusion of GDNF protein protected HCs from noise damage in both ears at one of the higher doses [Shoji et al, 2000b]. One cause of contralateral ear contamination is fluid displacement.…”