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Fuentes-Santamaria V.,Institute Investigacion en Discapacidades Neurologicas IDINE | Alvarado J.C.,Institute Investigacion en Discapacidades Neurologicas IDINE | Rodriguez-de la Rosa L.,University of Castilla - La Mancha | Murillo-Cuesta S.,Autonomous University of Madrid | And 10 more authors.
Brain Structure and Function | Year: 2016

Insulin-like growth factor 1 (IGF-1) is a neurotrophic protein that plays a crucial role in modulating neuronal function and synaptic plasticity in the adult brain. Mice lacking the Igf1 gene exhibit profound deafness and multiple anomalies in the inner ear and spiral ganglion. An issue that remains unknown is whether, in addition to these peripheral abnormalities, IGF-1 deficiency also results in structural changes along the central auditory pathway that may contribute to an imbalance between excitation and inhibition, which might be reflected in abnormal auditory brainstem responses (ABR). To assess such a possibility, we evaluated the morphological and physiological alterations in the cochlear nucleus complex of the adult mouse. The expression and distribution of the vesicular glutamate transporter 1 (VGluT1) and the vesicular inhibitory transporter (VGAT), which were used as specific markers for labeling excitatory and inhibitory terminals, and the involvement of the activity-dependent myocyte enhancer factor 2 (MEF2) transcription factors in regulating excitatory synapses were assessed in a 4-month-old mouse model of IGF-1 deficiency and neurosensorial deafness (Igf1−/− homozygous null mice). The results demonstrate decreases in the cochlear nucleus area and cell size along with cell loss in the cochlear nuclei of the deficient mouse. Additionally, our results demonstrate that there is upregulation of VGluT1, but not VGAT, immunostaining and downregulation of MEF2 transcription factors together with increased wave II amplitude in the ABR recording. Our observations provide evidence of an abnormal neuronal cytoarchitecture in the cochlear nuclei of Igf1−/− null mice and suggest that the increased efficacy of glutamatergic synapses might be mediated by MEF2 transcription factors. © 2014, Springer-Verlag Berlin Heidelberg. Source

Alvarado J.C.,Institute Investigacion en Discapacidades Neurologicas IDINE | Alvarado J.C.,University of Castilla - La Mancha | Fuentes-Santamaria V.,Institute Investigacion en Discapacidades Neurologicas IDINE | Fuentes-Santamaria V.,University of Castilla - La Mancha | And 10 more authors.
Frontiers in Aging Neuroscience | Year: 2015

The growing increase in age-related hearing loss (ARHL), with its dramatic reduction in quality of life and significant increase in health care costs, is a catalyst to develop new therapeutic strategies to prevent or reduce this aging-associated condition. In this regard, there is extensive evidence that excessive free radical formation along with diminished cochlear blood flow are essential factors involved in mechanisms of other stress-related hearing loss, such as that associated with noise or ototoxic drug exposure. The emerging view is that both play key roles in ARHL pathogenesis. Therapeutic targeting of excessive free radical formation and cochlear blood flow regulation may be a useful strategy to prevent onset of ARHL. Supporting this idea, micronutrient-based therapies, in particular those combining antioxidants and vasodilators like magnesium (Mg2+), have proven effective in reducing the impact of noise and ototoxic drugs in the inner ear, therefore improving auditory function. In this review, the synergistic effects of combinations of antioxidant free radicals scavengers and cochlear vasodilators will be discussed as a feasible therapeutic approach for the treatment of ARHL. © 2015 Alvarado, Fuentes-santamaría, Melgar-rojas, Valero, Gabaldón-ull, Miller and Juíz. Source

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