Morphological consequences of acoustic trauma on cochlear hair cells and the auditory nerve.

AIMS: Hearing loss is the most common form of sensory impairment in humans. Short impulses of a high intensity noise can trigger sudden hearing loss, which is generally irreversible and associated with structural tissue damage of the cochlea and auditory nerve. It is well established that myelination is essential for the rapid propagation of action potentials along axons, and that Schwann cells are responsible for myelin sheath production in the peripheral nervous system. In the cochlea, spiral ganglion neuron axons are myelinated by Schwann cells. This myelin contributes to axonal protection and allows for efficient action potential transmission along the auditory nerve. For this reason, here we studie the morphological changes on cochlear hair cells and myelin sheaths of the auditory nerve, directly linked to hearing impairment induced by acoustic trauma. MATERIAL AND METHODS: To study the auditory functions, auditory brainstem responses and distortion products were measured at baseline, 2 days, and 21 days after trauma in rats. Then, scanning and transmission electron microscopy techniques were performed to analyze cochleae and the auditory nerve at 21 days after trauma. RESULTS: We observed that acoustic trauma induced cochlear outer hair cell loss and fusion of inner hair cell stereocilia. We also observed an axonal loss and myelin sheath disorganization of the auditory nerve. CONCLUSIONS: These data confirm that a strong acoustic trauma induced histological changes in the cochlea and auditory nerve, leading to permanent hearing loss.

Senescence-accelerated mouse prone 8 (SAMP8) as a model of age-related hearing loss.

Hearing loss is the most common form of sensory impairment in humans, affecting 5.3% worldwide population. In industrial countries, age-related hearing loss is a major health problem affecting one-third of individuals over 65years old. However, the physiological and molecular changes involved in this senescence process remain unclear. In this study, we determined the influence of age on auditory brainstem response (ABR) and the distortion product otoacoustic emissions (DPOAE) in the premature senescence mouse model SAMP8 for five months. We showed a progressive increase of ABR thresholds and a decrease of distortion product amplitude from 37days old in SAMP8 compared to CBA mice. The data we show here provide new knowledge in functional auditory changes during the senescence process and open up new opportunities for the development of new drugs involved in age-related hearing loss treatment.

SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias.

SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 µM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.