The spread of adenoviral vectors to central nervous system through pathway of cochlea in mimetic aging and young rats

Abstract

There is no definitive conclusion concerning the spread of viral vectors to the brain after a cochlear inoculation. In addition, some studies have reported different distribution profiles of viral vectors in the central auditory system after a cochlear inoculation. Thus, rats were grouped into either a mimetic aging group or a young group and transfected with adenoviral vectors (AdVs) by round window membrane injection. The distribution of AdV in central nervous system (CNS) was demonstrated in the two groups with transmission electron microscopy and immunofluorescence. We found that the AdV could disseminate into the CNS and that the neuronal damage and stress-induced GRP78 expression were reduced after transfection with PGC-1α, as compared with the control vectors, especially in the mimetic aging group. We also found that the host immune response was degraded in CNS in the mimetic aging group after transduction through the cochlea, as compared with the young group. These results demonstrate that viral vectors can disseminate into the CNS through the cochlea. Moreover, mimetic aging induced by D-galactose could facilitate the spread of viral vectors into the CNS from the cochlea. These findings may indicate a new potential approach for gene therapy against age-related diseases in the CNS.

The role of sodium hydrosulfide in attenuating the aging process via PI3K/AKT and CaMKKβ/AMPK pathways

“…The brains were removed and postfixed in 4% paraformaldehyde overnight at 4 °C. The selection and orientation of the auditory cortex and the following procedures were previously published [33]. Primary antibodies against cleaved-caspase-3 (1:500, servicebio, Wuhan, Hubei, China) and glial fibrillary acidic protein (GFAP; 1:1000, Proteintech, Wuhan, Hubei, China) were used for the IHC analysis.…”

“…The Nissl staining analysis was performed according to our published paper with few modifications [33]. Briefly, serial transverse sections made from paraffin-embedded brains were dewaxed with xylene, followed by rehydration in graded alcohol and immersion in 0.3% toluidine blue for 40 min at 60 °C.…”

“…Briefly, serial transverse sections made from paraffin-embedded brains were dewaxed with xylene, followed by rehydration in graded alcohol and immersion in 0.3% toluidine blue for 40 min at 60 °C. The number of neurons in the V layer of the auditory cortex was counted in accordance with our previous criterion [33].…”

“…The following processes were performed as previously described in our laboratory [33]. Detailed information for the primary antibodies used are listed in the following table:…”

Toward the Optical Cochlear Implant

“…Although initial studies showed substantial dose-and time-dependent hair cell toxicity (Dazert et al 1997;Holt et al 1999;Luebke et al 2001a), multiply deleted (E1 − , E3 − , pol − , pTP − ) adenoviruses without impaired viral infectivity (Holt 2002) preserved cochlear function and hair cell transduction (Luebke et al 2001b;Holt 2002;Corey et al 2004). However, because of their potential immunogenicity, cell toxicity, and possible CNS virus spread (Chen et al 2015), future use of adenoviruses is under further investigation. Newer development of adenoviruses, mainly using helper-dependent adenoviruses (Wenzel et al 2007) or different serotypes (Ad28) additionally supported their potential use in future cochlear gene therapy (Kraft et al 2013).…”