Selective degeneration of synapses in the dorsal cochlear nucleus of chinchilla following acoustic trauma and effects of antioxidant treatment

Du, Xiaoping; Chen, Kejian; Choi, Chul-Hee; Li, Wei; Cheng, Weihua; Stewart, Charles A.; Hu, Ning; Floyd, Robert A.; Kopke, Richard D.

doi:10.1016/j.heares.2011.11.013

Cited by 26 publications

(31 citation statements)

References 97 publications

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“…This suggested that synapses are primed for increased neurotransmitter release and synaptic transmission, which may results in greater synaptic efficacy. The observations were comparable with ultrastructural changes reported by a previous study, which found large, lucent pleomorphic vesicles in the synapses of the dorsal cochlear nucleus of the chinchilla following acoustic trauma (35). Of note, images from the TEM analysis showed that there were fewer microtubules and neurofilaments in the synapses of salicylate-treated animals, which may possibly lead to reduced vesicular and protein transport to the synapse.…”

Section: Discussionsupporting

confidence: 91%

Salicylate-induced changes in immediate-early genes in the hippocampal CA1 area

Yin

et al. 2015

Molecular Medicine Reports

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Studies have suggested that salicylate affects neuronal function via interactions with specific membrane channels/receptors. However, the effect of salicylate on activity and synaptic morphology of the hippocampal Cornu Ammonis (CA) 1 area remains to be elucidated. The activation of immediate-early genes (IEGs) was reported to correlate with neuronal activity, in particular activity-regulated cytoskeleton-associated protein and early growth response gene 1. The aim of the present study was to evaluate the expression of these IEGs, as well that of N-methyl D-aspartate (NMDA) receptor subunit 2B in rats following acute and chronic salicylate treatment. Protein and messenger RNA levels of all three genes were increased in rats following chronic administration of salicylate (300 mg/kg for 10 days), returning to baseline levels 14 days post-cessation of treatment. The transient upregulation of gene expression following treatment was accompanied by ultrastructural alterations in hippocampal CA1 area synapses. An increase in synaptic interface curvature was observed as well as an increased number of presynaptic vesicles; in addition, postsynaptic densities thickened and lengthened. In conclusion, the results of the present study indicated that chronic exposure to salicylate may lead to structural alteration of hippocampal CA1 neurons, and it was suggested that this process occurs through induced expression of IEGs via NMDA receptor activation.

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Section: Discussionsupporting

confidence: 91%

Salicylate-induced changes in immediate-early genes in the hippocampal CA1 area

Yin

et al. 2015

Molecular Medicine Reports

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“…Results of GFAP expression in the DCN suggest that the lateral and middle regions of the DCN may be more sensitive to blast exposure than the medial region (Figure 4). Our laboratory previously documented a similar regional specificity with respect to synaptic degeneration in the DCN after noise exposure [62]. Therefore, biomarker studies may provide useful information for understanding the mechanisms of bTBI and developing treatment methodologies.…”

Section: Discussionmentioning

confidence: 78%

“…A combinatorial treatment regimen of hypothermia plus NAC has been shown to attenuate hypoxic ischemic brain injury [111]. Co-administration of NAC with 4-hydroxy phenyl N-tert-butyl nitrone (4-OHPBN, a structural ortholog of HPN-07) attenuated oxidative stress in the cochlea [70] and synaptic degeneration in the DCN associated with acute acoustic trauma [62]. Our unpublished data also suggest that a combination of NAC with HPN-07 provides synergistic protection to the peripheral auditory system.…”

Section: Discussionmentioning

confidence: 99%

“…Identification of the nuclei or brain regions was guided by anatomical landmarks described within a pictorial atlas of the rat brain [61]. A modified two-dimensional quantification method was employed to count positive immunostained cells in these nuclei or regions [62,63]. A color camera (DP70) attached to an Olympus microscope (BX51) and DPController and DPManager programs (Olympus, Melville, NY) were used to obtain images.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Antioxidant Treatment on Blast-Induced Brain Injury

Ewert

Cheng

et al. 2013

PLoS ONE

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Blast-induced traumatic brain injury has dramatically increased in combat troops in today’s military operations. We previously reported that antioxidant treatment can provide protection to the peripheral auditory end organ, the cochlea. In the present study, we examined biomarker expression in the brains of rats at different time points (3 hours to 21 days) after three successive 14 psi blast overpressure exposures to evaluate antioxidant treatment effects on blast-induced brain injury. Rats in the treatment groups received a combination of antioxidants (2,4-disulfonyl α-phenyl tertiary butyl nitrone and N-acetylcysteine) one hour after blast exposure and then twice a day for the following two days. The biomarkers examined included an oxidative stress marker (4-hydroxy-2-nonenal, 4-HNE), an immediate early gene (c-fos), a neural injury marker (glial fibrillary acidic protein, GFAP) and two axonal injury markers [amyloid beta (A4) precursor protein, APP, and 68 kDa neurofilament, NF-68]. The results demonstrate that blast exposure induced or up-regulated the following: 4-HNE production in the dorsal hippocampus commissure and the forceps major corpus callosum near the lateral ventricle; c-fos and GFAP expression in most regions of the brain, including the retrosplenial cortex, the hippocampus, the cochlear nucleus, and the inferior colliculus; and NF-68 and APP expression in the hippocampus, the auditory cortex, and the medial geniculate nucleus (MGN). Antioxidant treatment reduced the following: 4-HNE in the hippocampus and the forceps major corpus callosum, c-fos expression in the retrosplenial cortex, GFAP expression in the dorsal cochlear nucleus (DCN), and APP and NF-68 expression in the hippocampus, auditory cortex, and MGN. This preliminary study indicates that antioxidant treatment may provide therapeutic protection to the central auditory pathway (the DCN and MGN) and the non-auditory central nervous system (hippocampus and retrosplenial cortex), suggesting that these compounds have the potential to simultaneously treat blast-induced injuries in the brain and auditory system.

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“…In addition another potential areas where therapeutics are needed includes dementia which may be an excellent target indication for specific nitrones and/or for a specific nitrone combined with another compound such as lanthionine which can act as a neurotropic agent. Although not presented here, current R&D efforts at various stages of development are now ongoing where specific therapeutic nitrones are being targeted for: A) treatment of noise-induced hearing loss [138–141], B) treatment for macular dementia [142], and C) treatment for brain damage and hearing loss caused by explosive blasts [143]. With so much R&D focused on nitrones as therapeutics it provides optimism that treatment for one or more of the indications discussed above may arise from these efforts.…”

Section: Summary and Prospective Future Directionsmentioning

confidence: 99%

Nitrone-based therapeutics for neurodegenerative diseases: Their use alone or in combination with lanthionines

Floyd

Neto

Zimmerman

et al. 2013

Free Radical Biology and Medicine

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The possibility of free radical reactions occurring in biological processes led to the development and employment of novel methods and techniques focused on determining their existence and importance in normal and pathological conditions. For this reason the use of Nitrones for spin trapping free radicals came into widespread use in the 1970s and 1980s when surprisingly the first evidence of their potent biological properties was first noted. Since then wide-spread exploration and demonstration of the potent biological properties of phenyl-tert-butylnitrone (PBN) and derivatives were shown in preclinical models of septic shock and then in experimental stroke. The most extensive commercial effort done in order to capitalize on the potent properties of the PBN-Nitrones was for acute ischemic stroke. This occurred during the 1993–2006 time interval where the 2,4-disulfonyl-phenyl PBN derivative, called NXY-059 in the stroke studies, was shown to be safe in humans and was taken all the way through clinical phase 3 trials and was deemed to be ineffective. As summarized in this review because of its excellent human safety profile 2,4-disulfonyl-phenyl PBN, now called OKN-007 in the cancer studies, was tested as an anti-cancer agent in several preclinical glioma models and shown to be very effective. Based on these studies this compound is now scheduled to enter into early clinical trials for astrocytoma/glioblastoma multiform this year. The potential use of OKN-007 in combination with neurotropic compounds such as the lanthionine ketamine esters (LKE) is discussed for glioblastoma multiform as well as for various other indications leading to dementia such as aging, septic shock, and malaria infections. There is much more research and development activity on-going for various indications with the nitrones alone or in combination with other active compounds as briefly noted in this review.

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Selective degeneration of synapses in the dorsal cochlear nucleus of chinchilla following acoustic trauma and effects of antioxidant treatment

Cited by 26 publications

References 97 publications

Salicylate-induced changes in immediate-early genes in the hippocampal CA1 area

Salicylate-induced changes in immediate-early genes in the hippocampal CA1 area

Effects of Antioxidant Treatment on Blast-Induced Brain Injury

Nitrone-based therapeutics for neurodegenerative diseases: Their use alone or in combination with lanthionines

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