The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina

Tao, Ye; Chen, Tao; Liu, Bei; Guo, Yang; Peng, Guang-Hua; Zhang, Hua; Huang, Yi

doi:10.1016/j.taap.2015.03.013

Cited by 20 publications

(18 citation statements)

References 47 publications

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“…Furthermore, the formerly reported abnormities in the visual signal pathway of MNU-administered retinas were also studied after TES therapy. 26 These topographic findings would enrich our knowledge about this electrical therapeutic strategy. It is our hope that the protective effects as evidenced by the present study will provide a better understanding of candidate treatments for human RP.…”

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confidence: 89%

“…26,27 Briefly, 10 mice from each animal group were killed under dim red light and their eyes were enucleated. The neural retina was gently removed from the pigment epithelium layer of the eye cup and placed into the recording chamber.…”

Section: Multielectrode Array (Mea) Recordingmentioning

confidence: 99%

“…The signal-to-noise ratio (SNR ¼ average driven firing rate/ spontaneous background firing rate 26,31,32 ) was calculated to analyze the efficiency of visual signal transmission. Compared with normal controls, the impaired light-induced response and spontaneous hyperactivity collectively contributed to decreased SNR values in the sham group (sham versus normal controls, P < 0.01, n ¼ 10; Table 2).…”

Section: Signal-to-noise Ratio and Synaptic Efficacymentioning

confidence: 99%

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Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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METHODS. N-methyl-N-nitrosourea-administered mice received TES or sham stimulations and were subsequently subjected to electroretinography (ERG), multielectrode array (MEA), and histologic and immunohistochemistry examinations. Quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analyses were also performed to determine the mRNA levels of Bax, Bcl-2, Calpain-2, Caspase-3, brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF). RESULTS.Amplitudes of ERG b-wave in the TES-treated mice were significantly larger than those in the sham controls (P < 0.01). Microelectrode array examination revealed that the photoreceptors in TES-treated retina were efficiently preserved (P < 0.01). Morphologic measurements showed that the central retina region was more consolidated than the other areas in the TES-treated mice. Together with the disproportionate distribution of immunostaining in retinal flat mounts, these findings indicated that different rescuing kinetics existed among regional photoreceptors. Compared with the sham controls, a significantly increased signal-to-noise ratio was also found in the TES-treated mice (TES100: 2.02 6 1.12; TES200: 4.42 6 1.51; sham: 0.25 6 0.13; P < 0.01). Moreover, qRT-PCR measurements suggested that the altered expression of several apoptotic factors and neurotrophic cytokines was correlated with TES-induced protection.CONCLUSIONS. Regional photoreceptors in the MNU-administered retinas exhibit different sensitivities to TES. Transcorneal electrical stimulation is capable of ameliorating MNUinduced photoreceptor degeneration and rectifying abnormalities in the inner visual signal pathways.Keywords: transcorneal electrical stimulation, therapeutic strategy, retinitis pigmentosa R etinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases characterized by initially impaired dark-adapted sight, progressive deterioration of visual fields, and eventual blindness. 1,2 Currently, the pathologic mechanisms of RP remain poorly understood, and there is no satisfactory therapeutic intervention.3 Retinitis pigmentosa models can be used to explore the pathologic mechanisms underlying this disorder, providing insights into the development of effective therapeutics. The N-methyl-N-nitrosourea (MNU) can pharmacologically induce photoreceptor degeneration. After a single systemic administration, active signs of retinal degeneration, such as decreased outer nuclear layer (ONL) thickness, degraded electroretinogram (ERG) response, and hyperexpressed apoptotic labeling, are indistinct in the MNU-treated retinas due to the selective photoreceptor cell loss. The mechanism underlying MNU-induced photoreceptor death is the principal alkylation of DNA, depending on the action of alkyladenine DNA glycosylase (Aag), an enzyme that removes alkylated bases via cleavage of glycosyl bond connecting base to the sugar phosphate backbone, thus generating abasic sites that can be further processed by the base excision repair machinery.4 N-methyl-N-nitrosourea ...

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mentioning

confidence: 89%

Section: Multielectrode Array (Mea) Recordingmentioning

confidence: 99%

Section: Signal-to-noise Ratio and Synaptic Efficacymentioning

confidence: 99%

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Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…The present study sought to clarify the protective effects of peonidin against the MNU-induced retinal damage by topographic measurements. Moreover, with the helping of the MEA recording, the formerly described MNU induced abnormalities of the visual signal transmission were systematically examined after peonidin treatment [28]. Our results suggested that peonidin could counteract the MNU induced photoreceptors degeneration and rectify the abnormities in the inner visual signal pathways.…”

Section: Introductionmentioning

confidence: 85%

“…The MEA recording was described in detail in previous reports [28,29]. Briefly, the animals were sacrificed under dim red light and their eyes were enucleated.…”

Section: Mea Recordingmentioning

confidence: 99%

Integrating Topographic Measures to Explore the Protective Effects of Peonidin Against the N-Methyl-N-Nitrosourea Induced Photoreceptor Degeneration

Tao

Chen²,

Liu³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The pathphysiological properties of N-Methyl -N -nitrosourea (MNU) induced photoreceptor degeneration are similar to the hereditary retinitis pigmentosa (RP). The present study sought to explore the beneficial effects of the peonidin, a common aglycone form of anthocyanin, on the MNU induced photoreceptor degeneration via topographic measurements. Methods: The MNU administrated mouse received peonidin or vehicle injections, and then they were examined by electroretinography (ERG), multi electrode array (MEA), histological and immunohistochemistry studies. Results: The protective effects of peonidin on the MNU administrated retinas were systematically verified and quantified by topographic measures. The peonidin treatment could protect the photoreceptor against the MNU toxicity both functionally and morphologicaly. The most sensitive zone to peonidin therapy was sorted out, indicating that different rescuing kinetics existed between the retinal hemispheres and retinal quadrants. Moreover, the hyperactive spontaneous firing response and the debilitated light induced response in MNU administrated retinas could be partially reversed by peonidin treatment. To our knowledge, this was the first study to explore the pharmacological effects of peonidin on the electrophysiological properties of inner visual signal pathways. Conclusion: The peonidin could ameliorate the MNU induced photoreceptors degeneration and rectify the abnormities in the inner visual signal pathways. Future refinements of the knowledge cast insights into the discovery of a novel treatment for human RP.

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N‐methyl‐N‐nitrosourea induces retinal degeneration in the rat via the inhibition of NF‐κB activation

Xiong

Song

et al. 2016

Cell Biochemistry & Function

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Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by the loss of photoreceptor cells through apoptosis. N-methyl-N-nitrosourea (MNU) is an alkylating toxicant that induces photoreceptor cell death resembling hereditary RP. This study aimed to investigate the role of nuclear factor κB (NF-κB) in MNU-induced photoreceptor degeneration. Adult rats received a single intraperitoneal injection of MNU (60 mg/kg bodyweight). Hematoxylin and eosin staining demonstrated progressive outer nuclear layer (ONL) loss after MNU treatment. Transmission electron microscopy revealed nuclear pyknosis, chromatin margination in the photoreceptors, increased secondary lysosomes, and lobulated retinal-pigmented epithelial cells in MNU-treated rats. Numerous photoreceptor cells in the ONL showed positive TUNEL staining and apoptosis rate peaked at 24 hours. Enhanced depth imaging spectral-domain optical coherence tomography showed ONL thinning and decreased choroid thickness. Electroretinograms showed decreased A wave amplitude that predominated in scotopic conditions. Western blot analysis showed that nuclear IκBα level increased, whereas nuclear NF-κB p65 decreased significantly in the retinas of MNU-treated rats. These findings indicate that MNU leads to selective photoreceptor degradation, and this is associated with the inhibition of NF-κB activation.

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The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina

Cited by 20 publications

References 47 publications

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Integrating Topographic Measures to Explore the Protective Effects of Peonidin Against the N-Methyl-N-Nitrosourea Induced Photoreceptor Degeneration

N‐methyl‐N‐nitrosourea induces retinal degeneration in the rat via the inhibition of NF‐κB activation

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