Protective Effects of Everolimus against &lt;i&gt;N&lt;/i&gt;-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats

Hayashi, Ikumi; Aoki, Yuto; Asano, Daiki; Ushikubo, Hiroko; Mori, Akira; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

doi:10.1248/bpb.b15-00464

Cited by 13 publications

(20 citation statements)

References 29 publications

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“…Therefore, everolimus may play a protective role in neuroinflammation via inhibiting ERK phosphorylation. Interestingly, in N -methyl- d -aspartic acid-induced retinal neurotoxicity in rats, the protective effect of everolimus was mediated partially by the activation of ERK pathway [42]. Nevertheless, both anti-inflammation and neuroprotection by everolimus are beneficial.…”

Section: Discussionmentioning

confidence: 99%

Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures

Yang

Lin

et al. 2017

J Neuroinflammation

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BackgroundMicroglia is responsible for neuroinflammation, which may aggravate brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) kinase is related to microglial activation with subsequent neuroinflammation. In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation.MethodsIn vitro, we treated BV2 cells with KA and LPS. In vivo, KA was used to induce seizures on postnatal day 25 in B6.129P-Cx3cr1tm1Litt/J mice. Rapamycin and everolimus were evaluated in their modulation of neuroinflammation detected by real-time PCR, Western blotting, and immunostaining.ResultsEverolimus was significantly more effective than rapamycin in inhibiting iNOS and mTOR signaling pathways in both models of neuroinflammation (LPS) and seizure (KA). Everolimus significantly attenuated the mRNA expression of iNOS by LPS and nitrite production by KA and LPS than that by rapamycin. Only everolimus attenuated the mRNA expression of mTOR by LPS and KA treatment. In the present study, we also found that the modulation of mTOR under LPS and KA treatment was not mediated by Akt pathway but was primarily mediated by ERK phosphorylation, which was more significantly attenuated by everolimus. This inhibition of ERK phosphorylation and microglial activation in the hippocampus by everolimus was also confirmed in KA-treated mice.ConclusionsRapamycin and everolimus can block the activation of inflammation-related molecules and attenuated the microglial activation. Everolimus had better efficacy than rapamycin, possibly mediated by the inhibition of ERK phosphorylation. Taken together, mTOR inhibitor can be a potential pharmacological target of anti-inflammation and seizure treatment.

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Section: Discussionmentioning

confidence: 99%

Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures

Yang

Lin

et al. 2017

J Neuroinflammation

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“…Similar findings of apoptic retinal ganglion cells were reported in mice [27][28][29] (and rabbits [30] subjected to N-methyl-D-aspartate. Administration of aspartame (200 mg/kg) to rats led to two fold increase of phenylalanine and its product tyrosine in brain and plasma level [31] and contributed to decrease the ganglion cells [32][33][34][35]. Monosodium glutamate exhibited similar reduction of ganglion cells in rat [36] and rabbits [27].…”

Section: Discussionmentioning

confidence: 99%

Abnormal Retinal Structure and Function of Mother Wistar Rats Supplemented Aspartame, Glutamate and Galactose

El‐Sayyad¹,

El-Naga²,

Khalifa³

2016

J Drug Metab Toxicol

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Three dietary supplements are investigated in the present study. Aspartame is a low calorie sweetener utilized instead of sugar for diabetic patients. Monosodium Glutamate (MSG) is used in varieties of food stuffs to enhance food flavor. Meanwhile galactose is presents in many of food items such as milk, dairy products, fruits and vegetables and overloads enhanced aging like process and altered body function. The present work aimed to illustrate the effect of dietary supplements of aspartame, glutamate and galactose in retina of mother Wistar rats. Virgin Wistar rats were mated with fertile male and zero date of pregnancy was determined. Pregnant rats were orally administered aspartame (100 mg/kg), monosodium glutamate (500 mg/kg) and galactose (1 g/kg body weight) from 6th day of gestation until parturition and 21 days post-partum. Four main groups of pregnant rats were used; control, aspartame, glutamate and galactose treatment. Each animal group was composed of ten individuals. Mother rats were sacrificed at 21 days post-partum and their retinas were dissected and processed for histological, and transmission electron microscopic investigation. Biochemical assessments of vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), adhesion molecules (ICAM-1 & VCAM-1), 8-hydroxy-deoxyguanosine (8-hdG), iron, and zinc content were done. The present findings revealed that the used dietary supplements induced retinal damage assessed by degeneration of ganglion cells, inner and outer nuclear layer and widespread necrotic patches of photoreceptor outer segment. A striking missing of outer nuclear and photoreceptor outer segments was detected post-glutamate treatment. Glutamate and galactose treatment showed apparent increase of pleomorphic and pyknotic nuclei of inner and outer nuclear cells. The retinal thickness was markedly decreased in experimental groups especially in those of glutamate treatment. Retinal serotonin, dopamine and zinc and iron contents were markedly depleted, however, VEGF and ICAM-1& VCAM-1 and 8-hydroxy-guanosine were overexpressed in experimentally-treated groups compared to the control. It can be concluded that the applied dietary supplements affected the retinal structure and function of mother rats.

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“…Moreover, it was reported that pS6 immunoreactivity is enhanced in Müller cells in the injured retina, and mTORC1 inhibitors exhibit protective effects against retinal neuronal damage. 40,43) Rapamycin markedly reduced pS6 immunoreactivity in these nonvascular cells as well as in endothelial cells; therefore, it will be important to determine the effects of mTORC1 inhibitors on such nonvascular cells in future studies.…”

Section: Role Of the Mtor In Nonvascular Cells In The Retinamentioning

confidence: 99%

Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis

Nakahara

Morita

Yagasaki

et al. 2017

Biological & Pharmaceutical Bulletin

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Pathological ocular angiogenesis is a causative factor of retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. Vascular endothelial growth factor (VEGF) plays an important role in pathological angiogenesis, and anti-VEGF agents have been used to treat the ocular diseases that are driven by pathological angiogenesis. However, adverse effects associated with the blockade of VEGF signaling, including impairments of normal retinal vascular growth and retinal function, were suggested. Therefore, the development of a safe, effective strategy to prevent pathological ocular angiogenesis is needed. Recent studies have demonstrated that inhibitors of the mammalian target of rapamycin (mTOR) target proliferating endothelial cells within the retinal vasculature. Here, we review the potential of targeting the mTOR pathway to treat pathological ocular angiogenesis.

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Protective Effects of Everolimus against <i>N</i>-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats

Cited by 13 publications

References 29 publications

Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures

Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures

Abnormal Retinal Structure and Function of Mother Wistar Rats Supplemented Aspartame, Glutamate and Galactose

Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis

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