Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson’s Model in Rats

Mishra, Akanksha; Krishnamurthy, Sairam

doi:10.1007/s12640-018-9983-2

Cited by 15 publications

(5 citation statements)

References 90 publications

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“…Interestingly, REB markedly lowered the levels of renal oxidative injury biomarkers and restored the oxidant/antioxidant balance, which plays an important role in the alleviation of MTX‐induced renal damage. These findings coincide with the remarkable antioxidant and potent free radical scavenger effects of REB (Mishra & Krishnamurthy, 2019; Park et al, 2003). Several investigators have reported similar outcomes of REB treatments in different murine models, such as in ethanol‐induced gastric mucosal injury (Choi et al, 2013), antral ulcers (Ohashi, Aihara, Takasuka, Takahashi, & Takeuchi, 2009), acetic acid‐induced colitis (Sakurai, Osaka, & Yamasaki, 1998), and ischemia–reperfusion (Kim & Hong, 1995) models.…”

Section: Discussionsupporting

confidence: 66%

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Elmansy

Seleem

Mahmoud

et al. 2020

The Anatomical Record

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Methotrexate (MTX) is a widely used chemotherapeutic agent; nevertheless, the nephrotoxicity associated with its use has limited its clinical use. Rebamipide (REB) is a gastro‐protective agent with diverse promising biological activities. Here, we investigated the renoprotective effects of REB against MTX‐induced nephrotoxicity in rats. Male Wistar rats were allocated into four groups: the normal control group, the REB group (100 mg kg−1 day−1, PO, for 12 days), the MTX group (which received a single injection of 20 mg/kg, ip), and the REB + MTX group (which received 100 mg kg−1 day−1 REB for 7 days before and 5 days after being injected with 20 mg/kg MTX). Interestingly, MTX triggered kidney injury, characterized by renal dysfunction along with histopathological alterations. Moreover, increased reactive oxygen species level and inflammatory response were detected in the kidney of MTX‐treated rats. However, REB prevented MTX‐induced oxidative kidney injury and boosted an antioxidant balance. Mechanistically, REB markedly activated the NRF‐2 protein and upregulated the expression of both SIRT‐1 and FOXO‐3 genes. Additionally, REB administration strongly inhibited the inflammatory response by downregulating both NF‐κB‐p65 and TLR‐4. Finally, the coadministration of REB and MTX activated the mTOR/PI3K/AKT signaling pathway. Simultaneously, REB treatment attenuated the reduction in glomerular size, the widening of the capsular spaces, and the tubular cell damage due to MTX administration. Taken together, these results indicate the potential of REB as adjuvant therapy to prevent nephrotoxicity in patients receiving MTX treatment.

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Section: Discussionsupporting

confidence: 66%

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Elmansy

Seleem

Mahmoud

et al. 2020

The Anatomical Record

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“…(2019) revealed the influence of rebamipide (20, 40, and 80 mg/kg- oral ingestions twice per day; i.e., 4th–27th day) against 6-OHDA-lesioned (20 µg 6-OHDA in 4 µL at 1 µL/min) Parkinsonian in the male Charles Foster strain albino rats. The rebamipide repressed 6-OHDA-lesioned motor impairments using behavioral tests such as apomorphine-induced (1 mg/kg, intraperitoneally) head rotation test, open-field test, rotarod test, grip strength test, and bar catalepsy test, and also the α-synuclein aggregations in substantia nigra [ 100 ]. Lima et al (2017) revealed the neuroprotective effect of Spirulina platensis using 6 µg 6-OHDA in 1 µL-induced lesion in male Wistar rats.…”

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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“…To investigate the impact of α-Syn accumulation under oxidative stress on OMM proteins, we evaluated the effects of PD-associated neurotoxins and pro-oxidant metals-known for generating mitochondrial and cytosolic ROS and fostering α-Syn aggregation in PD models-on the levels of TOM40 and TOM20 (Fig. 2A) 11,46,47 . Immunoblot analysis revealed a signi cant decrease in TOM40 levels in SH-SY5Y cells overexpressing ectopic α-Syn and exposed to 6OHDA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson’s Disease and Parkinsonism-Dementia of Guam

Hegde,

Vasquez,

Kodavati

et al. 2024

Preprint

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Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson’s Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.

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Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson’s Model in Rats

Cited by 15 publications

References 90 publications

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson’s Disease and Parkinsonism-Dementia of Guam

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