Epalrestat improves motor symptoms by reducing oxidative stress and inflammation in the reserpine induced mouse model of Parkinson’s disease

Rahman, Md. Mahbubur; Chakraborti, R.; Potol, Md. Abdullah; Abir, Ariful Haque; Sharmin, Ozayra; Alam, Mahabub Maraj; Khan, Md. Fazlur Rahman; Afrin, Rownock; Jannat, Humayra; Wadud, Rasiqh; Habib, Zaki Farhad

doi:10.1002/ame2.12097

Cited by 20 publications

(5 citation statements)

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“…Animal models of PD play an important role in the discovery of potential therapies and molecular mechanisms of the illness ( Dauer and Przedborski, 2003 ; Duty and Jenner, 2011 ; Im et al, 2016 ; Hamadjida et al, 2019 ; Salari and Bagheri, 2019 ; Rahman et al, 2020 ). The 6-OHDA striatal lesion model, more closely approximating early PD, has been commonly used for studying neuroprotective and neurotrophic strategies for PD, an active and important area of research ( Lundblad et al, 2004 ; Marie et al, 2022 ; Mazzocchi et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice

Sun

Zhang

et al. 2022

Front. Behav. Neurosci.

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IntroductionDespite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound’s long-term therapeutic effects.Materials and methodsIn the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.ResultsOur results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH+ cells and TH+ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.ConclusionIn summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.

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Section: Discussionmentioning

confidence: 99%

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice

Sun

Zhang

et al. 2022

Front. Behav. Neurosci.

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“…This protocol induces progressive motor changes (catalepsy, decreased spontaneous motor activity and oral dyskinesia), in addition to non-motor signs and neuronal changes compatible with the pathophysiology of PD in both rats (Fernandes et al, 2012;Santos et al, 2013;Sarmento-Silva, 2015;Brandão et al, 2017;Leão et al, 2017;Lins et al, 2017) and mice (Campêlo et al, 2017;Beserra-Filho et al, 2019). Recent adaptations of this protocol have also shown the applicability of reserpine in the study of several aspects of parkinsonism (Pereira et al, 2020;Rahman et al, 2020). In this study, we sought to extend the validation of this protocol, by verifying if neuroinflammation is induced concomitantly to the other alterations related to PD pathophysiology seen in previous studies (decreased dopaminergic markers, increased alpha-synuclein and oxidative stress).…”

Section: Discussionmentioning

confidence: 99%

“…In the past, reserpine was used in high doses ranging from 1 to 10 mg/kg, which rapidly induced severe motor impairments (Baskin and Salamone, 1993;Salamone and Baskin, 1996). More recent studies have proposed the repeated administration of 0.1 mg/kg of this drug, which leads to the gradual appearance of motor signs in rats or mice, similar to the condition in humans (Fernandes et al, 2012;Santos et al, 2013;Peres et al, 2016;Campêlo et al, 2017;Leão et al, 2017;Lins et al, 2018;Beserra-Filho et al, 2019;Bispo et al, 2019;Rahman et al, 2020). Furthermore, Santos et al (2013) demonstrated that animals that received repeated reserpine at low dosages also had cognitive deficits compatible with the non-motor sings of PD.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation in early, late and recovery stages in a progressive parkinsonism model in rats

et al. 2022

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Parkinson’s disease (PD) is characterized by motor and non-motor signs, which are accompanied by progressive degeneration of dopaminergic neurons in the substantia nigra. Although the exact causes are unknown, evidence links this neuronal loss with neuroinflammation and oxidative stress. Repeated treatment with a low dose of reserpine—inhibitor of VMAT2—has been proposed as a progressive pharmacological model of PD. The aim of this study was to investigate whether this model replicates the neuroinflammation characteristic of this disease. Six-month-old Wistar rats received repeated subcutaneous injections of reserpine (0.1 mg/kg) or vehicle on alternate days. Animals were euthanized after 5, 10, or 15 injections, or 20 days after the 15th injection. Catalepsy tests (motor assessment) were conducted across treatment. Brains were collected at the end of each treatment period for immunohistochemical and RT-PCR analyzes. Reserpine induced a significant progressive increase in catalepsy duration. We also found decreased immunostaining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc) and increased GFAP + cells in the SNpc and dorsal striatum after 10 and 15 reserpine injections. Phenotyping microglial M1 and M2 markers showed increased number of CD11b + cells and percentage of CD11b + /iNOS + cells in reserpine-treated animals after 15 injections, which is compatible with tissue damage and production of cytotoxic factors. In addition, increased CD11b + /ArgI + cells were found 20 days after the last reserpine injection, together with an increment in IL-10 gene expression in the dorsal striatum, which is indicative of tissue repair or regeneration. Reserpine also induced increases in striatal interleukin TNF-alpha mRNA levels in early stages. In view of these results, we conclude that reserpine-induced progressive parkinsonism model leads to neuroinflammation in regions involved in the pathophysiology of PD, which is reversed 20 days after the last injection. These findings reveal that withdrawal period, together with the shift of microglial phenotypes from the pro-inflammatory to the anti-inflammatory stage, may be important for the study of the mechanisms involved in reversing this condition, with potential clinical applicability.

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“…[24,25] Thus, inhibiting the inflammation and oxidative stress of PD might bring out direct therapeutic effects for clinical treatment. For instance, niacin, [26] epalrestat, [27] and bruceine D [28] could ameliorate PD progression via modulating inflammation and oxidative stress. In our study, we also detected the levels of proinflammatory cytokines (including IL-1β, TNF-α, and IL-6) in the serum of PD patients.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of long noncoding RNA SNHG7 protects against inflammation and apoptosis in Parkinson's disease model by targeting the miR‐425‐5p/TRAF5/NF‐κB axis

Zhang

Wang

et al. 2021

J Biochem & Molecular Tox

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BackgroundAccumulated evidence has established that long non-coding RNA (lncRNA) is involved in the progress of Parkinson's disease (PD). SNHG7, a novel lncRNA, has been found to play a key role in tumorigenesis.However, the SNHG7 expression and its functional effects on PD remain uncharted. MethodsRT-PCR was used to detect the expression of SNHG7, miR-425-5p and in ammatory cytokines in the plasma of PD patients and the healthy controls. Rotenone (Rot) was adopted to construct PD models in SD rats and SH-SY5Y cells, respectively. Gain-and loss-of functions of SNHG7 or miR-425-5p were conducted. The expression levels of Caspase3, tyrosine hydroxylase (TH), Iba1 in SD rat striatum was measured via immunohistochemistry and Western blot. Additionally, the expressions of in ammatory cytokines (IL-1β, IL-6, TNF-α) and oxidative stress factors (MDA, SOD, GSH-PX) in the brain tissues were examined using RT-PCR and ELISA. Moreover, the protein levels of TRAF5, I-κB, NF-κB, HO-1, Nrf2 were detected via Western blot. Bioinformatics was applied to predict the targeting relationship between SNHG7, miR-425-5p and TRAF5. Dual luciferase activity assay and RNA immunoprecipitation (RIP) assays were carried out to verify their interactions. ResultsSNHG7 was found up-regulated in PD patients while miR-425-5p expression was down-regulated (compared to healthy donors). Meanwhile, SNHG7 level was positively correlated with the level of in ammatory cytokines in PD patients. Functional experiments con rmed that SNHG7 downregulation or miR-425-5p overexpression attenuated neuronal apoptosis in the Rot-mediated PD model, TH-positive cell loss and microglia activation by mitigating in ammation and oxidative stress. Mechanistically, SNHG7 served as a competitive endogenous RNA (ceRNA) by sponging miR-425-5p and promoted TRAF5 mediated in ammation and oxidative stress. ConclusionInhibition of SNHG7 ameliorated neuronal apoptosis in PD through relieving miR-425-5p/TRAF5/NF-κB signaling pathway modulated in ammation and oxidative stress.

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Epalrestat improves motor symptoms by reducing oxidative stress and inflammation in the reserpine induced mouse model of Parkinson’s disease

Cited by 20 publications

References 91 publications

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice

Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice

Neuroinflammation in early, late and recovery stages in a progressive parkinsonism model in rats

Downregulation of long noncoding RNA SNHG7 protects against inflammation and apoptosis in Parkinson's disease model by targeting the miR‐425‐5p/TRAF5/NF‐κB axis

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