Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat

Speiser, Zipora; Mayk, Adi; Eliash, Sarah; Cohen, Sasson

doi:10.1007/s007020050182

Cited by 72 publications

(39 citation statements)

References 24 publications

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“…Sham: Thoracotomy without MI induction or any treatment, RG: MI and RG, 2.0 mg/kg/day, N/S: MI and normal saline (N/S) 0.9%/day. RG or N/S was administered by intraperitoneal injections,19, 20 for 28 days, beginning 24 h post‐MI.…”

Section: Methodsmentioning

confidence: 99%

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Varela¹,

Mavroidis

Katsimpoulas³

et al. 2017

ESC Heart Failure

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AimRasagiline mesylate (N‐propargyl‐1 (R)‐aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase‐B with cardioprotective and anti‐apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery.Methods and resultsRG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end‐systolic and diastolic dimensions and preserved fractional shortening in RG‐treated compared with normal saline group at 28 days post‐MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non‐infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress.ConclusionsOur study demonstrates a positive effect of RG in the post‐MI period with a significant attenuation in cardiac remodelling.

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Section: Methodsmentioning

confidence: 99%

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Varela¹,

Mavroidis

Katsimpoulas³

et al. 2017

ESC Heart Failure

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“…59,60 Therefore, inactivation of MAO is thought to be a good strategy for the protection of neuronal cells in vitro and in vivo. 61,62 In fact, MAO inhibitors such as l-deprenyl (selegiline) and (R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine (rasagiline) have become archived pharmacologic therapeutic options for human neuropsychiatric diseases such as Parkinson's disease, [63][64][65] treatment-resistant depression, 66 and anxiety disorders. 67 To clarify whether LSD1 and/or MAO were important factors in the neuroprotective effects provided by tranylcypromine, neuronal survival was investigated in Lsd1-knockdown samples using Lsd1-specific siRNA or via pharmacologic inhibition with S2101, which has a potent affinity for LSD1 despite a substantially weaker affinity for MAOs than tranylcypromine.…”

Section: Discussionmentioning

confidence: 99%

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

Tsutsumi

Iwao

Hayashi

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Tsutsumi T, Iwao K, Hayashi H, et al. Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK activity. Invest Ophthalmol Vis Sci. 2016;57:6461-6473. DOI:10.1167/ iovs.16-19494 PURPOSE. The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. METHODS.The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-Daspartate (NMDA)-induced excitotoxicity. Additionally, the molecules associated with tranylcypromine treatment were assessed by microarray and immunoblot analysis. RESULTS.Tranylcypromine significantly suppressed neuronal cell death following glutamate neurotoxicity and oxidative stress. Microarray and immunoblot analyses revealed that p38 mitogen-activated protein kinase (MAPK)c was a key molecule involved in the neuroprotective mechanisms induced by tranylcypromine because the significant suppression of p38 MAPKc by glutamate was reversed by tranylcypromine. Moreover, although pharmacologic inhibition of the phosphorylation of the total p38 MAPKs interfered with neuroprotective effects of tranylcypromine, the specific inhibition of p38 MAPKa and p38 MAPKb did not influence RGC survival. This suggests that the non-p38 MAPKa/b isoforms have important roles in neuronal survival by tranylcypromine. Additionally, the intravitreal administration of tranylcypromine significantly saved RGC numbers in an in vivo glaucoma model employing NMDA-induced excitotoxicity.CONCLUSIONS. These findings indicate that tranylcypromine-induced transcriptional and epigenetic regulation modulated RGC survival via the promotion of p38 MAPKc activity. Therefore, pharmacologic treatments that suppress LSD1 activity may be a novel therapeutic strategy that can be used to treat neurodegenerative diseases.

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“…14 The rats were evaluated twice a week, from 24 hours after MCAO until the end of the experimental period, by an investigator who was blinded to their treatment.…”

Section: Neurological Assessmentmentioning

confidence: 99%

A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

Ziv

Finkelstein

Geffen

et al. 2007

Stroke

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Abstract-The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy. Key Words: neuroprotection Ⅲ neurogenesis Ⅲ reactive microglia Ⅲ stroke P reviously, we have demonstrated that central nervous system (CNS) trauma spontaneously evokes a beneficial, T-cell-mediated immune response, which reduces neuronal loss. 1 In the damaged CNS tissue, CNS-specific T cells accumulate and become reactivated on recognizing and interacting with their corresponding autoantigens presented to them by local antigen-presenting cells. 2,3 This in turn leads to the production of specific neurotrophic factors (eg, brainderived neurotrophic factor) by T cells, and to the proper activation of microglia/macrophages. 4,5 Enhancing the activity of CNS-specific T cells (by a well-regulated passive or active immunization) was found to be beneficial in various animal models of CNS injuries. 6 -8 The ability to maintain autoimmunity in healthy individuals, without developing autoimmune disease, was shown to be regulated by naturally occurring CD4 ϩ CD25 ϩ regulatory T cells. However, recovery from CNS injury can benefit from a transient elimination or decreased activity of these cells. 9 Compounds that can downregulate the constitutive suppression of regulatory T cells (Treg) were therefore considered by us as potential candidates.We found that poly-YE, a high-molecular-weight (22 to 45 kDa) copolymer that was shown to exert modulatory effects on the immune system, 10,11 is capable of downregulating the activity of the regulatory T cells, and used this copolymer to facilitate the spontaneous response of effector T cells recognizing antigens associated with a ...

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Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat

Cited by 72 publications

References 24 publications

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

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