Rajiv R Ratan

Burke Medical Research Institute New York, New York City, New York, United States

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Publications (9)44.79 Total impact

  • Amit Kumar, Manisha Vaish, Rajiv R. Ratan
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    ABSTRACT: Huntington's disease (HD) is a signature polyglutamine disorder. An enduring theory of HD pathogenesis has involved dysregulation of transcription. Indeed, transcriptional regulatory proteins can be modulated to overcome cardinal features of HD-modeled mice, and efforts to move these into human studies are ongoing. Here, we discuss a unifying hypothesis emerging from these studies, which is that HD represents the pathological disruption of evolutionarily conserved adaptive gene programs to counteract oxidative stress, mitochondrial dysfunction and accumulation of misfolded proteins. Transcriptional dyshomeostasis of adaptive genes is further exacerbated by repression of genes involved in normal synaptic activity or growth factor signaling.
    Drug discovery today 07/2014; 19(7). DOI:10.1016/j.drudis.2014.03.016 · 6.63 Impact Factor
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    ABSTRACT: Aims: Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions including stroke, Huntington's disease and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia inducible factor (HIF)-dependent transcription. Results: Our screen identified more than forty compounds with the ability to induce hypoxia response element driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21cip1/waf1, in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro and this on-target effect also involves binding to free tubulin. Innovation and Conclusions: These studies demonstrate that tubulin-binding drugs can activate the component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin binding drugs, including antihelminthic benzimidazoles also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the CNS, antihelminthic benzimidazoles may be viable candidates for treating diseases associated with oxidative neuronal death, including stroke.
    Antioxidants & Redox Signaling 04/2014; DOI:10.1089/ars.2013.5595 · 8.20 Impact Factor
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    ABSTRACT: This review describes the catalytic mechanism, substrate specificity, and structural peculiarities of alpha-ketoglutarate dependent nonheme iron dioxygenases catalyzing prolyl hydroxylation of hypoxia-inducible factor (HIF). Distinct localization and regulation of three isoforms of HIF prolyl hydroxylases suggest their different roles in cells. The recent identification of novel substrates other than HIF, namely β2-adrenergic receptor and the large subunit of RNA polymerase II, places these enzymes in the focus of drug development efforts aimed at development of isoform-specific inhibitors. The challenges and prospects of designing isoform-specific inhibitors are discussed.
    Biochemistry (Moscow) 10/2012; 77(10):1108-19. DOI:10.1134/S0006297912100033 · 1.35 Impact Factor
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    ABSTRACT: Friedreich ataxia (FRDA) is the most common inherited ataxia caused primarily by an intronic GAA.TTC triplet repeat expansion in the frataxin (FXN) gene. FXN RNA and protein levels are reduced in patients leading to progressive gait and limb ataxia, sensory loss, reduced tendon reflexes, dysarthria, absent lower limb reflexes, and loss of position and vibration sense. Neurological manifestations ensue from primary loss of dorsal root ganglia neurons and their associated axons ascending centrally in the spinal cord and peripherally in large myelinated nerves. Small noncoding RNAs such as microRNAs have been shown to be dysregulated in neurodegenerative diseases such as Alzheimer's and Huntington's disease. Here we report that hsa-miR-886-3p (miR-886-3p) was increased in patient cells as well as peripheral patient blood samples. Selective reduction in miR-886-3p by an anti-miR led to elevation of FXN message and protein levels without associated changes in histone marks at the FXN locus. Nevertheless, derepression of frataxin by a histone deacetylase inhibitor leads to a decrease in miR-886-3p. These results outline involvement of a small RNA, miR-886-3p in FRDA and a novel therapeutic approach to this disease using an anti-miR-886-3p.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2012; 32(27):9369-73. DOI:10.1523/JNEUROSCI.0059-12.2012 · 6.75 Impact Factor
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    ABSTRACT: Abstract Although the etiology of Parkinson's disease (PD) remains unclear, ample empirical evidence suggests that oxidative stress is a major player in the development of PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that upregulates a battery of antioxidant response element (ARE)-driven antioxidative and cytoprotective genes that defend against oxidative stress. Aims: We evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with small molecule synthetic triterpenoids (TP) attenuate MPTP-induced PD in mice. Results: We show that synthetic TP are thus far the most potent and direct activators of the Nrf2 pathway using a novel Neh2-luciferase reporter. They upregulate several cytoprotective genes, including those involved in glutathione biosynthesis in vitro. Oral administration of TP that were structurally modified to penetrate the brain-induced messenger RNA and protein levels for a battery of Nrf2-dependent cytoprotective genes reduced MPTP-induced oxidative stress and inflammation, and ameliorated dopaminergic neurotoxicity in mice. The neuroprotective effect of these TP against MPTP neurotoxicity was dependent on Nrf2, since treatment with TP in Nrf2 knockout mice failed to block against MPTP neurotoxicity and induce Nrf2-dependent cytoprotective genes. Innovation: Extremely potent synthetic TP that are direct activators of the Nrf2 pathway block dopaminergic neurodegeneration in the MPTP mouse model of PD. Conclusion: Our results indicate that activation of Nrf2/antioxidant response element (ARE) signaling by synthetic TP is directly associated with their neuroprotective effects against MPTP neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD. Antioxid. Redox Signal. 00, 000-000.
    Antioxidants & Redox Signaling 07/2012; DOI:10.1089/ars.2011.4491 · 8.20 Impact Factor
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    ABSTRACT: Background. Higher fasting blood glucose (FBG) concentrations in the hyperglycemic range are associated with more severe strokes. Whether this association also extends into patients with FBG in the normoglycemic range is unclear. We studied the association of stroke severity and FBG in normoglycemic patients with ischemic stroke in a median of 7 days after stroke when the initial glycemic stress response has resolved. Method and Material. Included were 361 nondiabetic ischemic stroke patients with admission fasting blood glucose within 70-130 mg/dL admitted into an acute stroke rehabilitation unit in a median of 7 days after stroke. Data including neuroimaging, vital signs, cardiovascular risk factors, and admission functional independence measure (AFIM) were recorded prospectively. Results. FBG correlated with stroke severity in the normoglycemic 70-130 mg/dL range (FBG-AFIM correlation coefficient -0.17; P = 0.003). Odds ratio for more severe injury (below average AFIM score) was 2.02 for patients with FBG 110-130 mg/dL compared to FBG 70-90 mg/dL (95% confidence interval 1.10-3.73, P = 0.022). Each mg/dL increase in FBG was associated with an average decrease of 0.25 FIM points. In a multiple linear regression model, FBG was associated with more severe stroke (P = 0.002). Conclusion. One week after ischemic stroke, FBG within the normoglycemic range was associated with stroke severity.
    03/2012; 2012:659610. DOI:10.1155/2012/659610
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    ABSTRACT: A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2012; 32(7):1347-61. DOI:10.1038/jcbfm.2012.28 · 5.46 Impact Factor
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    Drug Discovery and Development - Present and Future, 12/2011; , ISBN: 978-953-307-615-7
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    ABSTRACT: Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative conditions, but clinically approved therapeutic interventions are only just emerging. Here we demonstrate the potential clinical utility of low molecular weight inhibitors of the hypoxia inducible factor prolyl-4-hydroxylases (HIF PHDs) in preventing mitochondrial toxin-induced cell death in mouse striatal neurons that express a "knock-in" mutant Huntingtin allele. Protection from 3-nitropropionic acid (3-NP, a complex II inhibitor)-induced toxicity by HIF PHD inhibition occurs without rescue of succinate dehydrogenase activity. Although HIF-1alpha mRNA is dramatically induced by mutant huntingtin, HIF-1alpha depletion by short interfering RNAs (siRNA) does not affect steady-state viability or protection from 3-NP-induced death by HIF PHD inhibitors in these cells. Moreover, 3-NP-induced complex II inhibition in control or mutant striatal neurons does not lead to activation of HIF-dependent transcription. HIF PHD inhibition also protects cortical neurons from 3-NP-induced cytotoxicity. Protection of cortical neurons by HIF PHD inhibition correlates with enhanced VEGF but not PGC-1alpha gene expression. Together, these findings suggest that HIF PHD inhibitors are promising candidates for preventing cell death in conditions such as Huntington's disease and Alzheimer's disease that are associated with metabolic stress in the central nervous system.
    Antioxidants & Redox Signaling 09/2009; 12(4):435-43. DOI:10.1089/ars.2009.2800 · 8.20 Impact Factor

Publication Stats

79 Citations
44.79 Total Impact Points

Institutions

  • 2012–2014
    • Burke Medical Research Institute New York
      New York City, New York, United States
    • Weill Cornell Medical College
      • Department of Neurology and Neuroscience
      New York, New York, United States
    • White Plains Hospital
      White Plains, New York, United States