CYTOKINES IN GLIAL CELLS AND EAE BRAIN

Summary

Principal Investigator: Inderjit Singh
Abstract: DESCRIPTION (provided by applicant): Multiple Sclerosis (MS), an inflammatory demyelinating disease, lacks effective treatment because the current MS drugs targeting immunosuppression provide limited, if any, benefit to the central nervous system (CNS) disease where it continues to progress. This proposal is designed to investigate the potential of drugs targeting the Rho family GTPases (RFGs) for induction of endogenous myelin repair mechanisms in the CNS of EAE/MS. Previous studies from our laboratory and others have demonstrated that isoprenoids mediated regulation of RFGs with statins provides immunomodulatory and blood-brain-barrier protection activities in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our recent studies provide evidence for involvement of RFGs mediated mechanisms in neuroprotection as revealed by reduced demyelination (loss of both myelin proteins and lipids) and loss of OL-progenitors in EAE. Moreover, in vitro studies with mixed glial cultures document that RFGs mediated mechanisms may also potentially provide promyelinating effects as evidenced by enhanced survival and differentiation of oligodendrocyte (OL)-progenitors. Importantly, these effects of statins were attributed to be the specific depletion of intracellular isoprenoids rather than the level of cholesterol in the cells or CNS. Moreover, the observed reduced levels of peroxisome proliferator activated receptors (PPARs) in the CNS of EAE and their normalization and activation by statin indicates that statin-RFGs mediated mechanisms may regulate the cellular homeostasis of PPARs. Based on this information, we hypothesize that statin mediated regulation of RFGs may modulate PPARs activities in OL-progenitors to promote their differentiation into remyelinating OLs in the CNS of EAE animals. The following studies are proposed to test this hypothesis. Specific aim 1: To investigate the RFGs mediated regulatory mechanisms for PPARs activation for the survival and differentiation of OL-progenitors in vitro cell culture systems. Specific aim 2: To evaluate the significance of RFGs induced PPARs activities in the induction of myelin repair in the inflammatory demyelinating model of EAE. The novelty of the study is to identify new therapeutic targets for induction of myelin repair for improved treatment and management of neurodegenerative diseases such as MS. Therapeutic targeting of neural cell mechanisms in inflammatory demyelinating model is essentially an innovative approach. PUBLIC HEALTH RELEVANCE: MS an autoimmune inflammatory demyelinating disease, affects approximately 400,000 individuals in US only and over 2.0 million individuals worldwide. In spite of the current therapeutics targeting immune response, the disease often progresses leading to neurodegeneration and thus physical disability reflecting the CNS injury. Therefore, the lack of effective treatments for MS represents a significant gap for treating the CNS disease. In addition to the anti-inflammatory and immunomodulatory properties the recently observed neuroprotective activities of statins identify novel aspect of their mechanisms for myelin repair by targeting the endogenous precursor cell. The proposed studies are innovative as they will improve our understanding of mechanisms for pharmacological enhancement of the potential of CNS endogenous cells to treat CNS disease (myelin repair) in MS. These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases.
Funding Period: 1998-08-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc PPARα activation induces N(ε)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1
    Miguel A Contreras
    Department of Pediatrics, The Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC, 29425, USA
    Lipids 49:119-31. 2014
  2. pmc Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis
    Manjeet K Paintlia
    Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neurochem 116:508-21. 2011
  3. pmc Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout the brain
    Carrie L Tatar
    Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, U S A
    ASN Neuro 2:e00043. 2010
  4. pmc Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis
    Je Seong Won
    Department of Pathology and Laboratory Medicine, Medical University of South Carolina, SC 29425, USA
    Biochem Biophys Res Commun 399:487-91. 2010
  5. pmc Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis
    Inderjit Singh
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC, USA
    Brain Pathol 20:838-44. 2010
  6. pmc Activation of PPAR-γ and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cells
    Ajaib S Paintlia
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, South Carolina, USA
    Glia 58:1669-85. 2010
  7. pmc Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease
    Miguel Agustin Contreras
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Biochim Biophys Acta 1802:601-8. 2010
  8. pmc Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy
    Mushfiquddin Khan
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC, USA
    J Lipid Res 51:1685-95. 2010
  9. pmc S-nitrosoglutathione a physiologic nitric oxide carrier attenuates experimental autoimmune encephalomyelitis
    Narender Nath
    Darby Children s Research Institute, Medical University of South Carolina, 173 Ashley Avenue CRI 505, Charleston, SC 29425, USA
    J Neuroimmune Pharmacol 5:240-51. 2010
  10. pmc Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroinflammation 6:32. 2009

Detail Information

Publications59

  1. pmc PPARα activation induces N(ε)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1
    Miguel A Contreras
    Department of Pediatrics, The Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC, 29425, USA
    Lipids 49:119-31. 2014
    ..This is the first report that demonstrates posttranslational acetylation of a peroxisomal enzyme in PPARα-dependent proliferation of peroxisomes in rat liver...
  2. pmc Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis
    Manjeet K Paintlia
    Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neurochem 116:508-21. 2011
    ....
  3. pmc Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout the brain
    Carrie L Tatar
    Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, U S A
    ASN Neuro 2:e00043. 2010
    ....
  4. pmc Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis
    Je Seong Won
    Department of Pathology and Laboratory Medicine, Medical University of South Carolina, SC 29425, USA
    Biochem Biophys Res Commun 399:487-91. 2010
    ..Taken together, this is the first report on the role of AMPK in regulation of neuronal amyloidogenesis...
  5. pmc Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis
    Inderjit Singh
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC, USA
    Brain Pathol 20:838-44. 2010
    ..An improved understanding of the molecular mechanisms associated with these three phases of cALD disease should facilitate the development of effective pharmacological therapeutics for X-ALD...
  6. pmc Activation of PPAR-γ and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cells
    Ajaib S Paintlia
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, South Carolina, USA
    Glia 58:1669-85. 2010
    ..Collectively, these data provide initial evidence that statin-mediated activation of the PPAR-γ-PTEN cascade participates in OL differentiation, thus suggesting new therapeutic-interventions for MS or related CNS-demyelinating diseases...
  7. pmc Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease
    Miguel Agustin Contreras
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Biochim Biophys Acta 1802:601-8. 2010
    ....
  8. pmc Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy
    Mushfiquddin Khan
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC, USA
    J Lipid Res 51:1685-95. 2010
    ..In sum, through 5-LOX activation, VLCFA accumulation causes a lipotoxic response consistent with cALD brain pathology...
  9. pmc S-nitrosoglutathione a physiologic nitric oxide carrier attenuates experimental autoimmune encephalomyelitis
    Narender Nath
    Darby Children s Research Institute, Medical University of South Carolina, 173 Ashley Avenue CRI 505, Charleston, SC 29425, USA
    J Neuroimmune Pharmacol 5:240-51. 2010
    ..Collectively, GSNO attenuated EAE via modulation of Th17 cells and its effects are independent of Th1 or Th2 cells functions, indicating that it may have therapeutic potential for Th17-mediated autoimmune diseases...
  10. pmc Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroinflammation 6:32. 2009
    ..Therefore, we tested whether GSNO shows efficacy in a rat model of experimental TBI...
  11. pmc Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat
    Md Nasrul Hoda
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroinflammation 6:21. 2009
    ..In this study, we investigated whether impeding membrane lipid breakdown by inhibiting secretory phospholipase A2 (sPLA2) activity reduces BBB leakage, leading to neuroprotection and functional recovery...
  12. pmc Peroxisomal dysfunction in inflammatory childhood white matter disorders: an unexpected contributor to neuropathology
    Inderjit Singh
    Department of Pediatrics, Division of Developmental Neurogenetics, Charles Darby Children s Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Child Neurol 24:1147-57. 2009
    ..Dysfunctions of peroxisomes may therefore contribute in part to white matter disease and to the mental and physical disabilities that develop in patients affected by these diseases...
  13. pmc S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroinflammation 8:78. 2011
    ..Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury...
  14. pmc HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes
    Jaspreet Singh
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    J Lipid Res 52:2056-69. 2011
    ..These observations indicate that SAHA corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be an ideal drug candidate to be tested for X-ALD therapy in humans...
  15. pmc Spinal cord injury induced arrest in estrous cycle of rats is ameliorated by S-nitrosoglutathione: novel therapeutic agent to treat amenorrhea
    Anandakumar Shunmugavel
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Sex Med 9:148-58. 2012
    ..Amenorrhea following spinal cord injury (SCI) has been well documented. There has been little research on the underlying molecular mechanisms and therapeutics...
  16. pmc STAT3 regulation by S-nitrosylation: implication for inflammatory disease
    Jinsu Kim
    1 Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
    Antioxid Redox Signal 20:2514-27. 2014
    ..In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis...
  17. pmc Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells
    Jaspreet Singh
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
    PLoS ONE 8:e70712. 2013
    ..These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD. ..
  18. pmc Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-α-dependent mechanism
    Ajaib S Paintlia
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Glia 61:1500-17. 2013
    ....
  19. pmc AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model
    Ajaib S Paintlia
    Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Am J Pathol 183:526-41. 2013
    ..We conclude that AMPK activators, including metformin, have the potential to limit neurologic deficits in multiple sclerosis and related neurodegenerative disorders. ..
  20. pmc Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease
    Je Seong Won
    Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
    Brain Res 1508:44-52. 2013
    ..These observations suggest for potential therapeutic efficacy of sPLA2 inhibitor in Krabbe disease...
  21. pmc Caffeic acid phenethyl ester induces adrenoleukodystrophy (Abcd2) gene in human X-ALD fibroblasts and inhibits the proinflammatory response in Abcd1/2 silenced mouse primary astrocytes
    Jaspreet Singh
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Biochim Biophys Acta 1831:747-58. 2013
    ..The observations indicate that CAPE corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be a potential drug candidate to be tested for X-ALD therapy in humans...
  22. pmc S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions
    Manjeet K Paintlia
    Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Biol Chem 288:3831-43. 2013
    ..Our data suggest that the endogenously produced NO or its exogenous source has potential to modulate the outcomes of reactive astrogliosis to protect CNS under pathological conditions...
  23. pmc Simvastatin ameliorates cauda equina compression injury in a rat model of lumbar spinal stenosis
    Anandakumar Shunmugavel
    Department of Pediatrics, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
    J Neuroimmune Pharmacol 8:274-86. 2013
    ..These outcomes are mediated through the neuroprotective and anti-inflammatory properties of simvastatin. The data indicate that simvastatin may be a promising drug candidate for LSS treatment in humans...
  24. pmc The inhibitory effect of S-nitrosoglutathione on blood-brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurochem 123:86-97. 2012
    ..Taken together, the results support the ability of GSNO to improve endothelial function by reducing nitroxidative stress in stroke...
  25. pmc Interference with RhoA-ROCK signaling mechanism in autoreactive CD4+ T cells enhances the bioavailability of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis
    Ajaib S Paintlia
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, USA
    Am J Pathol 181:993-1006. 2012
    ..Together, these data provide evidence that interfering with RhoA-ROCK signaling in autoreactive Th1/Th17 cells can improve vitamin D(3) efficacy in clinical trials of MS and related neurodegenerative disorders...
  26. pmc Stimulation of functional recovery via the mechanisms of neurorepair by S-nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion
    Harutoshi Sakakima
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Restor Neurol Neurosci 30:383-96. 2012
    ..Improvement of functions has been achieved through rehabilitation or therapeutic agents. Therefore, we combined exercise with a neurovascular protective agent, S-nitrosoglutathione (GSNO), to accelerate functional recovery...
  27. pmc Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis
    Narender Nath
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Immunol 182:8005-14. 2009
    ..Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases...
  28. pmc Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity
    Narender Nath
    Department of Pediatrics, Medical University of South Carolina, SC 29425, USA
    Biochem Biophys Res Commun 386:16-20. 2009
    ..Our study identifies AMPK as a down regulated target during disease in all immune cells and possibly restoring AMPK may serve as a novel therapeutic target in autoimmune diseases like multiple sclerosis (MS)...
  29. pmc Oxidative imbalance in nonstimulated X-adrenoleukodystrophy-derived lymphoblasts
    Takuhiro Uto
    Department of Pediatrics, Charles P Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Dev Neurosci 30:410-8. 2008
    ....
  30. ncbi Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury
    Ravinder Pannu
    Department of Pediatrics, Centre for Developmental Neurological Disorders Charles P Darby Children s Research Institute, Charleston, South Carolina 29425, USA
    J Neurochem 101:182-200. 2007
    ..In summary, this novel report presenting the efficacy of post-injury AT treatment might be of critical therapeutic value as effective treatments are currently unavailable for SCI...
  31. ncbi GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions
    Ratna Prasad
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Glia 55:65-77. 2007
    ..These observations suggest that GSNO exerts its protective effects in EAE by inhibition of cellular infiltration into the CNS by S-nitrosylation of p65, thereby modulating NF-kappaB-CAMs pathway in endothelial cells...
  32. pmc Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis
    Ajaib S Paintlia
    Medical University of South Carolina, Department of Pediatrics, 173 Ashley Ave, Charleston, SC 29425, USA
    Am J Pathol 169:1012-25. 2006
    ....
  33. pmc T-bet is essential for the progression of experimental autoimmune encephalomyelitis
    Narender Nath
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Immunology 118:384-91. 2006
    ..These data indicate that T-bet genes play a critical role in maintaining the encephalitogenic nature of CD4+ T cells in autoimmune responses during EAE disease progression...
  34. ncbi Molecular organization of peroxisomal enzymes: protein-protein interactions in the membrane and in the matrix
    Randhir S Makkar
    The Charles Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Arch Biochem Biophys 451:128-40. 2006
    ..These observations indicate that L-BFE might help in oligomerization and possibly in the localization of catalase at the site of H2O2 production in the peroxisomal beta-oxidation pathway...
  35. ncbi 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates experimental autoimmune encephalomyelitis via modulation of endothelial-monocyte interaction
    Ratna Prasad
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 84:614-25. 2006
    ..The data suggest that AICAR attenuates EAE progression by limiting infiltration of leukocytes across the BBB, thereby controlling the consequent inflammatory reaction in the CNS...
  36. ncbi Sphingolipid signaling and redox regulation
    Je Seong Won
    Division of Developmental Neurological Disorder in Charles P Darby Children s Research Institute, Department of Pediatrics, Medical University of South Carolina, Room 505, 171 Ashley Avenue, Charleston, SC 29425, USA
    Free Radic Biol Med 40:1875-88. 2006
    ..Therefore, this paper reviews the relationship between cellular redox and sphingolipid metabolism and its biological significance...
  37. ncbi Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death
    S Giri
    Department of Pediatrics, Charles P Darby Children s Research Institute, Medical University of South Carolina, Charleston, 29425, USA
    J Lipid Res 47:1478-92. 2006
    ....
  38. ncbi Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats
    Manu Jatana
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Pediatr Res 59:684-9. 2006
    ..These results indicate that hypothermia plus NAC combination therapy improves infarct volume, myelin expression and functional outcomes after focal HI injury...
  39. ncbi IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-kappaB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for C
    Ajaib S Paintlia
    Department of Pediatrics, Medical University of South Carolina and Ralph H Johnson Veterans Administration Medical Center, Charleston, 29425, USA
    J Immunol 176:4385-98. 2006
    ....
  40. ncbi Dysfunction of peroxisomes in twitcher mice brain: a possible mechanism of psychosine-induced disease
    Ehtishamul Haq
    Department of Pediatrics and The Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Biochem Biophys Res Commun 343:229-38. 2006
    ..Therefore, this study provides the first evidence of peroxisomal abnormality in a lysosomal disorder, suggesting that such dysfunction of peroxisomes may play a role in the pathogenesis of Krabbe disease...
  41. ncbi Cerebrovascular protection by various nitric oxide donors in rats after experimental stroke
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
    Nitric Oxide 15:114-24. 2006
    ..PAPA, MAHMA, and SIN-1 neither protected the brain nor reduced oxidative stress. We conclude that neuroprotective action of NO donors in experimental stroke depends on their ability to reduce oxidative stress both in brain and blood...
  42. ncbi Caffeic acid phenethyl ester reduces neurovascular inflammation and protects rat brain following transient focal cerebral ischemia
    Mushfiquddin Khan
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurochem 102:365-77. 2007
    ..Conclusively, CAPE is a promising drug candidate for ischemic stroke treatment due to its inhibition of oxidative stress and inflammation, and its clinically relevant wide therapeutic window...
  43. ncbi S-nitrosoglutathione prevents interphotoreceptor retinoid-binding protein (IRBP(161-180))-induced experimental autoimmune uveitis
    Ehtishamul Haq
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    J Ocul Pharmacol Ther 23:221-31. 2007
    ..The efficacy of GSNO treatment on interphotoreceptor retinoid-binding protein (IRBP)-induced EAU was investigated, using functional, histologic, and immunologic readouts...
  44. ncbi Lactosylceramide: a lipid second messenger in neuroinflammatory disease
    Je Seong Won
    Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 103:180-91. 2007
    ....
  45. pmc Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis
    Ajaib S Paintlia
    Darby Children s Research Institute, Medical University of South Carolina, USA
    Exp Neurol 214:168-80. 2008
    ....
  46. pmc Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy
    Jaspreet Singh
    Department of Pediatrics, Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC, USA
    J Lipid Res 50:135-47. 2009
    ..Our data represent the first study to suggest a direct link between the accumulation of VLCFA and the induction of inflammatory mediators...
  47. pmc Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis
    Ajaib S Paintlia
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Glia 57:182-93. 2009
    ..Together, these data suggest that combination therapy with LOV and RLP has the potential to provide neuroprotection and promote neurorepair in MS, and may have uses in other related CNS demyelinating diseases...
  48. pmc Psychosine-induced alterations in peroxisomes of twitcher mouse liver
    Miguel Agustin Contreras
    Department of Pediatrics and The Charles Darby Children s Research Institute, Medical University of South Carolina, Charleston, SC, USA
    Arch Biochem Biophys 477:211-8. 2008
    ..These observations indicate that twitcher mouse pathobiology extends to the liver, where psychosine-induced TNF-alpha and IL-6 compromise peroxisomal structure and functions...
  49. pmc Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death
    Jin Koo Lee
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Neurosci Lett 440:260-4. 2008
    ..These observations suggest a potential for use of statin treatment in modulation of seizures and other neurological diseases associated with excitotoxicity...
  50. pmc Attenuation of lipopolysaccharide-induced inflammatory response and phospholipids metabolism at the feto-maternal interface by N-acetyl cysteine
    Manjeet K Paintlia
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Pediatr Res 64:334-9. 2008
    ....
  51. pmc Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin
    Mushfiquddin Khan
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 106:1766-79. 2008
    ..In summary, this study reports that altered metabolism of PlsEtn and ROS in cALD may be corrected by lovastatin treatment...
  52. pmc Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl cysteine
    Manjeet K Paintlia
    Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
    Exp Neurol 210:560-76. 2008
    ....
  53. pmc Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts
    Je Seong Won
    Department of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurochem 105:1536-49. 2008
    ..Collectively, these data report that lovastatin mediates inhibition of LDLR distribution and beta-cleavage of APP in a geranylgeranyl-pyrophosphate and endocytosis-dependent manner...
  54. pmc The role of AMPK in psychosine mediated effects on oligodendrocytes and astrocytes: implication for Krabbe disease
    Shailendra Giri
    Charles P Darby Children s Research Institute, Department of Pediatrics Medical University of South Carolina, Charleston, SC 29425, USA
    J Neurochem 105:1820-33. 2008
    ..J. Lipid Res. 47 (2006), 1478]...
  55. pmc Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis
    Ajaib Singh Paintlia
    Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425, USA
    Mol Pharmacol 73:1381-93. 2008
    ..Together, these data provide unprecedented evidence that-like immune cells-geranylgeranyl-pyrophosphate depletion and thus inhibition of Rho family functions in glial cells by lovastatin promotes myelin repair in ameliorating EAE...
  56. pmc Modulation of peroxisome proliferator-activated receptor-alpha activity by N-acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures
    Manjeet K Paintlia
    Department of Pediatrics, Medical University of South Carolina and Ralph H Johnson VA Medical Center, Charleston, South Carolina 29425, USA
    J Neurochem 105:956-70. 2008
    ....
  57. ncbi Rho/ROCK pathway as a target of tumor therapy
    R Rattan
    Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 83:243-55. 2006
    ....

Research Grants30

  1. Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis
    Inderjit Singh; Fiscal Year: 2013
    ....
  2. The regulation of myeloid cell development and mobilization during autoimmune dem
    BENJAMIN MATTHEW SEGAL; Fiscal Year: 2013
    ..It is anticipated that our results will lead to the discovery of novel biomarkers and therapeutic targets related to myeloid cell dysregulation in MS. ..