Behavioral and histological assessment of a novel treatment of neuroHIV in humanized mice

Neurocognitive deficits are prevalent among people living with HIV, likely due to chronic inflammation and oxidative stress in the brain. To date, no pharmaceutical treatments beyond antiretroviral therapy (ARV) has been shown to reduce risk for, or severity of, HIV-associated neurocognitive disorder. Here we investigate a novel compound, CDDO-Me, with documented neuroprotective effects via activation of the nrf2 and inhibition of the NFkB pathways. Methods: We conducted three studies to assess the efficacy of CDDO-Me alone or in combination with antiretroviral therapy in humanized mice infected with HIV; behavioral, histopathological, and immunohistochemical. Results: CDDO-Me in combination with ARV rescued social interaction deficits; however, only ARV was associated with preserved functioning in other behaviors, and CDDO-Me may have attenuated those benefits. A modest neuroprotective effect was found for CDDO-Me when administered with ARV, via preservation of PSD-95 expression; however, ARV alone had a more consistent protective effect. No significant changes in antioxidant enzyme expression levels were observed in CDDO-Me-treated animals. Only ARV use seemed to affect some antioxidant levels, indicating that it is ARV rather than CDDO-Me that is the major factor providing neuroprotection in this animal model. Finally, immunohistochemical analysis found that several cellular markers in various brain regions varied due to ARV rather than CDDO-Me. Conclusion: Limited benefit of CDDO-Me on behavior and neuroprotection were observed. Instead, ARV was shown to be the more beneficial treatment. These experiments support the future use of this chimeric mouse for behavioral experiments in neuroHIV research

[1]  D. Kolson Developments in Neuroprotection for HIV-Associated Neurocognitive Disorders (HAND) , 2022, Current HIV/AIDS Reports.

[2]  M. Churchill,et al.  The role of oxidative stress in HIV-associated neurocognitive disorders , 2021, Brain, behavior, & immunity - health.

[3]  Yu Cheng,et al.  Longitudinal multivariate normative comparisons , 2020, Statistics in medicine.

[4]  M. Betts,et al.  Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression , 2020, Journal of Virology.

[5]  R. Gross,et al.  Heme oxygenase-1 promoter (GT)n polymorphism associates with HIV neurocognitive impairment , 2020, Neurology: Neuroimmunology & Neuroinflammation.

[6]  Y. J. Lee Knockout Mouse Models for Peroxiredoxins , 2020, Antioxidants.

[7]  B. Puri,et al.  The compensatory antioxidant response system with a focus on neuroprogressive disorders , 2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  P. Ghezzi,et al.  Differential induction of nuclear factor‐like 2 signature genes with toll‐like receptor stimulation , 2019, Free radical biology & medicine.

[9]  X. Lei,et al.  Role of glutathione peroxidase 1 in glucose and lipid metabolism‐related diseases , 2018, Free radical biology & medicine.

[10]  B. Stockwell,et al.  Regulation of lipid peroxidation and ferroptosis in diverse species , 2018, Genes & development.

[11]  D. Kolson,et al.  Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection , 2018, Journal of Neuroinflammation.

[12]  V. Valcour,et al.  Aging and Neurocognitive Functioning in HIV-Infected Women: a Review of the Literature Involving the Women’s Interagency HIV Study , 2016, Current HIV/AIDS Reports.

[13]  Gregory G. Brown,et al.  Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models , 2016, Journal of Neuroimmune Pharmacology.

[14]  N. Inestrosa,et al.  Posttranslational Modifications Regulate the Postsynaptic Localization of PSD-95 , 2016, Molecular Neurobiology.

[15]  Andrew Levine,et al.  Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study , 2016, Neurology.

[16]  D. Kolson,et al.  Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy , 2015, Journal of Virology.

[17]  Gregory G. Brown,et al.  Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice , 2015, European Neuropsychopharmacology.

[18]  Shufeng Zhou,et al.  Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties , 2014, Drug design, development and therapy.

[19]  N. Starkova,et al.  Scavenging of H2O2 by mouse brain mitochondria , 2014, Journal of Bioenergetics and Biomembranes.

[20]  F. Denaro,et al.  Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV-1 transgenic rat , 2014, Biogerontology.

[21]  Lingyun Wu,et al.  Tert-Butylhydroquinone Alleviates Early Brain Injury and Cognitive Dysfunction after Experimental Subarachnoid Hemorrhage: Role of Keap1/Nrf2/ARE Pathway , 2014, PloS one.

[22]  D. Kolson,et al.  Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIV-Associated Neurocognitive Disorders , 2014, Current HIV research.

[23]  Jijun Chen Heme oxygenase in neuroprotection: from mechanisms to therapeutic implications , 2014, Reviews in the neurosciences.

[24]  J. Berman,et al.  Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders. , 2014, Current HIV research.

[25]  Matthew E. Welsch,et al.  Regulation of Ferroptotic Cancer Cell Death by GPX4 , 2014, Cell.

[26]  S. Horvath,et al.  Transcriptome analysis of HIV-infected peripheral blood monocytes: Gene transcripts and networks associated with neurocognitive functioning , 2013, Journal of Neuroimmunology.

[27]  M. Andersen,et al.  Keap1 silencing boosts lipopolysaccharide-induced transcription of interleukin 6 via activation of nuclear factor κB in macrophages. , 2013, Toxicology and applied pharmacology.

[28]  S. Mammana,et al.  Heme oxygenase-1 expression in peripheral blood mononuclear cells correlates with disease activity in multiple sclerosis , 2013, Journal of Neuroimmunology.

[29]  S. Kang,et al.  Peroxiredoxin I is a ROS/p38 MAPK-dependent inducible antioxidant that regulates NF-κB-mediated iNOS induction and microglial activation , 2013, Journal of Neuroimmunology.

[30]  Q. Ma Role of nrf2 in oxidative stress and toxicity. , 2013, Annual review of pharmacology and toxicology.

[31]  A. Kakita,et al.  Keap1 Is Localized in Neuronal and Glial Cytoplasmic Inclusions in Various Neurodegenerative Diseases , 2013, Journal of neuropathology and experimental neurology.

[32]  G. Joshi,et al.  The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. , 2012, Recent patents on CNS drug discovery.

[33]  Adriana Yndart,et al.  HIV-1 gp120 induces antioxidant response element-mediated expression in primary astrocytes: Role in HIV associated neurocognitive disorder , 2012, Neurochemistry International.

[34]  M. Konopleva,et al.  A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas , 2012, Clinical Cancer Research.

[35]  B. Knoops,et al.  Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders , 2012, The Journal of comparative neurology.

[36]  Y. Kalkonde,et al.  The CC chemokine receptor 5 regulates olfactory and social recognition in mice , 2011, Neuroscience.

[37]  D. Kolson,et al.  Dimethyl Fumarate, an Immune Modulator and Inducer of the Antioxidant Response, Suppresses HIV Replication and Macrophage-Mediated Neurotoxicity: A Novel Candidate for HIV Neuroprotection , 2011, The Journal of Immunology.

[38]  Jialin C. Zheng,et al.  Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders , 2011, The Journal of Neuroscience.

[39]  G. Sykiotis,et al.  Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson’s disease , 2011, Disease Models & Mechanisms.

[40]  G. Scapagnini,et al.  Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders , 2011, Molecular Neurobiology.

[41]  D. Jeste,et al.  Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice , 2011, AGE.

[42]  Michael J. Taylor,et al.  HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors , 2010, Journal of NeuroVirology.

[43]  T. Kensler,et al.  When NRF2 talks, who's listening? , 2010, Antioxidants & redox signaling.

[44]  P. Saha,et al.  The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic-acid Methyl Ester Has Potent Anti-diabetic Effects in Diet-induced Diabetic Mice and Leprdb/db Mice* , 2010, The Journal of Biological Chemistry.

[45]  G. Stoica,et al.  Neuroprotective effects of the drug GVT (monosodium luminol) are mediated by the stabilization of Nrf2 in astrocytes , 2010, Neurochemistry International.

[46]  O. Combarros,et al.  Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease , 2010, Acta neurologica Scandinavica.

[47]  E. V. Bockstaele,et al.  HIV-1 gp120-induced neuroinflammation: Relationship to neuron loss and protection by rSV40-delivered antioxidant enzymes , 2010, Experimental Neurology.

[48]  C. Neumann,et al.  Peroxiredoxin 1 and its role in cell signaling , 2009, Cell cycle.

[49]  Stephanie D. Kraft-Terry,et al.  A Coat of Many Colors: Neuroimmune Crosstalk in Human Immunodeficiency Virus Infection , 2009, Neuron.

[50]  B. Gelman,et al.  Synaptic Proteins Linked to HIV-1 Infection and Immunoproteasome Induction: Proteomic Analysis of Human Synaptosomes , 2009, Journal of Neuroimmune Pharmacology.

[51]  V. Wojna,et al.  Antioxidant enzyme dysfunction in monocytes and CSF of Hispanic women with HIV-associated cognitive impairment , 2009, Journal of Neuroimmunology.

[52]  H. D. de Vries,et al.  Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? , 2008, Free radical biology & medicine.

[53]  Y. Surh,et al.  Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals , 2008, Planta medica.

[54]  R. Bendayan,et al.  HIV‐1 viral envelope glycoprotein gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein‐1 (Mrp1) in glial cells , 2008, Journal of neurochemistry.

[55]  N. Abraham,et al.  Pharmacological and Clinical Aspects of Heme Oxygenase , 2008, Pharmacological Reviews.

[56]  B. Ances,et al.  Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders , 2008, International review of psychiatry.

[57]  K. A. Lindl,et al.  Expression of the endoplasmic reticulum stress response marker, BiP, in the central nervous system of HIV‐positive individuals , 2007, Neuropathology and applied neurobiology.

[58]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[59]  W. Greene,et al.  The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo1 , 2007, The Journal of Immunology.

[60]  C. Leffler,et al.  HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. , 2006, American Journal of Physiology - Cell Physiology.

[61]  E. Masliah,et al.  Lithium improves HIV-associated neurocognitive impairment , 2006, AIDS.

[62]  M. Kaul,et al.  Mechanisms of neuronal injury and death in HIV-1 associated dementia. , 2006, Current HIV research.

[63]  A. Nath,et al.  HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: Changes in dopamine transporter binding and immunoreactivity , 2006, Neuroscience Letters.

[64]  Y. Surh,et al.  Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. , 2005, The Journal of nutrition.

[65]  Y. Surh,et al.  Nrf2 as a novel molecular target for chemoprevention. , 2005, Cancer letters.

[66]  F. L. van Muiswinkel,et al.  The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. , 2005, Current drug targets. CNS and neurological disorders.

[67]  G. Ronnett,et al.  Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP. , 2005, Current neurovascular research.

[68]  R. Cutler,et al.  Novel markers of oxidative stress in actively progressive HIV dementia , 2004, Journal of Neuroimmunology.

[69]  A. Moses,et al.  Transendothelial migration of CD16+ monocytes in response to fractalkine under constitutive and inflammatory conditions. , 2004, Immunobiology.

[70]  A. Nath,et al.  Temporal relationships between HIV-1 Tat-induced neuronal degeneration, OX-42 immunoreactivity, reactive astrocytosis, and protein oxidation in the rat striatum , 2003, Brain Research.

[71]  K. Itoh,et al.  Keap1-dependent Proteasomal Degradation of Transcription Factor Nrf2 Contributes to the Negative Regulation of Antioxidant Response Element-driven Gene Expression* , 2003, Journal of Biological Chemistry.

[72]  E. Chang,et al.  Heme Oxygenase-2 Protects against Lipid Peroxidation-Mediated Cell Loss and Impaired Motor Recovery after Traumatic Brain Injury , 2003, The Journal of Neuroscience.

[73]  R. Beschorner Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. , 2003, Brain pathology.

[74]  E. Masliah,et al.  Changing Patterns in the Neuropathogenesis of HIV During the HAART Era , 2003, Brain pathology.

[75]  Yong Woo Lee,et al.  HIV‐Tat protein induces oxidative and inflammatory pathways in brain endothelium , 2002, Journal of neurochemistry.

[76]  A. Nath Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. , 2002, The Journal of infectious diseases.

[77]  K. Kedzierska,et al.  The role of monocytes and macrophages in the pathogenesis of HIV-1 infection. , 2002, Current medicinal chemistry.

[78]  H. Gendelman,et al.  Glutamate is a mediator of neurotoxicity in secretions of activated HIV-1-infected macrophages , 2001, Journal of Neuroimmunology.

[79]  A. Bansal,et al.  Oxidative damage induced by the injection of HIV-1 Tat protein in the rat striatum , 2001, Neuroscience Letters.

[80]  H. Gendelman,et al.  Mononuclear phagocytes mediate blood‐brain barrier compromise and neuronal injury during HIV‐1‐associated dementia , 2000, Journal of leukocyte biology.

[81]  Mark A. Smith,et al.  Overexpression of Heme Oxygenase in Neuronal Cells, the Possible Interaction with Tau* , 2000, The Journal of Biological Chemistry.

[82]  Chrétien,et al.  Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage , 1999, Neuropathology and applied neurobiology.

[83]  M. Beal,et al.  Oxidative Stress in Huntington's Disease , 1999, Brain pathology.

[84]  C P Das,et al.  Neurological complications of HIV infection. , 1998, Neurology India.

[85]  E. Stopa,et al.  Neural Heme Oxygenase-1 Expression in Idiopathic Parkinson's Disease , 1998, Experimental Neurology.

[86]  M. McGrath,et al.  Unique monocyte subset in patients with AIDS dementia , 1997, The Lancet.

[87]  M. Smith,et al.  Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease , 1996, Brain Research.

[88]  J. Glass,et al.  Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia , 1995, Annals of neurology.

[89]  M. Smith,et al.  Evidence for oxidative stress in Pick disease and corticobasal degeneration , 1995, Brain Research.

[90]  E. Stopa,et al.  Expression of heme oxygenase‐1 in the senescent and alzheimer‐diseased brain , 1995, Annals of neurology.

[91]  A. Kappas,et al.  Reduction of the C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism. , 1987, Archives of biochemistry and biophysics.

[92]  Michael S. B. Edwards,et al.  A Trojan Horse mechanism for the spread of visna virus in monocytes. , 1985, Virology.

[93]  Zheng Wanga,et al.  Cross-sectional analys is of cognitive function using multivariate normative comparisons in men with HIV disease , 2019 .

[94]  D. Kolson,et al.  Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. , 2013, Critical reviews in immunology.

[95]  C. Ronco,et al.  Prospective safety study of bardoxolone methyl in patients with type 2 diabetes mellitus, end-stage renal disease and peritoneal dialysis. , 2012, Contributions to nephrology.

[96]  S. Spijker,et al.  Dissection of Rodent Brain Regions , 2011 .

[97]  Howard E Gendelman,et al.  HIV-1 transforms the monocyte plasma membrane proteome. , 2009, Cellular immunology.

[98]  Alcino J. Silva,et al.  Long‐term memory underlying hippocampus‐dependent social recognition in mice , 2000, Hippocampus.

[99]  J. D. Engel,et al.  Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. , 1999, Genes & development.