Yuri Persidsky, MD, PhD
Chair, Department of Pathology and Laboratory Medicine
Professor, Pathology and Laboratory Medicine
- Contact Information
- About Me
- Surgical pathology
- Administration of clinical laboratories
- Molecular mechanisms regulating functions of blood brain barrier under physiologic and pathologic conditions (neuroinflammation, HIV-1 brain infection, alcohol and drug abuse)
- Pericyte dysfunction in blood brain barrier impairment caused by HIV infection
- Biomarkers of blood brain barrier injury
- Neuroprotective strategies based on diminution of neuroinflammation and blood brain barrier injury
- Effects of cannabinoids on neural stem cells
BBB protection in HIV infection: Barrier shielding effects of poly (ADP-ribose) polymerase (PARP) 1 inhibition
Prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the introduction of combined antiretroviral therapy. HAND is associated with elevation of pro-inflammatory factors in blood and subsets of activated infected monocytes, both shown to cause blood brain barrier (BBB) impairment that contributes to HAND. Therapeutic strategies that disrupt monocyte migration can slow progression of HIV infection and BBB injury, thereby ameliorating HAND. Previously, we focused on studies of molecular mechanisms of BBB injury and anti-inflammatory and barrier protective properties of glycogen synthase kinase (GSK)-3ß inhibition in neuroinflammation driven by HIV infection. We uncovered molecular mechanisms of BBB dysfunction [tight junction (TJ) phosphorylation, CD40/CD40 ligand interactions at BBB and signaling events behind the direct effects of HIV on brain endothelium]. We demonstrated barrier tightening following GSK-3ß suppression in brain endothelium due to TJ stabilization. We showed potent anti-inflammatory effects of GSK-3ß inhibition in brain endothelium in vitro and in vivo. GSKß inhibition in monocytes attenuated their adhesion/migration across the BBB, down regulated active integrin expression via suppression of the small GTPase, Rac1, and protected the BBB. Yet, BBB shielding properties or inhibition of monocyte migration/adhesion were not fully attained in vitro or in vivo, suggesting that additional pathways complimentary to GSK-3ß are necessary for the restitution of BBB function. In search of such molecules, we turned our attention to poly(ADP-ribose) polymerase-1 (PARP-1) and its inhibitors, recently recognized as anti-inflammatory/immune modulating agents with significant neuroprotective properties. Based upon preliminary data, we propose that PARP inhibition will attenuate BBB injury caused by HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Indeed, preliminary data indicate that PARP suppression in primary human brain microvascular endothelial cells (BMVEC) improved BBB integrity and augmented expression of TJ proteins. PARP inhibitors prevented barrier disruption caused by inflammatory factors, diminished monocyte adhesion/migration across a BBB model, down regulated adhesion molecules/pro-inflammatory molecules and decreased activity of RhoA/Rac1. In monocytes, PARP inhibitors down regulated the active beta-integrin that paralleled RhoA/Rac1 suppression. PARP inhibitors decreased expression of pro-inflammatory molecules and diminished HIV replication in human macrophages. Although the modulatory effects of PARP inhibitors on immune cells have been studied to some extent, nothing is known about their effects in the setting of HIV CNS infection. PARP inhibitors have now reached the stage of clinical testing for cancer treatment, assuring quick translation to therapy of immune/inflammatory disorders.
CNS injury caused by HIV-1 and alcohol: Protective effects of cannabinoid receptor (CB) 2 activation
Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. CB2 agonists possess potent anti-inflammatory and neuroprotective properties. We propose that CB2 activation will attenuate neuronal dysfunction and BBB injury caused by alcohol and HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Relevance of this idea is confirmed by our findings of augmented CB2 expression on brain endothelium in alcoholics, patients with HIV encephalitis and up-regulated CB2 expression in primary human brain microvascular endothelial cells (BMVEC) by alcohol and cytokines. CB2 agonists protected the barrier against inflammatory and alcohol insults, blocked monocyte migration across BBB and decreased expression of pro-inflammatory factors in activated BMVEC. CB2 agonist decreased leukocyte adhesion to brain endothelium and prevented enhanced BBB permeability in mice with systemic inflammation. We investigate the therapeutic potential of CB2 activation in diminution of neuroinflammation caused by the combined effects of alcohol and HIV-1.
Secoisolariciresinol diglucoside to mitigate inflammation and toxicity in HAND
Clinical intervention over the past two decades has changed HIV infection from a death sentence to a chronic disease. Despite pharmacological management of HIV-infection, approximately 50% of patients continue to present with neurologic impairment termed HIV-associated neurocognitive disorders (HAND), with persistent neuroinflammation and oxidative tissue damage. Current approaches to mitigate HAND have focused on agents targeting a single cellular function, which may limit their efficacy in a complex multisystem disease. Therefore, novel, pluripotent agents capable of acting simultaneously on diverse pathways and cellular processes may present an opportunity in the short and long term management of HIV. Thus, brain penetrant agents capable of controlling oxidative and inflammatory processes with minimal toxicity over prolonged administration to humans are attractive candidates in mitigating or preventing such effects associated with HAND. Our group has been investigating protective properties of secoisolariciresinol diglucoside (SDG), the main bioactive lignan phenolic in wholegrain flaxseed. Dietary SDG boosts endogenous antioxidant defenses in murine tissues, and exhibits potent anti-inflammatory and antioxidant activity in several tissues including the CNS. SDG and its metabolites can cross the blood-brain barrier (BBB) and enter brain tissues, making it an attractive candidate for mitigation of HIV-induced neurotoxicity. We therefore hypothesize that SDG, as a pluripotent agent, will mitigate HIV-associated neurotoxicity by reducing BBB damage, neuroinflammation, and oxidative stress. SDG is safe and well tolerated in humans and findings from numerous recent clinical trials enhance the translational aspect of our proposed study, which aims to provide novel insights into the usefulness of SDG, and to elucidate its mechanisms of action. Using in vitro modeling, Aims 1-3 will determine the effects of SDG on BBB damage, leukocyte trafficking across the BBB, microglial activation and neurotoxicity induced by HIV infection, and will elucidate mechanisms that underlie the efficacy of SDG as an agent that reduces neuroinflammation and oxidative stress. Aim 4 will investigate the ability of SDG to mitigate BBB damage, neuroinflammation, oxidative stress and neurotoxicity in the humanized mouse model of HIV infection, the huNSG-HIV mouse. Together, these studies will provide evidence to support SDG as adjunctive treatment for management of HAND.
- Education, Training & Credentials
- Residency, Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
- PhD, Pathology, Kiev Research Institute of Urology and Nephrology, Ukrainian Ministry of Health, Kiev, Ukraine
- MD, Kiev State Medical Institute, Kiev, Ukraine
- College of American Pathologists
- American Society of Clinical Pathologists
- American Society for Investigative Pathology
- American Society of Neuroscience
- Society for NeuroImmune Pharmacology
- American Society of Neurochemistry
Books, Book Chapters, Monographs
Persidsky Y, Steffan AM, Gendrault JL, Berger S, Royer C, Hurtrel B, Stutte HJ, Aubertin AM, Kirn A: Involvement of liver sinusoidal cells at different stages of simian immunodeficiency virus (SIV) infection in macaques. In: Cells of the Hepatic Sinusoid, vol 5, Wisse, Knook, Wake, eds, Kupffer Cell Foundation, Leiden. The Netherlands. 1995; 33-36.
Persidsky Y, Steffan AM, Gendrault JL, Royer C, Aubertin AM, Kirn A: Morpho-functional changes of follicular dendritic cells (FDC) and lymph node structure in simian immunodeficiency virus (SIV) infection. In: Dendritic Cells in Fundamental and Clinical Immunology. Banchereau and Schmitt, eds, Plenum Press, New York. 1995; 329-331.
Persidsky Y, Gendelman HE: HIV-1 encephalitis is a consequence of viral infection and immune activation. In: Biology and Physiology of the Blood Brain Barrier (Couraud, Sherman, eds.), Plenum Press, New York, 1996; 365-367.
Persidsky Y, Tyor W: Nontransgenic murine animal model systems for the HIV-associated cognitive motor complex. In: Neurological and Neuropsychiatric Manifestations of HIV-1 Infection, Gendelman HE, Lipton S, Epstein L, Swidells S, eds. Chapman & Hall Publishers, NY 1997, pp. 168-178.
Gendelman HE, Ghorpade A, Persidsky Y: The neuropathogenesis of HIV-1 dementia. In: In Defense of the Brain, Peterson, Remington (eds.), Blackwell Sci, 1997, 290-304.
Persidsky, Y. Murine animal model systems for studies of HIV-1-associated dementia. In: The Neurology of AIDS, 2nd Edition. Gendelman HE, Grant I, Lipton SA, Everall IP, Swindells S. (Eds.). Oxford University Press, 2005, p. 289-296.
Persidsky Y. NeuroAIDS. In: Neuroimmune Pharmacology. Ikezu T, Gendelman HE, Kabanov AV, Pahan K, Pseborski S. (Eds). Springer, NY. 2008. 297-312.
Haorah J, Floreani NA, Persidsky Y. Alcohol-induced blood-brain barrier dysfunction. In: Research on the Neurobiology of Alcohol Use Disorders. Sher L. (Ed.). Nova Science Publishers, New York, 2008. p.239-260.
Persidsky Y, Ramirez SH. The blood-brain barrier in the setting of neuroinflammation. In: The Neurology of AIDS, 3rd Edition. Gendelman, H.E., Grant, I., Lipton, S.A., Everall, I.P. and Swindells, S. (Eds.). Oxford University Press, 2011, p. 220-230.
Persidsky Y, Ho WZ, Wang X, Potula R. Alcohol Abuse, HIV-1 and Hepatitis C Infection. Chapter 11. Neuro-Immune Effects of Alcohol. Springer. 2012, p. 509-534.
Persidsky Y, Gofman L, Potula R. Alcohol and Neurodegeneration. Chapter 24. Book “Neuroinflammation and Neurodegeneration”. Edited by Peterson PK and Toborek M. 2014, pp.511-528.
Merkel S, Ramirez SH, Persidsky Y. Blood brain barrier (BBB) dysfunction in HIV Infection. Chapter 3, Volume II Book “The Blood-Brain Barrier in Health and Disease”. 2015. Edited by Dorovini-Zis, K. CRC Press, Francis and Taylor.