Youssef Sari, Ph.D.
Associate Professor of Pharmacology
Frederic and Mary Wolfe Center, 282G
- B.S. Cellular Biology, Denis Diderot University (Paris, France).
- M.S. Cellular Biology, Orsay University (Paris, France)
- Ph.D. Neuroscience, Pierre and Marie Curie University, Institute of Neuroscience (Paris, France).
- Postdoc and Associate Scientist: Indiana University
Two research projects are ongoing in my Neuroprotection and Drug Abuse Research Lab:
The first project is dealing with the investigation of the role of glutamate transport in alcohol dependence. While it has been clearly established that dopaminergic neurotransmission plays an important role in reward and drug addiction, increasing evidence suggests that many aspects of the plasticity of drug addiction involves changes in glutamatergic neurotransmission. I have recently identified an FDA-approved drug and other related compounds that can cross the brain blood barrier and facilitate glutamate neurotransmission. We have tested one of these drugs and found potential therapeutic effects in a model of drug abuse such as cocaine addiction. Our ongoing research projects focused on the identification and pharmacological studies of drugs known to upregulate the glutamate transporter 1 (termed also excitatory amino acid transporter 2, EAAT2) and their role for the treatment of alcohol dependence. We use animal model of alcohol dependence to determine the behavioral, molecular and pharmacological manipulations of all these therapeutic drugs. This project is currently funded by the National Institutes of Health-NIAAA (R01).
The second project is dealing with the use of derived neurotrophic peptides and other neuroprotective compounds in the treatment of diseases involving oxidative stress. Oxidative stress is the major cause for most of neurodegenerative diseases. We have tested the role of neurotrophic factors in a model of oxidative stress involving alcohol exposure in brain development and have shown neuroprotective effects. We have demonstrated that derived neurotrophic peptides prevent alcohol-induced mitochondrial dysfunction. Mitochondrion is a key play in oxidative stress, thus preventing its dysfunction will be a therapeutic useful tool to prevent or delay the progression of neurodegenerative diseases. Since my lab is focusing in Huntington’s disease, we are currently working in testing these novel trophic factors to prevent or slow the progression of the disease. We are using transgenic mice. that have the dysfunctional human huntingtin protein. We are also testing other compounds that have anti-oxidative effects. We aim to delineate the precise signaling pathways that mediate these trophic factors and other anti-oxidative compounds in neuroprotection using Huntington’s disease mouse models.
|Dr. Sari (center) and members of his laboratory|
- Y. Sari, K. Lefèvre, M. Bancila, M. Quignon, M.-C. Miquel, X. Langlois, M. Hamonand D. Vergé.Light and electron microscope visualization of 5‑HT1B receptors in the rat brain. Brain Res 760 (1997) 281-286.
- Y. Sari, C. Sibella, D. Vergé, M. Hamon and M-C. Miquel. Limited inhibition of 5‑HT1A receptor expression in the rat brain by antisense RNA and oligodesoxynucleotides. Neurosci Letters 259 (1999) 191-195.
- Y. Sari, M.-C. Miquel, M.-J. Brisorgueil, G. Ruiz, E. Doucet, M. Hamon and D. Vergé. Cellular and subcellular localization of 5‑hydroxytryptamine1B receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies. Neuroscience 88 (3) (1999) 899-915.
- F.C. Zhou, Y. Sari and J.K. Zhang.Expression of serotonin transporter protein in developing rat brain.Brain Res Dev Brain Res 119 (1) (2000) 33-45.
- Y. Sari, T. Powrozek, F.C. Zhou. Alcohol deters the outgrowth of serotonergic neurons at midgestation. J Biomedical Sci 8 (2001) 119-125.
- E.P. Riley, J.D. Thomas, C.R. Goodlett, A.Y. Klintsova, W.T. Greenough, B.L. Hungund, F.C. Zhou, Y. Sari, T. Powrozek, T.-K. Li. Fetal Alcohol Effects: Mechanisms and Treatment. Alcohol Clin Exp Res 25(5) (2001) 110S-116S.
- F.C. Zhou, Y. Sari, JK. Zhang, C.R. Goodlett, T.-K. Li. Prenatal alcohol exposure retards the migration and development of serotonin neurons in fetal C57BL mice. Brain Res Dev Brain Res 126 (2) (2001) 147-155.
- F.C. Zhou, Y. Sari, C.G. Goodlett, T.-K Li. Deviations in brain early serotonergic development as a result of fetal alcohol exposure. Neurotoxicity Res, 4(4) (2002) 337-342.
- F.C. Zhou, Y. Sari, C.R. T. Powrozek, Goodlett, T.-K. Li. Moderate alcohol exposure compromises neural tube midline development in prenatal brain. Brain Res, 144 (2003) 43-55.
- Y. Sari, F.C. Zhou. Serotonin and its transporter on proliferation of fetal heart cells. Int J Dev Neurosci, 21(8) (2003) 417-424.
- Y. Sari, F.C. Zhou. Prenatal alcohol exposure causes long term serotonin neuron deficit in mice. Alcohol Clin Exp Res 28(6) (2004) 941-948.
- Y. Xu, Y. Sari, FC Zhou. Selective serotonin reuptake inhibitor disrupted the organization of thalamic afferents in rat somatosensory cortex during early postnatal development. Brain Res Dev Brain Res 150(2) (2004) 151-161.
- T.A. Powrozek*, Y. Sari*, R.P. Singh*, F.C. Zhou*. Neurotransmitters and drugs of abuse: Effects on adult neurogenesis. Current Neurovascular Research, 1 (2004) 251-260. (*All authors contributed equally to this review manuscript)
- F.C. Zhou, Y. Sari, T. Powrozek, C.Y. Spong. A neuroprotective peptide antagonizes fetal alcohol exposure compromised brain growth. J Mol Neurosci, 24(2) (2004) 189-200.
- Y. Sari. Serotonin1B Receptors: From Protein to Physiological Function and Behavior. Neuroscience and Biobehavioral Reviews, 28 (2004) 565-582.
- F.C. Zhou, Y. Sari, T.A. Powrozek. Fetal alcohol exposure reduces serotonin innervation and compromise development of the forebrain and the serotonergic pathway. Alcohol Clin Exp Res, 29(1) (2005) 141-149.
- Y. Sari, R. Bell, F.C. Zhou. Effects of continuous consumption of alcohol with and without repeated deprivations on dopamine D1 and D2 receptors in the extended amygdala of inbred alcohol-preferring rats. Alcoholism: Clin Exp Res, 30(1) (2006) 46-56.
- L.J. Chandler, E. Carpenter-Hyland, A. Hendricson, R. Maldve, R. Morrisett, F.C. Zhou, Y. Sari, R. Bell, K. Szumlinski. Structural and functional modifications in glutamateric synapses following prolonged ethanol exposure. Alcoholism: Clin Exp Res, 30(2) (2006) 368-376.
- Y. Sari, I. Gozes. Brain deficits associated with fetal alcohol exposure may be protected, in part, by peptides derived from activity-dependent neurotrophic factor and activity-dependent neuroprotective protein. Brain Res Reviews, 52(1) (2006) 107-118.
- F.C. Zhou, R.N. Sahr, Y. Sari, K. Behbahani. Glutamate and dopamine synaptic terminals in extended amygdala after 14-week chronic alcohol drinking in inbred alcohol-preferring rats. Alcohol, 39 (1) (2006) 39-49.
- B.R. Miller, J.L. Dorner, M. Shou,Y. Sari, R.T. Kennedy, G.V. Rebec. Ceftriaxone elevates GLT1 expression and improves the Huntington’s disease phenotype in R6/2 mice. Neuroscience 153 (2008) 329-337.
- Y. Sari. Activity-dependent neuroprotective protein-derived peptide, NAP, preventing alcohol-induced apoptosis in fetal brain of C57BL/6 mouse. Neuroscience (2009) 158(4):1426-435.
- Y. Sari, K. Smith, A. Pir, G.V. Rebec. Up-regulation of GLT1 attenuates cue-induced reinstatement of cocaine seeking behavior in rats. J. Neuroscience (2009) 29(29):9239-43.
- Y. Sari, T. Chiba, M. Yamada, G.V. Rebec,S. Aiso. A novel peptide, colivelin, preventing alcohol-induced apoptosis in fetal brain of C57BL/6 mouse: signaling pathway investigations. Neuroscience (2009) 164(4):1653-64.
- Y. Sari, M. Zhang, Y. Mechref. Differential expression of proteins in fetal brains of alcohol-treated prenatally C57BL/6 mice: a proteomic investigation. Electrophoresis, (2010) 31 (3): 483-496.
- Y. Sari, L.A. Hammad, M.M. Saleh, M.V. G.V. Rebec, Y. Mechref. Alteration of selective neurotransmitters in fetal brains of prenatally alcohol-treated C57BL/6 mice: quantitative analysis using liquid chromatography/tandem mass spectrometry. Int. J. Dev. Neurosci., (2010) 28: 263-269.
- Y. Sari; A. L. Prieto, S. Barton, B. R. Miller, G. V. Rebec. Regulation of GLT1 expression at multiple stages of disease progression in the R6/2 model of Huntington’s disease. J. Biomed. Sci. (2010) 17(1):62.
- Y. Sari, V. R. Johnson, J.M. Weedman. Role of the serotonergic system in alcohol-drinking behavior: from animal models to clinics.Prog Mol Biol Transl Sci. (2011) 98:401-43. (Invited)
- Y. Sari, M. Sakai, J.M. Weedman, G.V. Rebec, R.L. Bell. Ceftriaxone, a beta lactam antibiotic, reduces alcohol consumption in alcohol-preferring rats. Alcohol and Alcoholism, (2011) 46(3):239-46.
- Y. Sari. Huntington’s disease: from mutant huntingtin protein to neurotrophic factor therapy. Int. J. Biomed. Sci. (2011) 7(2):89-100. (Invited)
- Y. Sari. Potential drugs and methods for preventing or delaying the progression of Huntington’s disease.Recent Pat CNS Drug Discov. (2011) 1;6(2):80-90. (Invited)
- Y. Sari, Z.M. Segu, A. YoussefAgha, J.A. Karty, and D. Isailovic. Neuroprotective peptide, ADNF-9, in fetal brain of C57BL/6 mice exposed prenatally to alcohol. J. Biomed. Sci. (2011) 18(1):1-12.
- Y. Sari, J.M. Weedman, Ge. Shufan. Activity-dependent neurotrophic factor-derived peptide prevents alcohol-induced apoptosis, in part, through Bcl2 and JNK signaling pathways in fetal brain of C57BL/6 mouse. Neuroscience (2012) 202:465-473
- H.W. Nam, S.R. McIver, D.J. Hinton, M.M. Thakkar, Y. Sari, F.E. Parkinson, P.G. Haydon, and D-S. Choi. Adenosine and Glutamate Signaling in Neuron-Glial interactions: Implications in Alcoholism and Sleep Disorders. Alcoholism: Clin Exp Res, (2012) 36(7):1117-25.
- Y. Kawanabe, M. Takahashi, S. Abdul-Majeed, Y. Sari, S.M. Nauli. Effect of cilostazol on extracellular calcium influx in smooth muscle contraction and proliferation. PLoS ONE, 2012;7(9):e44476
- P.S.S. Rao and Y. Sari. Glutamate transporter 1: target for the treatment of alcohol dependence. Current Medicinal Chemistry, 2012; 19(30):5148-5156.
- Y. Sari and S.N. Sreemantula. Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats. Neuroscience, 2012, 227: 327-335.
- Y. Sari. Role of 5-HT1B receptors in the regulation of Ethanol intake in rodents. J. Psychopharmacology, 2013, 27(1) 3-12.
- Y. Sari, J.M. Weedman, M. Nkrumah-Abrokwah. Neurotrophic peptides, ADNF-9 and NAP, prevent alcohol-induced apoptosis at midgestation in fetal brains of C57BL/6 mouse. Journal of Molecular Neuroscience, 2013, 49(1), 150-156.
- Y. Sari, K.M. Franklin, Adnan Alazizi, P.S.S. Rao, R.L. Bell. Effects of ceftriaxone on the acquisition and maintenance of ethanol drinking in peri-adolescent and adult female alcohol-preferring (P) rats. Neuroscience, 2013, 241-229-238.
- Sari, Y. Experimental Methods for Testing the Effects of Neurotrophic Peptide, ADNF-9, Against Alcohol-induced Apoptosis During Pregnancy in C57BL/6 Mice. J. Vis. Exp. (), e50092, doi:10.3791/50092 (2013). Link to video
- A.M. Qrunfleh, A. Alazizi, Y. Sari. Activation of glutamate transporter 1 attenuates relapse to alcohol- seeking behavior in alcohol-preferring rats. Journal of Psychopharmacology, in press
- J. Ciesler, Y. Sari. Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic Lateral Sclerosis and Alzheimer’s disease. Open Journal of Neuroscience, in press (Invited)
- Y. Sari. Potential therapeutic role of glutamate transporter 1 for the treatment of alcohol
dependence. OA Alcohol, (invited) in press
- Y. Sari. The role of GLT1 in the modulation of alcohol-drinking behavior in P rats. International Innovation Report, (invited) in press
- Y. Sari, S.N. Sreemantula, Ryan Lee, and Choi D-S. Ceftriaxone attenuates alcohol intake through regulatory effects of both GLT1 and ENT1 in central reward brain regions in alcohol-preferring rats. Journal of Molecular Neuroscience, in press
Y. Sari, V. R. Johnson, J.M. Weedman. Role of the serotonergic system in alcohol-drinking behavior: from animal models to clinics. In The Brain as a Drug Target, volume 98, Progress in Molecular Biology and Translational Science, (2011), pages 401-443.
“Treatment of Alcohol Dependence”. Provisional Patent application filed October 4, 2012. US Serial No: 61/709,724