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Principal Investigator Rao M Adibhatla, Ph. D. Personnel |
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Research
Professor Address: H4-330; Clinical Science Ctr., Dept. of Neurological Surgery Univ. of Wisconsin-Madison WI 53792-3232 Phone: (608) 263-1791 Fax: (608) 263-6901 VA lab:(608) 256-1901 X17809 |
James F. Associate
Researcher Phone:
608-265-1101 hatcher@neurosurg.wisc.edu |
NTP_Course_675 Lipids in Brain injury and disease
List 1 List of papers for student presentation
List 2 General references pertinent to course
Sept
2, 2009 Lecture 1 (2 hrs Introduction, lipids in CNS injury and disorders);
list
of papers will be provided to make selection for final paper presentation
Sept 2, 2009 Lecture 2 (2 hrs Lipid Synthesis)
Sept 9, 2009 Lecture
3-4, (2 hrs Lipid hydrolysis, Lipid analysis, Brain cells, Arachidonic acid
metabolism and lipid peroxidation)
Sept 16, 2009 Lecture
5-6, (Atherosclerosis, Plaque, Stroke Part I, Stroke neuroprotection and CDP
choline) (1hr and stroke video) Student presentation schedule, selection of papers
Sept 23, 2009 Lecture
7-8, (Liposomes, clinical trials Stroke Part II) (Stroke Part IV) (Lipid in
cell cycle)
Sept 30, 2009 Lecture
9-10, (Huntington and Parkinson)
Oct 7, 2009 Lecture
11-12 (Multiples sclerosis-EAE; Lysosomal
disorders/Niemann-Pick/Peroxisomes/Zellweger
Oct 14, 2009 Lecture
13-14, (Traumatic brain injury, Spinal cord injury)
Oct 21, 2009 Lecture 15-16,
(Epilepsy, bipolar disorders, Schizophrenia)
Oct 28, 2009 Lecture
17-18, (Topics that have not been covered)
Nov 4, 2009 Lecture 19 (Luigi Puglielli guest lecture;
Instructor 1 hr Alzheimer’s disease and lipid connection)
Nov 11, 2009 Lectures 14
and 15, (Course evaluation; Guest lecture summary/250 words due)
TEST
Nov 18 2009 1—3 students
paper presentation 35 min (20-25min + 5-10 min discussion)
Nov 25, 2009 4—6
students paper presentation 35 min (20-25min + 5-10 min discussion)
Dec 2, 2009, 7—9
students paper presentation 35 min (20-25min + 5-10 min discussion)
Dec 9, 2009 10-12
students paper presentation 35 min (20-25min + 5-10 min discussion)
Dec 16, 2009 13—16
students paper presentation 35 min (20-25min + 5-10 min discussion)
Final reports due (4
page, ~10 ref topic of choice)
COURSE EVALUATION FORM
(for students)
Helpful Reviews (provided
to the students)
BMB reports 2008
Subcell.
Biochem 2008
Front. Biosci.
2007
Future Lipidology
2007
Free Rad. Biol. Med 2006
Am. Assn.
Pharmaceutical Scientist J 2006
Brain Res. 2005
Papers
for presentation (presenter’s last and first name_date_author)
Fallace_Kathe_8Oct2008_Stack.pdf
Algiers_Tim_22Oct2008_Fergani.pdf
Gadow_Brett_22Oct2008_Djebaili.pdf
Elliott_Shaina_29Oct2008_Ehehalt.pdf
Guglielmetti_Caroline_5Nov2008_sahlin.pdf
Supplemental material
Lois_Kathrynn_5Nov2008_Kalyvas.pdf
Neuroscience 500 NTP Undergraduate Stroke talk
(PowerPoint presentation)
Route of
administration is critical.
Up-date
on CDP-choline clinical trials
Neuroscience 625 course: Brain Cultures: Laboratory course:
Use of HPLC and GC in Neuroscience
Research (PowerPoint presentation)
APCAS 2007
NBRC 2007
Cytokines, lipid metabolism &
stroke
Polyamines & stroke
·
70 papers in peer reviewed national and
international journals.
·
73 presentations at various national and
international meetings.
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Project
1 Cytidine-5’-Diphosphocholine
(CDP–Choline
or Citicoline) in Stroke
and other
CNS Disorders |
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CDP-choline
improved the outcome of patients in phase III clinical trials of stroke. It
was shown to have beneficial effects in a number of CNS injury models. Al Integration of cytokine biology and
lipid metabolism: CDP-choline beneficial
effects could be attributed to interactions at TNF-α/IL-1 mediated
events, differentially affecting phospholipases and CCT. This limits
phospholipid hydrolysis and increases synthesis, thereby restoring PC and SM
levels Return to Top of page |
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Virtually no side
effects and is well tolerated in stroke clinical trials. |
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Recent phase III stroke clinical studies by Davalos et al (Stroke 2002) showed that CDP-choline
is effective in stroke |
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In light of these developments, future studies are
warranted to further confirm the efficacy of CDP-choline for stroke
treatment. Route of administration is critical. •
Route of administration: Oral ( •
Brain uptake of CDP-choline, 0.5% (oral) vs 2% i.v. •
Liposome
encapsulated CDP-choline (brain uptake 23%) attenuated cerebral infarction
better than other routes (ip and iv) of administration. Up-date on CDP-choline Clinical Trials ·
IVAX,
a ·
Elder
Pharmaceuticals ( |
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Other links to CDP- choline http://www.cdpcholine.com/ |
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Project 2. Phosphatidylcholine
Homeostasis in Stroke |
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Significance: Tumor necrosis factor-α (TNF-α) and
interleukin-1 (IL-1) are major pro-inflammatory cytokines and are rapidly
up-regulated in brain after cerebral ischemia. Blockade of TNF-α by
administration of TNF-α antibodies (TNF-α ab) or TNF-α binding
protein attenuated ischemic brain injury in a number of studies. Transgenic
mice deficient in both IL-1α and IL-1ß showed dramatic reduction in
infarcts compared to wild-type mice. Similarly, treatment with IL-1 receptor
antagonist (IL-1ra) reduced
neuronal death in all forms of experimental cerebral ischemic injury. TNF-α and IL-1 disrupt PC homeostasis (Scheme 3): In vitro studies have shown that PLA2 and PC-phospholipase C (PC-PLC) are induced
by TNF-α and mediate their
cytotoxicity. Activation of PLA2 by PC synthesis: TNF-α and IL-1
inhibit CCT, the rate-limiting
enzyme
in PC synthesis. Thus these two proinflammatory cytokines may
simultaneously stimulate PC hydrolysis and inhibit its synthesis (Scheme 2). CDP-choline,
formed by CCT, is the rate-limiting intermediate in the PC synthesis. Cholinephosphotransferase (CPT)
catalyzes ultimate step of making PC from CDP-choline and 1,2-diacylglycerol. We have
shown that CDP-choline treatment attenuated PLA2 activity, loss of
CCT activity, hydroxyl radical (OH•)
generation, lipid peroxidation, phospholipid hydrolysis and showed
significant neuroprotection after transient cerebral ischemia. Return to Top of page |
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Project 3 Polyamines in Stroke |
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Polyamines
(putrescine, spermidine and spermine) are ubiquitous cellular components. The
role of alterations in polyamine metabolism in neuronal degeneration after
CNS injury remains an unresolved issue. Polyamines are Return to Top of page |
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• American Heart Association Greater
Midwest Affiliate, Principal
Investigator
(2006-08) for ‘Phosphatidylcholine metabolism and pro-inflammatory factors in
stroke’ (Active).
•
•
phospholipase
C (PC-PLC) inhibitor, D609 in stroke (Active)
• Univ. of Wisconsin Graduate School, Univ. of Wisconsin
Med. School, Dept. of Neurological Surgery Principal Investigator (2005-2008) Cytokines and lipid homeostasis in CNS
injury (active)
• NIH/NINDS/RO1 grant, Principal Investigator (2008-2012) for ‘Deregulated Lipid metabolism in Stroke’ (pending)
• NIH/NINDS/R21 grant, Principal Investigator (2009-2011) for ‘Cell cycle regulation by lipid second messengers after stroke’ (pending)
• American Heart Association Greater
Midwest Affiliate, Principal
Investigator
(2008-10) ‘Cytokine modulation of phosphatidylcholine and sphingomyelin
metabolism in stroke’ (pending).
• NIH/NINDS RO1 National
Institutes of Health/NINDS RO1 grant, Principal Investigator (2003-2008) ‘CDP-choline: Mechanisms in Cerebral
Ischemia’ (Completed)
•
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American
Heart Association (Northland affiliate) (2003-04), ‘Polyamines in Cerebral
Ischemia (PI: RJ
• NIH/NINDS RO1, Co-PI “Ornithine Decarboxylase and Ischemic
Brain Edema” RJ
• NIH/NINDS Co-PI “Mechanisms of Brain Injury. Project 3. Acute
Cellular Response to Brain Injury” AB Young, (PI) (completed).
Return to Top of
page
·
“CDP-Choline neuroprotective mechanisms in
stroke” An update on Citicoline; Mini-symposium organized by Ferrer group, La
Cantera Westin Resort, San Antonio, TX, July 2009.
·
“CDP-Choline neuroprotective mechanisms in
stroke” Dept of Neurology, Leonard M.
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“The Stroke Story of D609:
Multifunctional or non specific?” Dept of Neurological Surgery
Grand Rounds,
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Invited to participate in the
"Citicoline-Update on its role in stroke recovery" a symposium organized by leading neurologists
Drs Marc Fisher; Antoni Davalos, Jeff Saver, Larry Wecsler and Steve Warach
during International Stroke Conference in San Diego, Feb 19, 2009; and
sponsored by Ferrer Grupo of Spain (the parent company of Citicoline).
·
“Altered phosphatidylcholine and
sphingomyelin metabolism after stroke: Therapeutic strategies” Centre for Cellular
and Molecular Biology,
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“Altered phosphatidylcholine
metabolism after stroke: Therapeutic strategies”. International Conference on Advances in Neuroscience,
·
“Cell cycle and altered lipid
metabolism: Anti-proliferative effects of phosphatidylcholine-phospholipase c
(PC-PLC) inhibitor, D609 after stroke”. Soc. Neurosci. Nov 2008,
• “Altered phosphatidylcholine
metabolism after stroke: Therapeutic strategies”. Dept of Neurological
Surgery Grand Rounds,
• ‘Primer on Brain disorders and diseases’ Guest of Honor lecture at
VITHAM Institute of Technology, Vishakapatnam, India, April 2007.
• ‘Lipid
metabolism and cytokines in stroke’ National Brain Research Institute, Manesar,
Guragon,
• ‘Mechanistic
aspects of Citicoline actions in Stroke’ Asia Pacific
Conference Against
Stroke (APCAS
2007), Jointly organized by India,
Pakistan, Bangladesh, Sri Lanka, New Delhi, March 2007.
• ‘Primer on Brain disorders and diseases’ Indian Institute of
Technology, New Delhi, India, March 2007.
• ‘Lipid metabolism and cytokines in
stroke’ Neuroscience lecture for undergraduates, UW Madison, WI, January,
October 2007, Feb 2008
• ‘Lipid metabolism and cytokines in
stroke’ Neuroscience Training Program, UW Madison, WI, January 2007.
• ‘Cytokine, lipid metabolism, and CDP-choline in stroke’
Alzheimer’s and neurodegenerative diseases seminar series, UW-Madison September
2006
• ‘Loss of cellular phosphatidylcholine: a cause or a result of
cell death?’ Alzheimer’s and neurodegenerative diseases seminar series,
UW-Madison September 2006
CDP-choline mechanisms and Efficacy
in Stroke
• Department of Pathology, UW-Madison, May 2006
• Grand Rounds, Dept of Neurological Surgery, UW-Madison, May 2005
• Presented series of lectures to
Neurologists/Neurosurgeons (at major Indian metropolitan cities) sponsored by
Ferrer Grupo,
• Molecular and Integrative Physiology,
• Brain and Cognitive Sciences & MIT
clinical Research Center, Massachusetts Institute of Technology, Boston, MA,
February 2005.
• National Institute of Nutrition,
•
• Neural Environment Cluster, Natl. Inst.
Neurological Disorders and Stroke (NINDS, extramural); NIH,
• 34th
Am. Soc. Neurochemistry, New
• VA
• Cardiovascular
• Natl. Inst. Neurological Disorders and
Stroke (NINDS, intramural); NIH,
• Center for Cellular and Molecular
Biology,
ODC, Polyamines and
CNS Injury
• Gordon Conference on Polyamines, June 15-20, 2003,
•
• V A
• Center for Cellular and Molecular
Biology,
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PROFESSIONAL SERVICES
• Editorial board member for Neurochemical Research
• Editorial
board member for Current
Neuropharmacology
• Editorial
board member for Annals of Neurosciences
(
• Grant Reviewer for the
Austrian Genome Research Programme GEN-AU sponsored by The Austrian Federal
Ministry for Education, Science and Culture.
• Grant Reviewer for the
Alzheimer’s Association.
• Grant Reviewer for the Canadian ALS Association.
• Grant Reviewer for the Unity
through Knowledge_Croatia
• Member of the National Brain
Committee, American Heart Association Peer Review Study Group.
• Abstract reviewer for The 22nd
International Symposium on Cerebral Blood Flow, Metabolism, and Function &
7th International Conference on
• Abstract reviewer for The 23rd International Symposium on
Cerebral Blood Flow, Metabolism, and Function & 8th
International Conference on
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Atherosclerosis |
Essays in Biochem. |
Neurochem. Res. (Editorial board member) |
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Biochemical J. |
Eur. J. Neurosci. |
Neuroscience |
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Biochim. Biophys. Acta |
Eur. J. Pharmacol. |
Neuroscience Lett. |
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Brain Res. |
Future Lipidology |
Neurotoxic. Res. |
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Br. J. Pharmacol. |
J Cereb Blood Flow Metab. |
Neurosurgery |
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Cancer |
J. Neurochem. |
Prostaglandins, Leukotrienes and
Essential Fatty Acids |
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Cell Biology International |
J Neuroinflammation |
Pediatric Res. |
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Cell. Mol. Neurobiol. |
J. Neurosci. Res. |
Pharmacol. Res. |
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Current Eye Res. |
J. Neurosurgery |
Stroke |
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Current Neuropharmacology (Editorial advisory board member) |
Neurobiol. Disease |
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CDP-CHOLINE & STROKE |
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Last update:
April 2009 |