Rao M. Adibhatla’s Research Laboratory

 

Principal Investigator

          Rao M Adibhatla, Ph. D.

Personnel

        James F. Hatcher, B. S.

        Eric Larsen, Ph. D.

        Francis Tsao, Ph. D.

 

 
 

Rao M. Adibhatla, Ph. D

Research Professor

Adibhatla’s CV

 

Address:

H4-330; Clinical Science Ctr.,

600 Highland Avenue

Dept. of Neurological Surgery

Univ. of Wisconsin-Madison

WI 53792-3232

Phone: (608) 263-1791

Fax: (608) 263-1409

VA lab:(608) 256-1901 X17809

adibhatl@neurosurg.wisc.edu

 

James F. Hatcher, BS

Associate Researcher

Phone: 608-263-4012 hatcher@neurosurg.wisc.edu

 

 

Eric Larsen, Ph. D

Postdoctoral fellow

Phone: 608-256-1901 X 17809

e.larsen@neurosurg.wisc.edu

 

 

Francis HC Tsao, Ph. D.

Senior Scientist

Dept of Medicine/Neurological Surgery

Phone: (608) 262-9299

fhtsao@wiscmail.wisc.edu

 

 

 

Research Interests

Project 1

       Route of administration is critical.

Up-date on CDP-choline clinical trials

Project 2

Project 3

Funding

Invited Talks

Professional Services

AD-hoc reviewer

Neuroscience 500 NTP Undergraduate Stroke talk (PowerPoint presentation)

Neuroscience 625 course: Brain Cultures: Laboratory course:

Use of HPLC and GC in Neuroscience Research (PowerPoint presentation)

APCAS 2007

Delhi IIT 2007

NBRC 2007

Publications

Cytokines, lipid metabolism & stroke

CDP-choline & stroke

Polyamines & stroke

Other Publications

Adibhatla’s CV

PUBLICATIONS

·         69 papers in peer reviewed national and international journals.

·         70 presentations at various national and international meetings.

 

Research Interests

 

Project 1

Cytidine-5’-Diphosphocholine (CDP–Choline or Citicoline) in Stroke and other CNS Disorders

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. AlText Box:  though experimental evidence is limited, the therapeutic action of CDP-choline is thought to be due to stimulation of phosphatidylcholine (PC) synthesis in a damaged brain. Understanding the actions of CDP-choline could lead to development of more efficient treatment strategies for ischemia/reperfusion injury. Our studies of transient cerebral ischemia suggest that CDP-choline might enhance reconstruction (synthesis) of PC and sphingomyelin. CDP-choline could also act by inhibiting destructive processes (activation of phospholipases). The major mechanism of action of CDP-choline may be in modulating activation of phospholipase A2 (PLA2) (Scheme 1).

 

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 (Scheme. 2). Our recent studies also showed that PC loss is a cause rather than a result of cell death. Since all cells (neurons, astrocytes, and endothelial cells etc., called the ‘neurovascular unit’) contain PC as a membrane building block, CDP-choline protection may arise from stabilizing the ‘neurovascular unit’. These studies provide an integration of CDP-choline effects with cytokine biology and lipid metabolism in stroke.

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CDP-CHOLINE IN STROKE CLINICAL TRIALS:

What factors might be critical?

Virtually no side effects and is well tolerated in stroke clinical trials.

Recent phase III stroke clinical studies by Davalos et al (Stroke 2002) showed that CDP-choline is effective in stroke

 

 

 

 

 

 

 

 

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 (USA) vs i.v. (non-USA).

              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 Florida based company, in agreement with Grupo Ferrer (Barcelona, Spain) is filing for FDA approval of CDP-choline for acute stroke treatment.

·            Elder Pharmaceuticals (Mumbai, India) with Grupo Ferrer (Barcelona, Spain) launched CDP-choline (Somazina) phase III clinical trials for acute stroke treatment in India.

 

Other links to CDP- choline http://www.cdpcholine.com/

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Project 2.

Phosphatidylcholine Homeostasis in Stroke

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 TNF-α/IL-1 may be mediated by increases in PLA2 activating protein (PLAP). PLAP in the rat brain has been characterized, but its role in cerebral ischemia has not been explored. PLA2 and PC-PLC hydrolyze PC, the major membrane phospholipid. PC loss is sufficient in itself to induce cell death. We have shown stimulation of PLA2, significant loss of phospholipids including PC  and significant decrease in cytidine triphosphate phosphocholine cytidylyltransferase (CCT) activity following transient brain ischemia.

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.

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Project 3

Polyamines in Stroke

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 important in the stabilization of cellular components such as cell membranes and chromatin structures; depletion of polyamines could lead to loss of cell integrity and cell death. Transient cerebral ischemia results in loss of spermine and spermidine. Our research seeks to determine whether normalization of the transient, ischemia–induced polyamine imbalance is neuroprotective. Spermine is considered to be an antioxidant and free radical scavenger, and restoring its levels may protect the brain from oxidative damage (either by scavenging hydroxyl radical or chelating Fe2+) following ischemia/reperfusion (Scheme 4).

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Research Funding

 

    NIH/NINDS RO1 National Institutes of Health/NINDS RO1 grant, Principal Investigator (2003-2008) ‘CDP-choline: Mechanisms in Cerebral Ischemia’ (Active)

    American Heart Association Greater Midwest Affiliate, Principal Investigator (2006-08) for ‘Phosphatidylcholine metabolism and pro-inflammatory factors in stroke’ (Active).

    University of Wisconsin Medical School Research Grant Principal Investigator (2008-2009) “Oxidized Phosphatidylcholine: A Marker for Neuroinflammation in Stroke” (Active).

    NIH/NINDS/RO1 Principal Investigator (2008-2012) for ‘Regulation of Phosphatidylcholine in Stroke’ (pending)

    NIH/NINDS/RO1 grant, Principal Investigator (2008-2012) for ‘Deregulated Lipid metabolism in Stroke’ (pending)

    NIH/NINDS/RO1 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).

    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)

    University of Wisconsin Medical School Research Grant Principal Investigator (2001-2002) for “Possible new mechanisms of CDP-choline neuro-protective in cerebral ischemia” (completed).

    NIH/NINDS RO1, Co-PI “Ornithine Decarboxylase and Ischemic Brain Edema” RJ Dempsey, (PI) (completed).

    NIH/NINDS Co-PI “Mechanisms of Brain Injury. Project 3. Acute Cellular Response to Brain Injury” AB Young, (PI) (completed).

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INVITED TALKS

    “Altered phosphatidylcholine metabolism after stroke: Therapeutic strategies”. Dept of Neurological Surgery Grand Rounds, Univ. of Wisconsin, April 2008.

    ‘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, New Delhi, India March 2007

    ‘Mechanistic aspects of Citicoline actions in Stroke’ Asia P