Dr. Soundar Regunathan serves as a Basic Science Mentor for the CPN. Dr. Regunathan completed his graduate training in Neurochemistry of amino acid transmitter systems in 1985 at the University of Madras. After completing two year post-doctoral program at McGill University in Montreal, he spent several years in the Division of Neurobiology at Cornell University Medical College in New York, working on novel receptors and neurotransmitter systems. He is a tenure-track Professor of the Division of Neurobiology and Behavior Research (since 2002). His research has been funded by R01 grant from NINDS.

Dr. Regunathan's laboratory's research interests have been the molecular and functional characterization of neurotransmitters and their receptors with particular focus in neuropsychiatric disorders. Recently, during attempts to identify endogenous ligand for imidazoline receptors, agmatine (decarboxylated arginine) was discovered in brain and other tissues. Since then, several studies have shown that agmatine exhibits various biological effects in mammalian brain and other tissues. Dr. Regunathan's laboratory currently focuses on the neurobiological role of this novel amine and its alterations during diseases. We have shown the expression of arginine decarboxylase (ADC), the biosynthetic enzyme, and agmatinase, the degradative enzyme in brain and we are in the process of molecular cloning of ADC. We have also shown that agmatine has potent anti-inflammatory properties and plays a protective role in drugs of abuse.

The current research programs in Dr. Regunathan's laboratory can be divided into following four distinct but inter related projects.

1. The localization and regulation of agmatine biosynthesis in brain: In this project, the objectives are to clone the biosynthetic enzyme, arginine decarboxylase (ADC), to investigate the regulation of ADC in glia as the source of neuronal agmatine and to determine the distribution of agmatine and ADC in brain. The aims of this project are to establish that mammalian ADC is a novel enzyme by molecular cloning, to express ADC in mammalian cells by transient and stable transfection and to determine the tissue/cell specific expression pattern by RNA analysis. Further studies are planned to establish that agmatine is primarily synthesized by ADC in glia and stored in neurons by measuring the activity of ADC in cultured neurons and glial cells, immunocytochemical localization of agmatine and ADC, measuring the activity of ADC in adult rat brain glial cells and synaptosomes, and immunohistochemical localization of ADC and agmatine in rat brain.

2. Anti-inflammatory effects of agmatine: Dr. Regunathan's earlier studies indicated that agmatine is a potent anti-proliferative agent in vascular smooth muscle cells and in brain astrocytes. More recently Dr. Regunathan has observed that agmatine is also effective in blocking the production of pro-inflammatory molecules such as nitric oxide synthase-2 (NOS-2) and tumor necrosis factor (TNF) in glia and macrophages. Although these are distinct actions, one common feature is the signal transduction pathways mediating these responses. Conceivably these agents could interfere with a common signal that mediate proliferation (ERK pathway) or inflammation (38P MAPK pathway). Dr. Regunathan's lab is currently working to identify the signal transduction molecules that are involved in the anti-proliferative/anti-inflammatory actions of agmatine.

3. Neuroprotective effects of agmatine: Agmatine protects neurons against injury in vivo and in vitro. The mechanism of this neuroprotection is not known. Our hypothesis is that agmatine acts at multiple sites to protect neurons/cells against ischemic/excitotoxic injury. One mechanism could be the blockade of ligand gated cation channels including N-methyl-D-aspartate (NMDA) channels. Agmatine could also prevent delayed neuronal degeneration by inhibiting inflammatory responses and as an anti-apoptotic agent. Studies are also in progress that will reveal the mechanisms of actions of agmatine in neuroprotection.

4. Agmatine and opioid system: Since our discovery of agmatine in brain, several studies have shown that agmatine interacts with opioid system to reduce morphine tolerance and withdrawal syndrome and potentiates morphine analgesia. Dr. Regunathan's lab is currently investigating the molecular mechanism of these actions of agmatine as well as the effect of chronic morphine exposure on agmatine biosynthesis in specific brain regions.

Selected Publications

Li, G., Regunathan, S., Barrow, C.J., Eshraghi, J. Cooper, R. and Reis, D.J.: Agmatine: An endogenous clonidine-displacing substance in brain. Science, 263: 966-969, 1994.

Regunathan, S., Youngson, C., Raasch, W., Wang, H. and Reis, D.J.: Imidazoline receptors and agmatine in blood vessels: A novel system inhibiting vascular smooth muscle proliferation. J. Pharmacol. & Exp. Ther., 276: 1272-1282 ,1996.

Galea, E., Regunathan, S., Eliopoulos, V., Feinstein, D.L. and Reis, D.J.: Inhibition of mammalian nitric oxide synthase by agmatine, an endogenous decarboxylated arginine. Biochem. J., 316: 247-249, 1996.

Sastre, M., Regunathan, S., Galea, E. and Reis, D.J.: Agmatinase activity in rat brain: A metabolic pathway for the degradation of agmatine. J. Neurochem., 67: 1761-1765, 1996.

Gonzelez, C., Regunathan, S., Reis, D.J. and Estrada, C.: Agmatine is an endogenous modulator of noradrenergic neurotransmission in the rat tail artery. Br. J. Pharmacol., 119: 677-684, 1996.

Sastre, M., Regunathan, S. and Reis, D.J.: Uptake of agmatine into rat brain synaptosomes: possible role of cation channels. J. Neurochem., 69: 2421-2426, 1997.

Otake, K., Ruggiero, D.A., Regunathan, S., Wang, H., Milner, T.A. and Reis, D.J.: Regional: localization of agmatine in the rat brain: an immunocytochemical study. Brain Res., 787: 1-14, 1998.

Sastre, M., Galea, E., Feinstein, D., Reis, D.J. and Regunathan, S.: Metabolism of agmatine in macrophages: modulation by LPS and inhibitory cytokines. Biochem. J., 330: 1405-1409, 1998.

Regunathan, S. and Reis, D. J.: Characterization of arginine decarboxylase in rat brain and liver: Distinction from ornithine decarboxylase. J. Neurochem., 74: 2201-2208, 2000.

Fairbanks, C.A., Schreiber, K.L., Brewer, K.L., Yu, C.H., Stone, L.S., Kitto, K.F., Nguyen, O.H., Grocholski, B.M., Shoeman, D.W., Kehl, L.J., Regunathan, S., Reis, D.J., Yezieski, R.P. and Wilcox, G.L.: Agmatine reverses pain induced by inflammation, neuropathy and spinal cord injury. Proc. Natl. Acad. Sci., 97: 10584-10589, 2000.

Gorbatyuk, O.S., Milner, T.A., Wang, G., Reis, D.J. and Regunathan, S.: Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei. Exp. Neurology., 171: 235-245, 2001.

Wang, G., Gorbatyuk, O.S., Dayanithi, G., Wang, J., Ouyang, W., Milner, T.A., Regunathan, S. and Reis, D.J.: Evidence for endogenous agmatine in hypothalamo-neurohypophysial tract and its specific modulation on Ca++ channels and neuropeptide release. Brain Res., 932:25-36, 2002.

Arcioglu-Kartal, F. and Regunathan, S.: Effect of chronic morphine treatment of the biosynthesis of agmatine in rat brain and other tissues. Life Sciences, 71: 1695-1701, 2002.

Zhu, M.-Y., Piletz, J.E., Harlaris, A. and Regunathan, S.: Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells. Cellular & Molecular Neurobiology, (in press).