Joseph L. Borowitz, Ph.D. Professor of Pharmacology Phone: (765) 494-1407 Fax: (765) 494-1414 E-mail: borowitz@purdue.edu Full directory listing

Specialization: Neurotoxicology

Education

Research: Neurotoxicology

Cyanide has long been known for its extreme toxicity and is of concern as an environmental hazard. Our laboratory has recently discovered that cyanide is produced in brain tissue. Rat brain concentration is estimated to be 7 micromolar. Treatment with morphine doubles brain cyanide 15 min after ip administration. Pretreatment with the morphine antagonist, naloxone abolishes the response. Similar results are obtained in a cultured neuronal model (rat pheochromocytoma, PC12 cells).

Cyanide levels for hypothalamus and hippocampus are above that for cerebral cortex. Cyanide generation may be more active in certain brain areas. Studies on the mechanism of cyanide generation reveal that an oxidative process is involved similar to that proposed for cyanide production in white blood cells. A blocker of myeloperoxidase inhibits cyanide generation and lowers cyanide concentrations in rat brain to undetectable levels. This inhibitor also blocks the increase in brain cyanide caused by morphine. Furthermore, glycine, which enhances cyanide production in white blood cells, also increases cyanide generation in PC12 cells. It appears that an oxidative process involving myeloperoxidase and glycine results in cyanide production in neuronal tissue as well as in white blood cells.

Cyanide can enhance neurotransmitter release and may function as a gaseous neuromodulator similar to nitric oxide. However the physiological and pathological significance of brain cyanide remains to be defined.

Our "Neurotox Lab" has also studied trimethyltin (TMT), a chemical used in the manufacture of plastics and silicon rubber. This substance is extremely neurotoxic and causes a complex syndrome including delerium, memory defects, stuttering, epileptic seizures and depression. The neurons involved in memory are especially sensitive and humans exposed to TMT show marked learning impairment, which greatly affects their lives. Using cultured brain cells and appropriate blocking agents, we have shown that TMT kills neurons by at least two mechanisms, one involving oxidative stress and the other a non-oxidative process. We also showed that when brain neurons are cultured with astrocytes, TMT-induced damage is attenuated, possibly by an antioxidant action of astrocytes. Further work needs to be done to clarify TMT's neurotoxic mechanisms.

Representative Publications

Y. Shou, P.G. Gunasekar, J.L. Borowitz, and G.E. Isom, "Cyanide-induced apoptosis involves oxidative stress-activated NF-kappaB in cortical neurons," Toxicol. Appl. Pharmacol. 164, 196-205 (2000).

L. Li, P.G. Gunasekar, J.L. Borowitz, and G.E. Isom, "Muscarinic receptor-mediated pyridostigmine-induced neuronal apoptosis," Neurotoxicology 21, 541-552 (2000).

P.G. Gunasekar, J.L Borowitz, J.J. Turek, D.A. VanHorn, and G.E. Isom, "Endogenous generation of cyanide in neuronal tissue: Involvement of a peroxidase system," J. Neurosci. Res. 61, 570-575 (2000).

P. Sun, S. Rane, P. Gunasekar, J. Borowitz, and G. Isom, "Cyanide interaction with redox modulatory sites enhances NMDA receptor responses," J. Biochem. Mol. Toxicol. 13, 253-259 (1999).

E.M. Mills, P.G. Gunasekar, J.L. Borowitz, and G.E. Isom, "Differential susceptibility of brain areas to cyanide involves different modes of cell death," Toxicol. Appl. Pharmacol. 156, 6-16 (1999).

P.G. Gunasekar, J.L. Borowitz, and G.E. Isom, "Cyanide-induced generation of oxidative species: Involvement of the nitric acid synthase and cyclooxygenase-2," J. Pharmacol. Exp. Ther. 285, 236-241 (1998).

J.L. Borowitz, P.G. Gunasekar, and G.E. Isom, "Hydrogen cyanide generation by mu-opiate receptor action: Possible neuromodulatory role of endogenous cyanide," Brain Res. 768, 294-300 (1997).

P.G. Gunasekar, P. Sun, A G. Kanthasamy, J.L. Borowitz, and G. E. Isom, "Cyanide-induced Neurotoxicity Involves Nitric Oxide and Reactive Oxygen Species Generation Following NMDA Receptor Activation," J. Pharmacol. Exptl. Therapeut., 277, 150-155 (1996).

P. Sun, J.L. Borowitz, A.G. Kanthasamy, M. Kane, P.G. Gunasekar, and G.E. Isom, "Antagonism of Cyanide Toxicity by Isosorbide Dinitrate: Possible Role of Nitric Oxide," Toxicology, 104, 105-111 (1995).

A.G. Kanthasamy, G.E. Isom, and J.L. Borowitz, "Role of Intracellular Cd2+ in Catecholamine Release and Lethality in PC12 Cells," Tox. Letters, 81, 151-157 (1995).