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12.03.2013

Researchers Discover Potential Target of Methamphetamine Brain Disruption

Methamphetamine is a highly addictive stimulant associated with serious health and psychiatric conditions, as well as the transmission of infectious diseases such as HIV/AIDS and hepatitis. Although methamphetamine abuse is one of the fastest growing drug problems, affecting more than 35 million users worldwide, there are no effective pharmacological treatments for neurotoxicity or dependency induced by this drug.

A group of researchers, led by the Miller School’s Michal Toborek, M.D., Ph.D., Leonard M. Miller Professor of Biochemistry and Molecular Biology, and Minseon Park, Ph.D., research assistant professor of biochemistry and molecular biology, have uncovered a method to prevent one of the drug’s primary effects on the brain. The findings were published in the November 15 edition of The Journal of Biological Chemistry and were selected as the cover article.

Methamphetamine abuse results in an impairment of vascular functions and disruption of the blood-brain barrier (BBB), which has been established as one of the most prominent events of Meth toxicity. Toborek, Park and the team of scientists discovered a new mechanism in the disruption of the BBB integrity by methamphetamine, opening the door to a potentially effective therapy. Their findings are based on removing a protein called occludin from cellular membranes in a process dependent on actin polymerization, the growth and conversion of actin filaments, thin flexible fibers in the cell.

The blood-brain barrier separates brain tissue from substances circulating in the blood and maintains central nervous system homeostasis. Actin polymerization is involved in various cellular processes, allowing reorganization of the cytoskeleton when subjected to environmental stress.

The scientists proposed that inhibiting actin polymerization can serve as one of the therapeutic targets to protect against alterations of the blood-brain barrier by methamphetamine. The actin-related protein 2/3 (Arp2/3) is a principal actin-polymerizing factor, stimulated by several regulatory proteins.

Researchers believe Meth induces Arp2/3 activation, which in turn stimulates a series of actin nucleation and polymerization, changes that result in a reduction of the protein occludin. “The change in occludin appears to disrupt the blood-brain barrier,” said Toborek, who is also Vice Chair of Research.

The scientists took the next step, blocking actin nucleation by using a small molecule, CK-666, a specific inhibitor of Arp2/3 processes. “Taking this step,” said Park, “protected against Meth-induced occludin reduction.”

In the study, Toborek wrote that the findings indicate “the importance of the actin cytoskeleton in regulating occludin levels and maintaining endothelial integrity.”
Sylvia Daunert, Ph.D., Pharm.D., M.S., Professor and Lucille P. Markey Chair of Biochemistry and Molecular Biology, said Toborek and Park elucidated the role of two key proteins, actin and occludin, in the blood-brain barrier process. “Their results give new insights into the mechanisms of blood-brain barrier disruption and – even more importantly — provide the means to repair it, thus offering significant translational implications,” Daunert said.

Other members of their team included Hyun-Jung Kim, M.S., research associate in the Department of Biochemistry and Molecular Biology, and Brian Lim and Adam Wylegala, both from the University of Kentucky College of Medicine.

Disruption of the blood-brain barrier occurs in a variety of neurological diseases including multiple sclerosis, meningitis, encephalitis, stroke, hypertension, diabetes, and Alzheimer’s disease. Therefore, the findings by Park and Toborek are not limited to methamphetamine-induced toxicity but are applicable to several other neurodegenerative brain disorders.

The selection of the study as a “Paper of the Week” puts it in the top 2 percent in importance and “reflects the strength and the quality of discovery research performed here,” said Daunert.

The study was funded by the NIH. In addition, Dr. Park is a recipient of a grant from the Miami Center for AIDS Research.

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