Abstract

Now days, there is a major drug abuse problem worldwide. In the USA, opioids and other abused drugs like amphetamine derivatives (e.g., “crystal meth” and methyl-methamphetamine [MMA]) are causing approximately 75,000 deaths each year with a growing number of strokes among the youth (16-40 years of age). The mechanisms for these strokes and their prevention and treatment have remained elusive. Our laboratories have been investigating the causes and potential treatments for substance abuse-induced strokes in animals and human subjects since the mid-1970’s. Below we review our studies with both “crystal meth” and MMA using a variety of “state-of-the-art” biophysical, biochemical and molecular techniques. Our results, so far, indicate that both “crystal meth” and MMA cause severe vasospasms of microcirculatory blood vessels in the brain cerebral and medullary circulations as evidenced with direct in-vivoquantitative TV microscopic observations (at magnifications >6,000x). Concomitant with these vasospasms, we noted adhesion of leukocytes, monocytes and platelets to the endothelial cell walls followed by rupture of post capillary venules with emigration of red blood cells, monocytes, leukocytes and macrophages into the perivascular tissue spaces with increased dose of the amphetamine derivatives. Use of ³¹P-nuclear magnetic resonance spectroscopy and near-infrared spectroscopy indicated reductions in brain intracellular ATP, ADP, PCr, and pH with concomitant elevation in intracellular P_i and reduction in blood oxyhemoglobin and mitochondrial cytochrome oxidase aa₃. Chronic “crystal meth” or MMA resulted in upregulation of both NF-kB and the proto-oncogenes c-fos and c-jun. Chronic administration of either “crystal meth” or MMA resulted in several epigenetic modifications: 1, acetylation of histone H3, 2. methylation of DNA, 3. upregulation of certain micro-RNAs, and 4. downregulation of telomerases.

Keywords

crystal meth, leukocytes, monocytes, platelets, methamphetamine