Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication Faith C. H. Li1,2, Jiin-Cherng Yen1, Samuel H. H. Chan2, Alice Y. W. Chang 2 * 1 Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan, Republic of China, 2 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China Abstract Background: Whereas sudden death, most often associated with cardiovascular collapse, occurs in abusers of the psychostimulant methamphetamine (METH), the underlying mechanism is much less understood. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. We tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by lethal doses of METH. Methodology/Principal Findings: Survival rate, cardiovascular responses and biochemical or morphological changes in RVLM induced by intravenous administration of METH in Sprague-Dawley rats were investigated. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of arterial pressure or heart rate and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion and necrotic cell death in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO; or an oxidative stress- induced necrotic cell death inhibitor, IM-54. Conclusion: We conclude that sustained anoxia and cessation of local blood flow that leads to bioenergetics failure and oxidative stress because of mitochondrial dysfunction, leading to acute necrotic cell death in RVLM underpins cardiovascular collapse elicited by lethal doses of METH. Citation: Li FCH, Yen J-C, Chan SHH, Chang AYW (2012) Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication. PLoS ONE 7(1): e30589. doi:10.1371/journal.pone.0030589 Editor: Ferenc Gallyas, University of Pecs Medical School, Hungary Received October 27, 2011; Accepted December 19, 2011; Published January 19, 2012 Copyright: 2012 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Chang Gung Medical Foundation and the Chang Gung Memorial Hospital, Taiwan, Republic of China (Grant number CMRPG891071 to A.Y.W.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cgmf.kmc@gmail.com Introduction The psychostimulant methamphetamine (N-methyl-1-phenyl- propan-2-amine; METH) is a cationic lipophilic molecule with potent actions on the central and sympathetic nervous system, and affects neurochemical mechanisms responsible for regulating attention, mood and emotional responses associated with alertness or alarm conditions, body temperature, blood pressure, heart rate and appetite [1]. Because it heightens alertness and energy, induces euphoria, enhances self-respect and increases sexual pleasure, METH possesses high potential for abuse and addiction and has become a serious societal problem worldwide [2,3]. At issue is that METH abusers have to constantly increase dosing to sustain an elevated mood and libido and a decrease in appetite and fatigue. As such, METH intoxication is a common cause of death within the abuse population [4,5]. Worse still, continuous use at larger doses results in not only acute METH poisoning but also METH-induced sudden death [6–8]. Death from METH abuse has been associated with cardiovas- cular collapse, cerebral edema and diffuse petechial hemorrhage in brain [6,9]. In particular, severe hypotension and bradycardia are critical omens in patients who exhibit acute METH intoxication [7,9]. Because of the irreversible cardiovascular failure that rapidly leads to death, treatment for METH intoxication is generally difficult [8], with 100% mortality despite intensive care in a hospital setting [9]. The prevalence of METH-induced cardiovas- cular collapse that leads to death notwithstanding, the underlying mechanism is much less understood. Three important clues on delineating the mechanisms that may underlie METH-induced cardiovascular collapse arise from studies by our laboratory and others on brain death. The first clue comes from the prognosis that asystole invariably takes place, PLoS ONE | www.plosone.org 1 January 2012 | Volume 7 | Issue 1 | e30589