Serotonin Toxicity and Urinary Analgesics: A Case Report and Systematic Literature Review of Methylene Blue-Induced Serotonin Syndrome.

BACKGROUND: Serotonin syndrome (SS) is a potentially serious side effect of serotonergic drugs. Cases of SS have been reported from the administration of methylene blue (MB), an agent with monoamine oxidase inhibiting properties. To date, the reported cases of MB-induced SS have all been with MB given parenterally. We report a case induced by the initiation of a MB-containing oral agent. METHODS: A case of SS felt to be induced by the initiation of an MB-containing orally-administered urinary analgesic, started in a patient concurrently treated with multiple serotonergic drugs, is presented. A systematic literature review of MB-induced SS follows. The review consisted of searches in MEDLINE databases using the key terms "methylene blue" and "serotonin syndrome". The authors read all abstracts, and articles related to MB and serotonin toxicity; non-associated articles were discarded. Results are summarized. RESULTS: 23 manuscripts were identified, resulting in 50 unique cases of MB-induced SS. The majority of cases were related to peri-operative use of MB in parathyroidectomies or for the treatment of vasoplegic shock. All cases were associated with MB given parenterally. Concurrent treatment with serotonergic antidepressants was described in all 50 cases. Symptoms of SS ranged from mild to severe. One fatality was reported. CONCLUSIONS: Methylene blue can induce SS, felt to be secondary to MAOI properties. Although previous reports have exclusively been associated with MB given via parental administration, our case suggests that SS can be induced by oral administration of MB-containing agents.

Leptin and cognition.

BACKGROUND: Leptin has been reported to have positive effects on cognition but has not been studied in a population-based sample or stratified by race or gender. METHODS: Leptin and fat mass were measured in 2,731 subjects, including 50% African Americans. Eight years later, subjects were administered the Montreal Cognitive Assessment (MoCA). Demographic factors and baseline measures, including a deficiency in leptin or levels in excess of what was predicted by fat, were investigated to see which predicted cognitive performance. RESULTS: There was a statistical trend for lower leptin levels to be associated with higher cognitive scores. Once stratified by race and gender, excessive leptin was associated with lower MoCA total scores and delayed recall domain score for black men, but white men demonstrated a reverse relationship. CONCLUSION: Excess leptin appears to have differential effects on delayed recall in black and white men.

Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats.

Club drug abuse is a growing problem in the United States. Beyond addiction and toxicity are endocrine effects which are not well characterized. Specifically, the changes in appetite following exposure to drugs of abuse are an interesting but poorly understood phenomenon. Serum hormones such as leptin, ghrelin, growth hormone (GH), and neuropeptide-Y (NP-Y) are known to affect appetite, but have not been studied extensively with drugs of abuse. In this work, we examine the effects of club drugs 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) and methamphetamine (METH) (doses of 5, 20 and 40 mg/kg) on serum concentrations of these hormones in adult male Sprague-Dawley rats 6, 12, 24 and 48 hours after drug administration. In a dose-dependent manner, MDMA was shown to cause transient significant decreases in serum leptin and GH followed by a base line recovery after 24 hours. Conversely, serum ghrelin increased and normalized after 24 hours. Interestingly, serum NP-Y showed a steady decrease in both treatment of MDMA and METH at different time points and dosages. In humans, abuse of these drugs reduces eating. As evident from these data, acute administration of METH and MDMA had significant effects on different serum hormone levels involved in appetite regulation. Future studies should be performed to see how chronic, low dose drug administration would affect hormone levels and try to answer questions about the physiological mechanisms involved in the anorexic paradigm observed in drug use.

Laparoscopic resection of a virilizing adrenocortical tumor.

Virilizing adrenocortical tumors are rare. Laparoscopic unilateral adrenalectomy with serum androgen surveillance may provide curative treatment for benign, functional adenomas. Herein, we describe a case of laparoscopic resection of a testosterone-producing adrenal tumor in a sixteen-year-old female.

Ecstasy toxicity: a comparison to methamphetamine and traumatic brain injury.

Ecstasy use is a growing problem in the United States. Techniques to demonstrate and characterize the toxicity associated with its use have been limited and employed infrequently. In this study, we compare the deleterious effects of ecstasy use in rats with that of methamphetamine and traumatic brain injury. Specifically, we investigate the degradation of structural proteins alphaII-spectrin and tau by the pro-necrotic calpain and pro-apoptotic caspase systems. Ecstasy-induced neurotoxicity is shown after 24 hours, although to a much lesser extent than that of methamphetamine or traumatic brain injury. Neurotoxicity is still evident after 72 hours. Furthermore, apoptosis of the liver is seen 72 hours after ecstasy use. Use of protease inhibitors may be useful in preventing ecstasy-induced toxicity.

Concurrent calpain and caspase-3 mediated proteolysis of alpha II-spectrin and tau in rat brain after methamphetamine exposure: a similar profile to traumatic brain injury.

Neurotoxicity in rat cortex and hippocampus following acute methamphetamine administration was characterized and compared to changes following traumatic brain injury. Doses of 10, 20, and 40 mg/kg of methamphetamine produced significant increases in calpain- and caspase-cleaved alpha II-spectrin and tau protein fragments, suggesting cell injury or death. Changes in proteolytic products were significantly increased over vehicle controls. Use of fragment specific biomarkers detected prominent calpain-mediated protein fragments in the cortex and hippocampus while caspase-mediated protein fragments were also detected in the hippocampus. Remarkably, proteolytic product increases at the 40 mg/kg dose after 24 h were as high as those observed in experimental traumatic brain injury. Use of calpain and caspase proteolytic inhibitors may be useful in preventing methamphetamine-induced neurotoxicity.

Cognitive impact of lacunar infarcts and white matter hyperintensity volume.

BACKGROUND: Subcortical lacunar infarcts and white matter hyperintensities (WMH) are common neuroradiological findings, but few studies associate between these insults and cognition in a community-dwelling population. METHODS: The Dallas Heart Study is a population-based initiative whose assessments included demographic and clinical findings including brain MRI and the Montreal Cognitive Assessment (MoCA). The presence and number of lacunes in subjects aged over 55 years were assessed by study physicians. The WMH volume was measured by an automated method. The association between the presence and number of lacunar infarcts and of WMH volume with the total MoCA score and subdomains was assessed using linear regression with adjustment for age, gender and self-reported ethnicity. RESULTS: In 609 subjects with valid data, both the presence and the increasing number of lacunes were associated with lower MoCA scores, even after adjusting for demographic variables. The presence of lacunes was also associated with lower scores in the memory, executive and attention subdomains. The WMH volume was not significantly associated with the MoCA score. CONCLUSION: The presence and increasing number of lacunes in midlife is associated with a lower performance in multiple domains of a cognitive screening measure after adjusting for demographic factors.

Differential metabolic effects of saturated versus polyunsaturated fats in ketogenic diets.

Ketogenic diets (KDs) are used for treatment of refractory epilepsy and metabolic disorders. The classic saturated fatty acid-enriched (SAT) KD has a fat:carbohydrate plus protein ratio of 4:1, in which the predominant fats are saturated. We hypothesized that a polyunsaturated fat-enriched (POLY) KD would induce a similar degree of ketosis with less detrimental effects on carbohydrate and lipid metabolism. Twenty healthy adults were randomized to two different weight-maintaining KDs for 5 d. Diets were 70% fat, 15% carbohydrate, and 15% protein. The fat contents were 60 or 15% saturated, 15 or 60% polyunsaturated, and 25% monounsaturated for SAT and POLY, respectively. Changes in serum beta-hydroxybutyrate, insulin sensitivity (S(I)), and lipid profiles were measured. Mean circulating beta-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group (P = 0.0004), compared with 3.1 mg/dl in the SAT group (P = 0.07). S(I) increased significantly in the POLY group (P = 0.02), whereas total and low-density lipoprotein cholesterol increased significantly in the SAT group (both P = 0.002). These data demonstrate that a short-term POLY KD induces a greater level of ketosis and improves S(I), without adversely affecting total and low-density lipoprotein cholesterol, compared with a traditional SAT KD. Thus, a POLY KD may be superior to a classical SAT KD for chronic administration.

Lipids and adipokines as risk factors for Alzheimer's disease.

To determine if measures of adipokines and other blood lipids differentiate between normal controls and persons with Alzheimer's disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 148 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference between leptin and adiponectin levels between normal controls and AD subjects. We were able to confirm observations of lower HDL and higher total and LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein E4 allele distinguished between the two groups.

Psychoproteomic analysis of rat cortex following acute methamphetamine exposure.

Methamphetamine (METH) is recognized as one of the most abused psychostimulants in the United States. METH is an illicit drug that is known to exert neurotoxic effects on both dopaminergic and serotonergic neural systems both in vivo and in vitro. Our laboratory and others have been studying the biochemical mechanisms underlying METH-induced neurotoxicity. Here, we applied a novel psychoproteomic approach to evaluate METH-induced neurotoxicity following acute METH administration (4x10 mg/kg, ip injections every 1 h). Samples of cortical tissue collected 24 h post METH treatment were pooled, processed and analyzed via a selective psychoproteomic platform. Protein separation was performed using our previously established offline tandem cation-anion exchange chromatography-SDS-1D-PAGE platform (CAX-PAGE). Gel bands exhibiting 2 or more fold changes were extracted, trypsinized and subjected to reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) analyses for protein identification. Differential changes of the selected proteins were further confirmed by quantitative immunoblotting. We identified 82 differentially expressed proteins, 40 of which were downregulated and 42 of which were upregulated following acute METH treatment. Proteins that decreased in abundance included collapsin response mediator protein-2 (CRMP-2), superoxide dismutase 1 (SOD 1), phosphatidylethanolamine-binding protein-1 (PEBP-1) and mitogen activated kinase kinase-1 (MKK-1). Proteins that increased in abundance included authophagy-linked microtubule-associated protein light chain 3 (LC3), synapsin-1, and Parkinsonism linked ubiquitin carboxy-terminal hydroxylase-L1 (UCH-L1). Lastly, we used these differentially expressed protein subsets to construct a "psychoproteomic" spectrum map in an effort to uncover potential protein interactions relevant to acute METH neurotoxicity.

Calpain- and caspase-mediated alphaII-spectrin and tau proteolysis in rat cerebrocortical neuronal cultures after ecstasy or methamphetamine exposure.

Abuse of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) and methamphetamine (Meth or Speed) is a growing international problem with an estimated 250 million users of psychoactive drugs worldwide. It is important to demonstrate and understand the mechanism of neurotoxicity so potential prevention and treatment therapies can be designed. In this study rat primary cerebrocortical neuron cultures were challenged with MDMA and Meth (1 or 2 mM) for 24 and 48 h and compared to the excitotoxin N-methyl-D-aspartate (NMDA). The neurotoxicity of these drugs, as assessed by microscopy, lactate dehydrogenase release and immunoblot, was shown to be both dose- and time-dependent. Immunoblot analysis using biomarkers of cell death showed significant proteolysis of both alphaII-spectrin and tau proteins. Breakdown products of alphaII-spectrin (SBDPs) of 150, 145, and 120 kDa and tau breakdown products (TBDPs) of 45, 32, 26, and 14 kDa were observed. The use of the protease inhibitors calpain inhibitor SJA6017 and caspase inhibitors z-VAD-fmk and Z-D-DCB, attenuated drug-induced alphaII-spectrin and tau proteolysis. The calpain inhibitor reduced the calpain-induced breakdown products SBDP145 and TBDP14, but there was an offset increase in the caspase-mediated breakdown products SBDP120 and TBDP45. The caspase inhibitors, on the other hand, decreased SBDP120 and TBDP45. These data suggest that both MDMA and Meth trigger concerted proteolytic attacks of the structural proteins by both calpain and caspase family of proteases. The ability of the protease inhibitors to reduce the damage caused by these drugs suggests that the treatment arsenal could include similar drugs as possible tools to combat the drug-induced neurotoxicity in vivo.

Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA.

Abuse of the club drugs Methamphetamine (Meth) and Ecstasy (MDMA) is an international problem. The seriousness of this problem is the result of what appears to be programmed cell death (PCD) occurring within the brain following their use. This follow up study focused on determining which cell types, neurons and/or glial cells, were affected in the brains of drug-injected rats. Two proteolytic enzyme families involved in PCD, calpains and caspases, were previously shown to be activated and to degrade the brain cytoskeletal associated protein alphaII-spectrin. Using methods employed and confirmed in traumatic brain injury (TBI) studies, rat brain tissues were examined, 24 and 48 h after Meth and MDMA exposure, for the activation of calpain-1 and caspase-3, and their subsequent alphaII-spectrin cleavage breakdown products (SBDPs), SBDP145, and SBDP120, respectively. Based upon our previous studies we know that activated calpain-1 and caspase-3 were up-regulated after drug use as were the levels of their cleaved SBDPs, SBDP145, and SBDP120, respectively, which is indicative of PCD. Here we show that activated calpain-1 and caspase-3 increases could be localized to neurons in the cortex where the products of their cleaved targets were found to be concentrated, particularly, to the axonal regions. These findings support the hypothesis that calpains and caspases mediate PCD in cortical neurons following club drug abuse and, more importantly, appear to contribute to the neuropathology suffered by abusers.