Recurrent Serotonin Syndrome After Ketamine-assisted Electroconvulsive Therapy: A Case Report and Review of the Literature.

Serotonin (5-HT) syndrome (SS) consists of changes in mental status as well as autonomic and neuromuscular changes. Though not well understood, serotonergic pathways have been implicated in the mechanism of action of electroconvulsive therapy (ECT). Ketamine has been used as an induction agent in ECT and as therapy for treatment-resistant depression. Utilizing a case report and literature review, we explored the underlying serotonergic mechanisms of ECT and ketamine by which a syndrome of serotonin toxicity may be precipitated. We describe the case of a 72-year-old woman who developed recurrent SS on 2 occasions in similar circumstances involving the administration of ketamine for ECT. In our literature review, we found 5 cases in which SS was associated with ECT and 1 case linking ketamine to SS. There is emerging evidence that the mechanism of ECT involves 5-HT1A and 5-HT2A receptors, the same receptors that are involved in SS. ECT can transiently increase the permeability of the blood-brain barrier, leading to increased levels of antidepressants in the brain. ECT can, therefore, enhance 5-HT transmission and the likelihood of SS in the presence of serotonergic agents. The effect of ketamine on 5-HT transmission is mediated by the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Ketamine increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid activity in the medial prefrontal cortex, which leads to downstream 5-HT release through glutamate. Through this mechanism, ketamine can increase 5-HT transmission, leading to SS. To our knowledge, this is the only case report of recurrent SS with concurrent use of ECT and ketamine. As ketamine is frequently used in ECT and many patients undergoing ECT are on serotonergic medications, it is important to recognize ketamine as a potential risk factor for SS. There is no evidence for added efficacy when combining ECT and ketamine. Thus, one should proceed with caution when combining these treatments. The burgeoning use of ketamine in ambulatory settings makes it necessary to elucidate the risks, which we discuss further. More research is needed into the mechanisms of ketamine and ECT, specifically how the combination of these treatments influence 5-HT levels.

Hepatic Adaptations to a High Fat Diet in the MRL Mouse Strain are Associated with an Inefficient Oxidative Phosphorylation System.

The MRL mice are resistant to a 12-week high fat diet (HFD) feeding protocol, with the proximal cause being an increased basal pAMPKT172 expression in the skeletal muscle. Here, we test if this lack of pathology extends to the liver at both the tissue and cellular levels and its correlation to pAMPKT172 levels. MRL and B6 mice were subjected to 12 weeks of diet intervention and tissues were either fixed for histology or snap-frozen for further processing (n= 3-6, per group). The HFD MRL mice remain insulin and glucose sensitive after 12 weeks of HFD. This phenomenon is correlated to increased liver pAMPKT172. The HFD-fed B6 control strain demonstrates the opposite trend with decreased pAMPKT172 expression after the HFD period. We have found further evidence of differential MRL metabolic adaptations. These differences include reduced glycogen content, reduced ectopic fat storage, and increased expression of Complex II (CII) and Complex V of the Electron Transport Chain (ETC). Whereas, B6 HFD control show unchanged glycogen content, increased ectopic fat and increased expression of Complex I and Complex V of the ETC. Taken together, the MRL adaptations point to an inefficient energy-producing phenotype that leads to glycogen depletion and attenuation of ectopic fat as secondary consequences with AMPK as the signaling mediator of these HFD- hepatic adaptations.

Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling.

BACKGROUND: Cardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM). It arises even in patients with normoglycemia (glycosylated hemoglobin, A1C ≤7 %). As obesity and T2DM are approaching epidemic levels worldwide, the cardiomyopathy associated with these diseases must be therapeutically addressed. We have recently analyzed the systemic effects of a 12-week high fat diet (HFD) on wild type mice from the C57Bl/6 (B6) strain and the wild type super-healing Murphy Roths Large (MRL) mouse strain. The MRL HFD mice gained significantly more weight than their control diet counterparts, but did not present any of the other usual systemic T2DM phenotypes. METHODS: Cardiac pathology and adaptation to HFD-induced obesity in the MRL mouse strain compared to the HFD C57Bl/6 mice were thoroughly analyzed with echocardiography, histology, qPCR, electron microscopy and immunoblots. RESULTS: The obese HFD C57Bl/6 mice develop cardiac hypertrophy, cardiomyocyte lipid droplets, and initiate an ineffective metabolic adaptation of an overall increase in electron transport chain complexes. In contrast, the obese HFD MRL hearts do not display hypertrophy nor lipid droplets and their metabolism adapts quite robustly by decreasing pAMPK levels, decreasing proteins in the carbohydrate metabolism pathway and increasing proteins utilized in the ß-oxidation pathway. The result of these metabolic shifts is the reduction of toxic lipid deposits and reactive oxygen species in the hearts of the obese HFD fed MRL hearts. CONCLUSIONS: We have identified changes in metabolic signaling in obese HFD fed MRL mice that confer resistance to diabetic cardiomyopathy. The changes include a reduction of cardiac pAMPK, Glut4 and hexokinase2 in the MRL HFD hearts. Overall the MRL hearts down regulate glucose metabolism and favor lipid metabolism. These adaptations are essential to pursue for the identification of novel therapeutic targets to combat obesity related cardiomyopathy.

The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia.

OBJECTIVE: Due to their previously identified naturally and chronically increased levels of skeletal muscle pAMPK we hypothesized and now investigated whether the MRL/MpJ (MRL) mice would be resistant to high fat diet (HFD)-induced metabolic changes. MATERIALS/METHODS: Three-week old male MRL and control C57Bl/6 (B6) mice were randomly assigned to 12weeks of high fat diets (HFD) or control diets (CD). Weekly animal masses and fasting blood glucose measurements were acquired. During the last week of diet intervention, fasted animals were subjected to glucose and insulin tolerance tests. At harvest, tissues were dissected for immunoblots and serum was collected for ELISA assays. RESULTS: The MRL mouse strain is known for its ability to regenerate ear punch wounds, cardiac cryoinjury, and skeletal muscle disease. Despite gaining weight and increasing their fat deposits the MRL mice were resistant to all other indicators of HFD-induced metabolic alterations assayed. Only the HFD-B6 mice displayed fasting hyperglycemia, hyperinsulinemia and hypersensitivity to glucose challenge. HFD-MRL mice were indistinguishable from their CD-MRL counterparts in these metrics. Skeletal muscles from the HFD-MRL contained heightened levels of pAMPK, even above their CD counterparts. CONCLUSIONS: The MRL mouse strain is the first naturally occurring mouse strain that we are aware of that is resistant to HFD-induced metabolic changes. Furthermore, the increased pAMPK suggests a proximal mechanism for these beneficial metabolic differences. We further hypothesize that these metabolic differences and plasticity provide the basis for the MRL mouse strain's super healing characteristics. This project's ultimate aim is to identify novel therapeutic targets, which specifically increase pAMPK.

Increased AMP-activated protein kinase in skeletal muscles of Murphy Roth Large mice and its potential role in altered metabolism.

Abstract Wild-type Murphy Roth Large (MRL) mice have long been investigated for their superior healing ability when subjected to various wound and disease models. Despite this long history, the mechanisms causing their extraordinary healing ability remain undefined. As we have recently demonstrated that MRL mice with muscular dystrophy are resistant to the associated fibrosis and the Heber-Katz group has demonstrated MRL mitochondrial mutations, we decided to investigate the skeletal muscle metabolic characteristics of the MRL mouse strain compared to the commonly utilized C57BL/6J control mouse strain. We now have evidence demonstrating an altered metabolism in the MRL quadriceps, triceps brachii, and diaphragm of 8-week-old animals compared to tissues from control animals. The MRL skeletal muscles have increased activated phosphorylated AMP-activated protein kinase (pAMPK). The increased pAMPK signaling coincides with increased skeletal muscle mitochondrial content. These metabolic changes may compensate for insufficient oxidative phosphorylation which is demonstrated by altered quantities of proteins involved in oxidative phosphorylation and ex vivo metabolic investigations. We also demonstrate that the MRL muscle cells have increased metabolic physiologic reserve. These data further the investigations into this important and unique mouse strain. Why the MRL mice have increased pAMPK and how increased pAMPK and the resultant metabolic alterations affect the healing ability in the MRL mouse strain is discussed. Understanding the molecular mechanisms surrounding the super healing characteristics of these mice will lead to relevant clinical intervention points. In conclusion, we present novel data of increased mitochondrial content, pAMPK, and glycolytic indicators in MRL skeletal muscles.