glyceryl-2-arachidonate and Cognition-Disorders

Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cognition; Cognition Disorders; Dronabinol; Endocannabinoids; Glycerides; Hippocampus; Humans; Memory; Neuronal Plasticity; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Synaptic Transmission; TOR Serine-Threonine Kinases

Endocannabinoids (ECs) are rapidly acting immune-modulatory lipid-signaling molecules that are important for adaptation to stressful and aversive situations.They are known to interact with glucocorticoids and other stress-responsive systems. Maladaptation to acute or chronic stress represents a major risk factor for the development of psychiatric disorders. In the present study, we administered stress doses of hydrocortisone ina prospective, randomized, placebo-controlled double blind study in patients undergoing cardiac surgery (CS) to examine the relationship between the use of glucocorticoids, plasma EC levels, and the occurrence of early postoperative cognitive dysfunction (delirium) and of later development of depression.. We determined plasma levels of the ECs anandamide and 2-arachidonoylglycerol (2-AG) in CS patients of the hydrocortisone (n=56) and the placebo group(n=55) preoperatively, at postoperative day (POD) 1, at intensive care unit discharge, and at 6 months after CS(n=68). Postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association IVth Edition (DSM-IV) criteria, and depression was determined by validated questionnaires and a standardized psychological interview (Structured Clinical Interview for DSM-IV).. Stress doses of hydrocortisone did not affect plasma EC levels and the occurrence of delirium or depression. However, patients who developed deliriumon POD 1 had significantly lower preoperative 2-AG levels of the neuroprotective EC 2-AG (median values, 3.8 vs. 11.3ng/ml; p=0.03). Preoperative 2-AG concentrations were predictive of postoperative delirium (sensitivity=0.70;specificity=0.69; cutoff value=4.9 ng/ml; receiver operating characteristic curve area=0.70; 95 o/o confidence interval=0.54-0.85). Patients with depression at 6 months after CS (n=16) had significantly lower anandamide and 2-AG levels during the perioperative period.. A low perioperative EC response may indicate an increased risk for early cognitive dysfunction and long-term depression in patients after CS. Glucocorticoids do not seem to influence this relationship.

Topics: Aged; Arachidonic Acids; Cognition Disorders; Depression; Double-Blind Method; Endocannabinoids; Female; Follow-Up Studies; Glucocorticoids; Glycerides; Heart Diseases; Humans; Hydrocortisone; Luria-Nebraska Neuropsychological Battery; Male; Middle Aged; Outcome Assessment, Health Care; Polyunsaturated Alkamides; Postoperative Complications; Prospective Studies; Psychiatric Status Rating Scales; Psychometrics; Statistics, Nonparametric

In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.

Topics: Aged; Animals; Arachidonic Acids; Cognition Disorders; Corticotropin-Releasing Hormone; Endocannabinoids; Enzyme Inhibitors; Female; Glycerides; Humans; Iodoacetates; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mood Disorders; Osteoarthritis; Prefrontal Cortex; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Glucocorticoid

Neuropathological, animal, and cell culture studies point to a role for the body's own endogenous cannabinoids (eCBs) system in Alzheimer's disease (AD) pathology and treatment. To date, no published studies have investigated the potential utility of circulating eCBs as diagnostic biomarkers for AD or the impact of central eCBs on cognition.. In comparison with healthy controls, there were no significant differences in measured eCB concentrations in plasma samples from patients with AD. Detectable eCBs in cerebrospinal fluid (CSF) had no relationship to cognitive performance in healthy controls at risk for AD. In pooled plasma samples, an inverse correlation was observed between plasma levels of the eCB 2-AG (2-arachidonoylglycerol) and TNF-alpha (r = -0.41, p < 0.02).. These results suggest that circulating endocannabinoids do not have utility as diagnostic biomarkers for AD and do not have a robust correlation with cognitive performance. Circulating levels of 2-AG may downregulate TNF-alpha production.

Topics: Aged; Alzheimer Disease; Arachidonic Acids; Biomarkers; Cannabinoid Receptor Modulators; Case-Control Studies; Cognition Disorders; Cohort Studies; Down-Regulation; Endocannabinoids; Female; Glycerides; Humans; Male; Tumor Necrosis Factor-alpha

Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries.. DFU [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2(5)H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model.. DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injury-induced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuroprotective endocannabinoid, in the injured brain.. These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Ataxia; Brain Chemistry; Brain Injuries; Cognition Disorders; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Drug Administration Schedule; Drug Evaluation, Preclinical; Eicosanoids; Endocannabinoids; Enzyme Induction; Exploratory Behavior; Furans; Glycerides; Male; Maze Learning; Neuroprotective Agents; Premedication; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Recovery of Function; Reflex, Abnormal

The discovery of blood platelet's ability to release 2-arachidonoyl-glycerol (2-AG), a highly lipophilic cannabinoid molecule may usher in a radical change in our understanding of how the vascular system interacts with the brain. This paper primarily extends Kayai's second messenger imbalance theory of schizophrenia, suggesting that 2-AG is the unidentified second messenger system that Kayai theorized was unbalanced in schizophrenia; furthermore, that a chronic over-release of 2-AG by platelets may be a causal factor in the cognitive deficits associated with negative symptom schizophrenia. Finally, platelet release of 2-AG may also be the causal agent in the cognitive deficits associated with states of high arousal, shock and in other conditions that feature heightened platelet activation. As such, heightened platelet activation may be a profoundly important vector for changing endogenous cannabinoid levels in the brain.

Topics: Antipsychotic Agents; Arachidonic Acids; Blood Platelets; Cannabinoid Receptor Modulators; Cannabinoids; Cognition Disorders; Dopamine; Endocannabinoids; Glycerides; Humans; Marijuana Smoking; Schizophrenia