salicylates and Cognition-Disorders

Although topical salicylates are widely used, toxicity from this route is rare.. We present an unusual case of salicylism from a topical salicylate preparation in an 80-year-old woman. The patient was admitted to the dermatology service with a diagnosis of erythroderma and was treated with salicylate containing ointments. After six days of treatment the patient became confused and paranoid. A serum salicylate was 3.36 mmol/L (46 mg/dL). The patient was admitted to the intensive care unit were she was rehydrated and treated with bicarbonate and activated charcoal.. Her serum salicylate fell to 1.90 mmol/L (26 mg/dL) over a two day period and she regained a normal mental status.

Topics: Acidosis; Administration, Topical; Aged; Aged, 80 and over; Cognition Disorders; Confusion; Dermatitis, Exfoliative; Drug Monitoring; Female; Humans; Keratolytic Agents; Paranoid Disorders; Risk Factors; Salicylates; Salicylic Acid; Sleep Stages

Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. We examined whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. We exposed 7-day-old rats to GA with or without either EUK-134, a synthetic ROS scavenger, or R(+) pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity. We found that GA causes extensive ROS upregulation and lipid peroxidation, as well as mitochondrial injury and neuronal loss in the subiculum. As compared to rats given only GA, those also given PPX or EUK-134 had significantly downregulated lipid peroxidation, preserved mitochondrial integrity, and significantly less neuronal loss. The subiculum is highly intertwined with the hippocampal CA1 region, anterior thalamic nuclei, and both entorhinal and cingulate cortices; hence, it is important in cognitive development. We found that PPX or EUK-134 co-treatment completely prevented GA-induced cognitive impairment. Because mitochondria are vulnerable to GA-induced developmental neurotoxicity, they could be an important therapeutic target for adjuvant therapy aimed at improving the safety of commonly used GAs.

Topics: Age Factors; Analysis of Variance; Anesthesia, General; Animals; Animals, Newborn; Antioxidants; Benzothiazoles; Brain; Cognition Disorders; Dinoprost; Dose-Response Relationship, Drug; Drug Administration Schedule; Exploratory Behavior; Female; Lipid Peroxidation; Male; Maze Learning; Midazolam; Mitochondria; Organometallic Compounds; Oxygen; Pramipexole; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salicylates; Time Factors; Up-Regulation

Continuous decline in cognitive performance accompanies the natural aging process in humans, and multiple studies in both humans and animal models have indicated that this decrease in cognitive function is associated with an age-related increase in oxidative stress. Treating aging mammals with exogenous free radical scavengers has generally been shown to attenuate age-related cognitive decline and oxidative stress. The present study assessed the effectiveness of the superoxide dismutase/catalase mimetics EUK-189 and EUK-207 on age-related decline in cognitive function and increase in oxidative stress. C57/BL6 mice received continuous treatment via osmotic minipumps with either EUK-189 or EUK-207 for 6 months starting at 17 months of age. At the end of treatment, markers for oxidative stress were evaluated by analyzing levels of free radicals, lipid peroxidation and oxidized nucleic acids in brain tissue. In addition, cognitive performance was assessed after 3 and 6 months of treatment with fear conditioning. Both EUK-189 and EUK-207 treatments resulted in significantly decreased lipid peroxidation, nucleic acid oxidation, and reactive oxygen species (ROS) levels. In addition, the treatments also significantly improved age-related decline in performance in the fear-conditioning task. Our results thus confirm a critical role for oxidative stress in age-related decline in learning and memory and strongly suggest a potential usefulness for salen-manganese complexes in reversing age-related declines in cognitive function and oxidative load.

Topics: Aging; Animals; Brain; Catalase; Cognition Disorders; Conditioning, Classical; Free Radicals; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Molecular Mimicry; Nootropic Agents; Nucleic Acids; Organometallic Compounds; Oxidation-Reduction; Oxidative Stress; Random Allocation; Reactive Oxygen Species; Salicylates; Superoxide Dismutase

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Axons; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Agents; Cognition Disorders; Cytokines; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroglia; Plaque, Amyloid; Proto-Oncogene Proteins c-fos; Salicylates

This article from Coma et al. shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX-1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Central Nervous System Agents; Cognition Disorders; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Humans; Membrane Proteins; Mice; Salicylates

Is universal screening of acetaminophen (APAP) and salicylate (SAL) necessary in patients with a suicidal ingestion or an altered mental status and suspected ingestion? This descriptive, retrospective chart review in an emergency department in a large urban county hospital examined all patients who presented with a history of suicidal ingestion or an altered mental status with a strong suspicion of ingestion from January 1992 through October 1993. APAP and SAL serum levels were measured in 1,820 patients, and charts of patients with APAP serum levels of > 1 microgram/mL or SAL serum levels of > 1 mg/dL were reviewed. The patient's history of ingesting APAP or SAL was recorded, as well as the clinician's interpretation of that level. Sixteen charts were not available. APAP levels of > 1 microgram/mL were found in 175 (9.6%) patients, 120 (6.5%) of whom were APAP history-positive and 55 (3%) APAP history-negative. None of the APAP history-negative group required therapy with N-acetylcysteine. Eight (0.3%) of the APAP history-negative group had potentially toxic levels of > 50 micrograms/mL. SAL levels of > 1 mg/dL were found in 155 (8.5%) patients, 44 (2.5%) of whom were SAL history-positive and 111 (6%) SAL history-negative. Three patients were SAL history-negative but had a significant chronic SAL intoxication. All these patients presented with an altered mental status and had an anion gap of > 20 mEq/L. Universal screening found that 0.3% of suicidal ingestions had a potentially toxic APAP intoxication not suggested by history. This incidence of infrequent but potentially life: threatening overdose should prompt clinicians to screen all of their patients with a suspected ingestion. Salicylate screening found that 0.16% of suicidal ingestions had a toxic SAL intoxication not suggested by history, although such intoxication should be suggested by an elevated anion gap and an altered mental status. Since this less severe intoxication is less frequent and usually suggested by commonly obtained laboratory data, universal screening is not indicated, but a more selective approach to screening could be taken.

Topics: Acetaminophen; Acid-Base Equilibrium; Adult; Aged; Analgesics, Non-Narcotic; Cognition Disorders; Drug Overdose; Female; Humans; Liver Function Tests; Male; Medical History Taking; Middle Aged; Poisoning; Retrospective Studies; Salicylates; Suicide, Attempted