Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

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NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice

Potential Therapeutic Effects of Curcumin, the Anti-inflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases

Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".

Curcumin: The Indian solid gold

Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. This is obvious from a steady year-to-year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non-drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre-clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre-treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self-administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in-depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade.

Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues.

Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death.

Neuroprotective mechanisms of curcumin against cerebral ischemia‐induced neuronal apoptosis and behavioral deficits

Locally recurrent, poorly differentiated carcinoma of the prostate was associated with hypokalemic alkalosis, marked hypernatremia, diabetes mellitus of recent onset, and hyperosmolar syndrome. These findings, with mild hypertension, in the absence of clinical features of Cushing's syndrome, suggested an ectopic ACTH syndrome. Plasma ACTH and cortisol levels were markedly elevated, and failed to suppress in response to either low or high-dose dexamethazone administration. The patient's condition deteriorated rapidly. Autopsy findings included carcinoma extensively infiltrating the prostate with extension to the urinary bladder, and metastases confined to the pelvic nodes and soft tissues. The adrenal glands weighed 23 g and showed diffuse hyperplasia. Extract of the prostatic tumor was analyzed for ACTH and showed approximately 40 times normal plasma levels (or about 4,010 pg/g of tissue); ultrastructural features showed secretory granules consistent with ACTH content of the tumor cells. Such cells were positive when stained for ACTH by peroxidase-tagged immunochemical methods. The case fulfills all established criteria for relating excess corticosteroid production and nonpituitary tumors.

Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia.

Concentrations of nicotine, cotinine, and nornicotine in brain and blood following both intermittent and continuous administration of [2'-(14)C]nicotine to rats were determined to assess nicotine metabolite accumulation in brain following repeated nicotine administration. For intermittent studies, rats were administered s.c. 1 to 10 doses of nicotine (0.3 mg/kg, 15 or 25 microCi of [2'-(14)C]nicotine; 30-min interinjection interval). For continuous administration studies, rats were implanted s.c. with an osmotic minipump delivering nicotine (0.8 mg/kg/day, 25 or 50 microCi of [2'-(14)C]nicotine for 1-21 days). Whole brain and trunk blood was collected. The concentration of [2'-(14)C]nicotine and its metabolites was determined via high-pressure liquid radiochromatography. Brain concentrations of nicotine, cotinine, and nornicotine increased 2-, 12-, and 9-fold, respectively, following 10 injections, reaching a plateau following the fifth injection. Brain blood ratios indicate an enhanced preferential distribution of nornicotine to brain with increasing numbers of injections. Across the 21-day period of continuous infusion, blood nicotine and nornicotine concentrations remained relatively constant, whereas concentrations in brain increased approximately 4-fold. Generally, cotinine concentrations in brain and blood did not change across the infusion period. Brain/blood ratios indicate an increase in nicotine distribution into brain across days of nicotine infusion. Results demonstrate that both nicotine and its metabolites accumulate in brain following repeated nicotine administration, and indicate that brain nicotine concentration can not be extrapolated from plasma cotinine or nicotine concentrations. Thus, nornicotine accumulation following repeated nicotine administration suggests that this metabolite plays a contributory role in the neuropharmacological effects of nicotine.

Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-14C]nicotine

Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS.

Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Recently, bupropion has been reported to noncompetitively inhibit α3β2, α3β4, and α4β2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native α3β2∗ and α3β4∗ nAChRs using functional neurotransmitter release assays, nicotine-evoked [3H]overflow from superfused rat striatal slices preloaded with [3H]dopamine ([3H]DA), and nicotine-evoked [3H]overflow from hippocampal slices preloaded with [3H]norepinephrine ([3H]NE). The mechanism of inhibition was evaluated using Schild analysis. To eliminate the interaction of bupropion with DAT or NET, nomifensine or desipramine, respectively, was included in the superfusion buffer. A high bupropion concentration (100 μM) elicited intrinsic activity in the [3H]DA release assay. However, none of the concentrations (1 nM–100 μM) examined evoked [3H]NE overflow and, thus, were without intrinsic activity in this assay. Moreover, bupropion inhibited both nicotine-evoked [3H]DA overflow (IC50 = 1.27 μM) and nicotine-evoked [3H]NE overflow (IC50 = 323 nM) at bupropion concentrations well below those eliciting intrinsic activity. Results from Schild analyses suggest that bupropion competitively inhibits nicotine-evoked [3H]DA overflow, whereas evidence for receptor reserve was obtained upon assessment of bupropion inhibition of nicotine-evoked [3H]NE overflow. Thus, bupropion acts as an antagonist at α3β2∗ and α3β4∗ nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function. The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.

Bupropion Inhibits Nicotine-Evoked [3H]Overflow from Rat Striatal Slices Preloaded with [3H]Dopamine and from Rat Hippocampal Slices Preloaded with [3H]Norepinephrine

Dennis K. Miller

Papers

Neuroprotective mechanisms of curcumin against cerebral ischemia‐induced neuronal apoptosis and behavioral deficits

Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia.

Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-14C]nicotine

Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS.

Bupropion Inhibits Nicotine-Evoked [3H]Overflow from Rat Striatal Slices Preloaded with [3H]Dopamine and from Rat Hippocampal Slices Preloaded with [3H]Norepinephrine