The Ethical Implications of Cognitive Enhancers

This review will explore the ethical use of cognitive enhancers which alter and improve cognitive function and performance. Cognitive enhancers are not only used in the treatment of certain cognitive disorders, such as schizophrenia and attention deficit hyperactivity disorder (ADHD), but also by individuals to change or enhance certain cognitive abilities. The review will explore and understand the possible ethical implications of the availability of these enhancers to the general population

Effects of Dexamethasone and Brain-Derived Neurotropic Factor in NT2 Cells

Stress is a major risk factor that can evoke neuropathological changes within the cortico-limbic system in neuropsychiatric, neurodegenerative, and metabolic disorders. Many of these disorders implicate the regulation of glucocorticoids (GCs) and neurotrophins, such as the brain-derived neurotropic factor (BDNF). GCs are steroidal hormones that have anti-inflammatory and immunosuppressive effects. They are widely used to treat allergy, inflammation and autoimmune diseases. GCs’ roles and functions in the central nervous system (CNS) is varied and not well understood at this time. BDNF is commonly known to play important roles in the survival, growth-promoting and synaptic plasticity of the CNS. However, it has also been reported that continuous exposure to BDNF results in widespread neuronal death. While several studies have shown functional interactions between BDNF and GCs in neural events, the relationship between these interactions has not been clearly defined. The goal of this study was to determine the effects of dexamethasone (DEX) and BDNF in Ntera-2 (NT2) cells. Our results show a decline in cell viability and proliferation in a time and dose dependent manner when NT2 cells were treated with DEX alone. Treatment with BDNF did not affect NT2 cell viability. Interestingly, when NT2 cells were treated with a combination of DEX and BDNF, there appeared to be greater loss of cell viability and cell proliferation compared to the treatment with DEX alone. This synergistic effect possibly occurred via the co-activation of the BDNF receptor p75 and glucocorticoid receptor common pathways that may be responsible for apoptosis and cellular death. &nbsp

Neuroprotective Role of SRT1720 Against Hydrogen Peroxide Induced Oxidative Stress in NT2 Cells

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by a significant increase in neuronal loss. Oxidative stress (OS) plays a significant role on neuronal damage. Reactive oxygen species (ROS) generated from agents such as hydrogen peroxide (H2O2) leads to cell damage and reduction of cell viability. Sirtuin 1 (SIRT1) is a therapeutic target for neurodegenerative disorders because it regulates several cellular functions and biological processes that promote cellular longevity. This study was undertaken to examine the role of SRT1720 in protecting cells from H2O2 induced stress in Ntera-2 cl.D1(NT2), which has been proven to be a useful in vitro system for the investigation of functions related to human neuronal and glial systems. The results provide evidence that H2O2 significantly induced oxidative stress in a concentration dependent manner. Moreover, pre-treatment with low concentrations of SRT1720 for 48 hours protected against the effects of H2O2. Also, a combination of H2O2 and SRT1720 improved cell viability. Interestingly, apoptotic or necrotic cell death was not detected after H2O2 treatment in the cell culture model system employed

Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Preliminary investigation of the radioiodinated (S,S)-reboxetine analogue, 123I-INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter (NAT) using single photon emission computed tomography (SPECT). More recently, the radioiodinated (R,S)-stereoisomer of 123I-INER, 123I-NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of 123I-NKJ64 in baboons and compares results with 123I-INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols: (1) bolus of 123I-INER or 123I-NKJ64; and (2) bolus plus constant infusion of 123I-NKJ64 with reboxetine (2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of 123I-NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of 123I-INER was consistent with known distribution of NAT in baboon brain. No displacement of 123I-NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for 123I-INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that 123I-NKJ64 may lack affinity and selectivity for NAT in baboon brain and 123I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo. Synapse, 2012. -® 2012 Wiley Periodicals, In

Dysfunction in Fatty Acid Amide Hydrolase Is Associated with Depressive-Like Behavior in Wistar Kyoto Rats

BACKGROUND: While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. METHODOLOGY/PRINCIPAL FINDINGS: The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats. CONCLUSIONS/SIGNIFICANCE: These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD