Andrew Chi Kin Law

Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type.

Alzheimers disease (AD) is the most common form of dementia, with progressive cognitive deficits being the primary symptom. AD is neuropathologically characterized by amyloid and neurofibrillary tangle depositions, basal forebrain cholinergic deficit, and extensive neuronal loss and synaptic changes in the cortex and hippocampus. Mutations of amyloid precursor protein or presenilin genes or apolipoprotein E gene polymorphism appear to affect amyloid formation, which in turn causes neuronal death via a number of possible mechanisms, including Ca(2+) homeostasis disruption, oxidative stress, excitotoxicity, energy depletion, neuro-inflammation and apoptosis. Nitric oxide (NO) is an enzymatic product of nitric oxide synthase, which exists in three isoforms. In addition to its vasoactive and immunological properties, NO has significant neurophysiological functions. However, NO can also be neurotoxic primarily due to its free radical properties, and it has been implicated in neurodegenerative diseases. Interestingly, there is increasing evidence that NO may have a role in the aforementioned AD pathogenetic mechanisms, and putative links between NO and AD are beginning to be recognized. This review focuses on these issues highlighting the possible relevance of NO in AD, either as a neuroprotective or neurotoxic agent.

The putative neurodegenerative links between depression and Alzheimer's disease

Alzheimers disease (AD) is the leading neurodegenerative cause of dementia in the elderly. Thus far, there is no curative treatment for this devastating condition, thereby creating significant social and medical burdens. AD is characterized by progressive cognitive decline along with various neuropsychiatric symptoms, including depression and psychosis. Depression is a common psychiatric disorder affecting individuals across the life span. Although the monoamine hypothesis of depression has long been proposed, the pathologies and mechanisms for depressive disorders remain only partially understood. Pharmacotherapies targeting the monoaminergic pathways have been the mainstay in treating depression. Additional therapeutic approaches focusing other pathological mechanisms of depression are currently being explored. Interestingly, a number of proposed mechanisms for depression appear to be similar to those implicated in neurodegenerative diseases, including AD. For example, diminishing neurotrophic factors and neuroinflammation observed in depression are found to be associated with the development of AD. This article first provides a concise review of AD and depression, then discusses the putative links between the two neuropsychiatric conditions.

Neuronal and inducible nitric oxide synthase expressions and activities in the hippocampi and cortices of young adult, aged cognitively unimpaired, and impaired Long–Evans rats

Nitric oxide (NO) is a neurosignaling molecule that appears to play a significant role in learning and memory. This molecule has also been implicated in neurotoxicity due to its oxidative properties. Previous experiments from our laboratories have demonstrated elevated hippocampal and cortical neuronal nitric oxide synthase (NOS) mRNA levels in aged cognitively unimpaired and impaired Long-Evans rats, which could represent either increased neuronal NOS activity thereby leading to NO-mediated neurotoxicity, or a compensatory response by aged neurones to maintain physiological nitric oxide output. The current study measured the protein expression and activity levels of neuronal and inducible NOS in young adult (6 months) and aged (24-26 months) Long-Evans rats by means of western blotting and NOS activity assay. Aged animals were assigned as either cognitively unimpaired or aged with moderate cognitive impairments based on their performances in the Morris water maze behavioural task. Our results showed that hippocampal and cortical neuronal NOS expressions were significantly decreased in aged animals. These aged animals also exhibited increased hippocampal and cortical inducible NOS expressions. Between the two aged animal groups, cognitively impaired rats showed significantly lower hippocampal and cortical neuronal but higher hippocampal inducible NOS expressions. Young adult rats exhibited significantly higher hippocampal and cortical NOS activities than the aged animals. Aged animals with cognitive deficits showed significantly lower hippocampal NOS activity than cognitively unimpaired aged rats. Our data indicate that aging is associated with a decline in neuronal but elevated inducible NOS functioning in brain areas involved in learning and memory. These phenomena could contribute to the cognitive deficits observed in a sub-population of aged animals.

Traditional needle acupuncture treatment for insomnia: a systematic review of randomized controlled trials.

OBJECTIVESnPrevious reviews regarding traditional needle acupuncture (TNA) treatment for insomnia were limited to English scientific literature. A comprehensive review including Chinese and English literature has therefore been conducted to examine the efficacy of TNA for insomnia.nnnMETHODSnWe performed systematic review of randomized controlled trials (RCTs) of TNA as intervention for insomnia against placebo, Western medication, and non-treated controls. The methodological quality of the studies was assessed by the modified Jadad score and the acupuncture procedure was appraised by the STRICTA criteria.nnnRESULTSnTwenty RCTs were identified for detailed analysis. Majority of the RCTs concluded that TNA was significantly more effective than benzodiazepines for treating insomnia, with mean effective rates for acupuncture and benzodiazepines being 91% and 75%, respectively. In two more appropriately conducted trials, TNA appeared to be more efficacious in improving sleep than sleep hygiene counseling and sham acupuncture. Standardized and individualized acupuncture had similar effective rates. Despite these positive outcomes, there were methodological shortcomings in the studies reviewed, including imprecise diagnostic procedure, problems with randomization, blinding issues, and insufficient safety data. Hence, the superior efficacy of TNA over other treatments could not be ascertained.nnnCONCLUSIONnSince the majority of evidence regarding TNA for insomnia is based on studies with poor-quality research designs, the data, while somewhat promising, do not allow a clear conclusion on the benefits of TNA for insomnia. Moreover, the results support the need for large scale placebo-controlled double-blinded trials.

Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity

Beta amyloid (Aβ) is implicated in Alzheimers disease (AD). Aβ1–42 (5, 10, or 20u2003μM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. L‐NOARG and SMTC (both at 10 or 100u2003μM) – type I NOS inhibitors – reduced cellular NO release in the absence of Aβ1–42. At 100u2003μM, both drugs decreased cell viability. L‐NIL (10 or 100u2003μM), and 1400W (1 or 5u2003μM) – type II NOS inhibitors – reduced NO release and improved viability when either drug was administered up to 4u2003h post Aβ1–42 (10u2003μM) treatment. L‐NOARG and SMTC (both at 10 or 100u2003μM) were only able to decrease NO release. Carboxy‐PTIO or Trolox (both at 10 or 100u2003μM) – a NO scavenger and an antioxidant, respectively–increased viability when administered up to 1u2003h post Aβ1–42 treatment. Either L‐NIL (50u2003μM) or 1400W (3u2003μM) and Trolox (50u2003μM) showed synergistic actions. Peroxynitrite (100 or 200u2003μM) reduced cell viability. Viabilities were improved by L‐NIL (100u2003μM), 1400W (5u2003μM), carboxy‐PTIO (10 or 100u2003μM), and Trolox (10 or 100u2003μM). Hence, the data show that Aβ1–42 induced NO release in neurons and glial cells, and that Aβ neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.

Alteration of expression levels of neuronal nitric oxide synthase and haem oxygenase-2 messenger RNA in the hippocampi and cortices of young adult and aged cognitively unimpaired and impaired Long-Evans rats

Neuronal nitric oxide synthase and haem oxygenase-2 are postulated to be important enzymes involved in neuronal transmission and modulation of free radical levels in neurons. Hippocampal and cortical neuronal nitric oxide synthase and haem oxygenase-2 expressions were compared in young adult (6 months) and aged (24-26 months) Long-Evans rats. Aged rats were assigned as either cognitively unimpaired or impaired based on their performances in the Morris water maze behavioural task. In situ hybridization revealed increased neuronal nitric oxide synthase messenger RNA levels in selected regions of the hippocampi and cortices of aged rats. Moreover, aged cognitively impaired animals showed significantly higher neuronal nitric oxide synthase messenger RNA expression than aged cognitively unimpaired animals in several brain regions. For haem oxygenase-2 mRNA expressions, both young and aged cognitively impaired rats showed increased expressions in hippocampi compared with aged cognitively unimpaired rats, while no difference was found in cortices between all three animal groups. The increase in neuronal nitric oxide synthase messenger RNA expression levels in the aged animals may be related to increased free radical production occurring in ageing. Alternatively, elevated neuronal nitric oxide synthase and haem oxygenase-2 messenger RNA expressions may represent compensatory responses to oxidative stress and age-related changes in neuronal functions. Regarding cognitive status, aged cognitively impaired rats showed significant spatial memory deficits relative to young and aged cognitively unimpaired rats. Our data suggest a correlation between age-related cognitive impairment and change in messenger RNA expressions for the neuronal nitric oxide synthase and haem oxygenase-2 systems in brain areas implicated in learning and memory processes.

The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells.

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.

Efficacy of Physical Exercise in Preventing Falls in Older Adults With Cognitive Impairment: A Systematic Review and Meta-Analysis

OBJECTIVEnNumerous studies have reported the prevention of falls through exercise among cognitively healthy older people. This study aimed to determine whether the current evidence supports that physical exercise is also efficacious in preventing falls in older adults with cognitive impairment.nnnMETHODSnTwo independent reviewers searched MEDLINE; EMBASE; PsycINFO; the Cumulative Index to Nursing & Allied Health Literature; the Cochrane Central Register of Controlled Trials; the Cochrane Bone, Joint, and Muscle Trauma Group Specialized Register; ClinicalTrials.gov; and the UK Clinical Research Network Study Portfolio up to July 2013 without language restriction. We included randomized controlled trials that examined the efficacy of physical exercise in older adults with cognitive impairment. The methodological qualities of the included trials were appraised according to the criteria developed for the Cochrane review of fall prevention trials. The primary outcome measure was the rate ratio of falls. A meta-analysis was performed to estimate the pooled rate ratio and summarize the results of the trials on fall prevention through physical exercise.nnnRESULTSnSeven randomized controlled trials involving 781 participants were included, 4 of which examined solely older people with cognitive impairment. Subgroup data on persons with cognitive impairment were obtained from the other 3 trials that targeted older populations in general. The meta-analysis showed that physical exercise had a significant effect in preventing falls in older adults with cognitive impairment, with a pooled estimate of rate ratio of 0.68 (95% confidence interval 0.51-0.91).nnnCONCLUSIONSnThe present analysis suggests that physical exercise has a positive effect on preventing falls in older adults with cognitive impairment. Further studies will be required to determine the modality and frequency of exercise that are optimal for the prevention of falls in this population.

Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: Implications for depression and Alzheimer's disease

The relationship between Alzheimers disease (AD) and depression has been well established in terms of epidemiological and clinical observations. Depression has been considered to be both a symptom and risk factor of AD. Several genetic and neurobiological mechanisms have been described to underlie these two disorders. Despite the accumulating knowledge on this topic, the precise neuropathological mechanisms remain to be elucidated. In this study, we propose that synaptic degeneration plays an important role in the disease progression of depression and AD. Using primary culture of hippocampal neurons treated with oligomeric Aβ and corticosterone as model agents for AD and depression, respectively, we found significant changes in the pre-synaptic vesicle proteins synaptophysin and synaptotagmin. We further investigated whether the observed protein changes affected synaptic functions. By using FM(®)4-64 fluorescent probe, we showed that synaptic functions were compromised in treated neurons. Our findings led us to investigate the involvement of protein degradation mechanisms in mediating the observed synaptic protein abnormalities, namely, the ubiquitin-proteasome system and autophagy. We found up-regulation of ubiquitin-mediated protein degradation, and the preferential signaling for the autophagic-lysosomal degradation pathway. Lastly, we investigated the neuroprotective role of different classes of antidepressants. Our findings demonstrated that the antidepressants Imipramine and Escitalopram were able to rescue the observed synaptic protein damage. In conclusion, our study shows that synaptic degeneration is an important common denominator underlying depression and AD, and alleviation of this pathology by antidepressants may be therapeutically beneficial.

A breach in the scaffold: the possible role of cytoskeleton dysfunction in the pathogenesis of major depression.

Depression is one of the most common psychiatric disorders with inadequately understood disease mechanisms. It has long been considered that dendritic regression and decrease in the number of dendritic spines are involved in depression. Dendrites made up of microtubules and actin filaments form synapses with neighboring neurons, which come together as an important communication network. Cytoskeletal proteins undergo post-translational modifications to define their structure and function. In depression and other psychiatric disorders, post-translational modifications may be disrupted that can result in altered cytoskeletal functions. The disruption of microtubule and actin in terms of morphology and functions may be a leading cause of dendritic regression and decrease in dendritic spine in depression.