Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed ...to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies.
Abstract Background A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are ...poorly investigated. Objective To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti-inflammatory effects within human carotid atherosclerosis. Methods Atheroma samples obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII (Sar1 , Ile8 -AII) and angiotensin converting enzyme (ACE)2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C–C motif chemokine (CCL)2, C-X-C motif chemokine (CXCL)5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting. Results Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture. Conclusion Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma.
Stroke is a leading cause of death and disability. It is a complex and largely heterogeneous condition. Prognosis for variations in impairment and recovery following stroke continues to be ...challenging and inaccurate, highlighting the need to examine the influence of other currently unknown variables to better predict and understand interindividual differences in stroke impairment and recovery. The concept of “cognitive reserve,” a feature of brain function said to moderate the relationship between brain pathology and clinical outcomes, might provide a partial explanation. This review discusses the potential significance of cognitive reserve in the context of stroke, with reference to reduced burden of disability poststroke, health promotion, intervention and secondary prevention of cognitive impairment, ease and challenges of translation into clinical practice, prognosis and prediction of recovery, and clinical decisions and trial stratification. Discussions from the review aim to encourage stroke clinicians and researchers to better consider the role of premorbid, lifestyle-related variables, such as cognitive reserve, in facilitating successful neurological outcomes and recovery following stroke.
Varenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a ...standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone.
Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks.
A total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities.
This is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.
The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, ...particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts and therapies, thus determining whether regenerative medicine will be able to live up to this potential that clearly excites clinicians, researchers and patients alike. This review summarises recent developments in regulatory frameworks across different countries that aim to ensure adequate oversight of the development of regenerative medicine products, which are unique in structural and functional complexity when compared to traditional chemical drugs and fully characterised biological drugs. It discusses the implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety.
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The human central nervous system has limited capacity for regeneration. Stem cell‐based therapies may overcome this through cellular mechanisms of neural replacement and/or through molecular ...mechanisms, whereby secreted factors induce change in the host tissue. To investigate these mechanisms, we used a readily accessible human cell population, dental pulp progenitor/stem cells (DPSCs) that can differentiate into functionally active neurons given the appropriate environmental cues. We hypothesized that implanted DPSCs secrete factors that coordinate axon guidance within a receptive host nervous system. An avian embryonic model system was adapted to investigate axon guidance in vivo after transplantation of adult human DPSCs. Chemoattraction of avian trigeminal ganglion axons toward implanted DPSCs was mediated via the chemokine, CXCL12, also known as stromal cell‐derived factor‐1, and its receptor, CXCR4. These findings provide the first direct evidence that DPSCs may induce neuroplasticity within a receptive host nervous system. STEM CELLS 2009;27:2229–2237
Stem cells have demonstrated encouraging potential as reparative therapy for patients suffering from post-stroke disability. Reperfusion interventions in the acute phase of stroke have shown ...significant benefit but are limited by a narrow window of opportunity in which they are beneficial. Thereafter, rehabilitation is the only intervention available. The current review summarises the current evidence for use of stem cell therapies in stroke from early-phase clinical trials. The safety and feasibility of administering different types of stem cell therapies in stroke seem to be reasonably proven. However, the effectiveness needs still to be established through bigger clinical trials with more pragmatic clinical trial designs that address the challenges raised by the heterogeneous nature of stroke per se, as well those due to unique characteristics of stem cells as therapeutic agents.
Stroke is a leading cause of permanent disability world-wide, but aside from rehabilitation, there is currently no clinically-proven pharmaceutical or biological agent to improve neurological ...disability. Cell-based therapies using stem cells, such as dental pulp stem cells, are a promising alternative for treatment of neurological diseases, including stroke. The ischaemic environment in stroke affects multiple cell populations, thus stem cells, which act through cellular and molecular mechanisms, are promising candidates. The most common stem cell population studied in the neurological setting has been mesenchymal stem cells due to their accessibility. However, it is believed that neural stem cells, the resident stem cell of the adult brain, would be most appropriate for brain repair. Using reprogramming strategies, alternative sources of neural stem and progenitor cells have been explored. We postulate that a cell of closer origin to the neural lineage would be a promising candidate for reprogramming and modification towards a neural stem or progenitor cell. One such candidate population is dental pulp stem cells, which reside in the root canal of teeth. This review will focus on the neural potential of dental pulp stem cells and their investigations in the stroke setting to date, and include an overview on the use of different sources of neural stem cells in preclinical studies and clinical trials of stroke.
Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose ...expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.
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